journal of neurochemistry

7212019 Journal of Neurochemistry

httpslidepdfcomreaderfulljournal-of-neurochemistry 115

Indian Institute of Science Education and Research Pashan Pune India

daggerCentre for Biomolecular Interactions Bremen University of Bremen Bremen Germany

DaggerCentre for Environmental Research and Sustainable Technology Bremen Germany

Abstract

Formaldehyde is an environmental pollutant that is alsogenerated in substantial amounts in the human body during

normal metabolism This aldehyde is a well-established

neurotoxin that affects memory learning and behavior In

addition in several pathological conditions including Alzhei-

mer rsquos disease an increase in the expression of formaldehyde-

generating enzymes and elevated levels of formaldehyde in

brain have been reported This article gives an overview on

the current knowledge on the generation and metabolism of

formaldehyde in brain cells as well as on formaldehyde-

induced alterations in metabolic processes Brain cells have

the potential to generate and to dispose formaldehyde In

culture both astrocytes and neurons ef1047297ciently oxidize form-

aldehyde to formate which can be exported or further oxidized

Although moderate concentrations of formaldehyde are not

acutely toxic for brain cells exposure to formaldehydeseverely affects their metabolism as demonstrated by the

formaldehyde-induced acceleration of glycolytic 1047298ux and by

the rapid multidrug resistance protein 1-mediated export of

glutathione from both astrocytes and neurons These formal-

dehyde-induced alterations in the metabolism of brain cells

may contribute to the impaired cognitive performance

observed after formaldehyde exposure and to the neurode-

generation in diseases that are associated with increased

formaldehyde levels in brain

Keywords formaldehyde glutathione glycolysis metabolism

neurodegeneration neurotoxicity

J Neurochem (2013) 127 7ndash 21

Formaldehyde chemistry

Formaldehyde (HCHO) is the simplest aldehyde that is also

known as methanal This compound was 1047297rst described in

1855 by Alexander Butlerov while its chemical synthesis by

methanol dehydration was 1047297rst achieved in 1867 by August

Wilhelm von Hofmann (Salthammer et al 2010) In the

following decades the properties of formaldehyde were

extensively studied and this compound was one of the

earliest to obtain a CAS registry number (50-00-0) Form-

aldehyde is highly reactive It can undergo hydration and

forms hemiacetals with alcohols or thiohemiacetals with

thiols Formaldehyde also reacts with amines to form Schiff

bases and cross-links proteins by forming methylene bridges

between amino groups (Metz et al 2004 2006) This high

reactivity of formaldehyde is the reason for its extensive use

in industries (Tang et al 2009)

Due to its protein cross-linking ability formaldehyde is

frequently used for tissue preservation and 1047297xation (Nazar-

ian et al 2009) Formalin solution that is used in pathology

contains 35 formaldehyde while for 1047297xation of tissues

tissue sections or cultured cells a 4 formaldehyde

solution is frequently used (Kiernan 2000) Such a 4

formaldehyde solution contains the aldehyde in a concen-

tration of above 1 M Thus the concentrations of formal-

dehyde that are used for technical processes are several

orders of magnitude higher than the concentrations of

Received May 30 2013 revised manuscript received June 12 2013

accepted June 21 2013

Address correspondence and reprint requests to Dr Ralf Dringen

Centre for Biomolecular Interactions Bremen University of Bremen

PO Box 330440 D-28334 Bremen Germany

E-mail ralfdringenuni-bremende

Abbreviations used AD Alzheimer rsquos disease ADH alcohol dehy-

drogenase ALDH aldehyde dehydrogenase GSH glutathione GSSG

glutathione disul1047297de JHDM JmjC domain-containing histone demeth-

ylases LSD lysine-speci1047297c demethylase MCT monocarboxylate

transporter Mrp multidrug resistance protein MS multiple sclerosis

MTHFD methylene tetrahydrofolate dehydrogenase SSAO semicar-

bazide-sensitive amine oxidases THF tetrahydrofolate VAP vascular

adhesion protein

copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21 7

JOURNAL OF NEUROCHEMISTRY | 2013 | 127 | 7ndash21 doi 101111jnc12356



formaldehyde (01 ndash 04 mM) that are found in body 1047298uids

and tissues under normal and pathological conditions (Heck

and Casanova 2004 Tong et al 2013a)

Endogenous and exogenous sources of formaldehyde

Formaldehyde exposure is caused by the generation of this

aldehyde within the body and can also be a consequence of

contact with elevated levels of environmental formaldehyde

(Fig 1) Some of the endogenous enzymatic reactions that

generate formaldehyde as well as exogenous sources of

formaldehyde are described below

Formaldehyde is the oxidation product of methanol This

alcohol can be generated within the body by hydrolysis of

protein carboxymethyl esters either non-enzymatically or

catalyzed by methylesterases (Lee et al 2008) In addition

accidental or intentional intake of methanol will further

expose the body to this alcohol In cells methanol is oxidized

to formaldehyde by alcohol dehydrogenase (ADH) 1 by

catalase or by a non-enzymatic reaction of methanol with

hydroxyl radicals (Harris et al 2003 MacAllister et al

2011) In humans and primates ADH1 appears to be

predominately responsible for methanol oxidation while

the majority of methanol oxidation in rats has been reported

to be mediated by catalase (Tephly 1991 Skrzydlewska

2003)

Another endogenous source of formaldehyde are semicar-

bazide-sensitive amine oxidases (SSAO) which represent agroup of copper-containing amine oxidases that are inhibited

by semicarbazide and most of them contain topa-quinone at

their catalytic centre (Jalkanen and Salmi 2001 Yu et al

2003) Oxidative deamination of methylamine by SSAO

generates formaldehyde together with ammonia and hydro-

gen peroxide (Yu et al 2003 OrsquoSullivan et al 2004) In

mammals SSAO are either membrane-associated or circulate

in a soluble form in the vascular system (Jalkanen and Salmi

2001) Among the SSAO the vascular adhesion protein

(VAP) 1 is one of the most extensively studied members of

this group of enzymes (Smith and Vainio 2007 Jalkanen and

Salmi 2008)

Formaldehyde is also generated as by-product of reactions

catalyzed by lysine-speci1047297c demethylase (LSD) 1 and JmjC

domain-containing histone demethylases (JHDM) (Cloos

et al 2008 Hou and Yu 2010) These enzymes remove

methyl groups from lysine residues in histones thereby

altering the chromatin structure (Cheng and Zhang 2007

Cloos et al 2008 Hou and Yu 2010 Izzo and Schneider

2010) LSD1 is a 1047298avin-containing enzyme that selectively

demethylates the mono- or dimethylated lysine residue in

position 4 of histone H3 (Forneris et al 2009 Hou and Yu

2010) On the other hand JHDM can remove methyl groups

from mono- di- or trimethylated lysine residues and require

Fe2+

and a-ketoglutarate as cofactors (Cloos et al 2008 Houand Yu 2010)

In addition to endogenous sources the body can also

encounter environmental formaldehyde since a number of

commonly used products contain either formaldehyde or

formaldehyde-releasing substances (Sasseville 2004

de Groot et al 2009) Some examples of such products are

construction materials agricultural fertilizers fumigants

paints cosmetics antiperspirants polish cleaning agents

and toiletries (Sasseville 2004 de Groot et al 2009 2010)

In addition formaldehyde can be produced and released from

burning of wood coal tobacco natural gas and kerosene

(de Groot et al 2009 Laitinen et al 2010) Moreover foods

like coffee cod1047297sh meat poultry and maple syrup naturally

contain formaldehyde (Dhareshwar and Stella 2008 de

Groot et al 2009) Thus this ubiquitously present compound

can enter the human body by inhalation ingestion or entry

through the skin

One pertinent question is whether exogenous formalde-

hyde can pose a big threat to the central nervous system by

entering the blood and ultimately reaching the brain after

crossing the blood ndash brain barrier In healthy individuals the

formaldehyde concentration in the blood is around 01 mM

(Heck and Casanova 2004) and that in the brain is

02 ndash 04 mM (Tong et al 2013a) Inhalation of moderate

Fig 1 Endogenous and exogenous sources of formaldehyde (HCHO)

and pathways involved in cellular formaldehyde disposal For details

see text ADH alcohol dehydrogenase ALDH aldehyde dehydroge-

nase cy cytosolic JHDM JmjC domain-containing histone demeth-

ylases LSD lysine-speci1047297c demethylase mt mitochondrial MTHFD

methylene tetrahydrofolate dehydrogenase SSAO semicarbazide-

sensitive amine oxidases VAP vascular adhesion protein

copy 2013 International Society for Neurochemistry J Neurochem (2013) 127 7--21

8 K Tulpule and R Dringen



doses of formaldehyde does not severely increase the

formaldehyde level in blood (Heck et al 1985 Franks

2005) This is expected as the formaldehyde-oxidizing

enzymes ADH3 and aldehyde dehydrogenase (ALDH) 2

(Fig 1) are ubiquitously expressed in all tissues (Nishimuraand Naito 2006 Alnouti and Klaassen 2008) and will

quickly clear a low excess of environmentally derived

formaldehyde However exposure to high concentrations of

exogenous formaldehyde that exceeds the peripheral form-

aldehyde oxidation capacity will elevate the normal tolerable

concentration of formaldehyde in the blood and could lead

to neural damage Indeed exposure to exogenous formal-

dehyde has been reported to cause neurotoxicity in humans

and animals and the extent of damage depends on the dose

of formaldehyde and the duration of the exposure (Kilburn

et al 1985a b Songur et al 2008 2010) Especially

individuals who carry functional polymorphisms in the

genes encoding for formaldehyde-metabolizing enzymes

ADH3 or ALDH2 which are discussed to be associated with

reduced formaldehyde-oxidizing capacity (Hedberg et al

2001 Wang et al 2002) may be more vulnerable to

neural damage by endogenously generated or environmental

formaldehyde

Metabolism of formaldehyde

Despite of the multiple endogenous and exogenous sources

of formaldehyde a low physiological level of formaldehyde

in body 1047298uids and tissue is maintained by the continuous

action of cellular formaldehyde-metabolizing enzymes(Fig 1) ADH1 is considered to play a negligible role in

formaldehyde reduction to methanol because of its very high

KM-value for formaldehyde (about 30 mM) (Skrzydlewska

2003) The formaldehyde oxidation product formate is

generated by two independent pathways that are mediated

by either the mitochondrial ALDH2 or the cytosolic ADH3

(Teng et al 2001 Friedenson 2011 MacAllister et al

2011) ADH3 also known as glutathione (GSH)-dependent

formaldehyde dehydrogenase oxidizes formaldehyde to

formate in a two-step process (Harris et al 2003 Staab

et al 2009 Thompson et al 2010 MacAllister et al 2011)

In the 1047297rst step GSH reacts with formaldehyde in an

enzyme-independent manner to form S-hydroxymethyl GSH

that is subsequently used as ADH3 substrate to generate S-

formyl GSH (Harris et al 2003 Staab et al 2009 Thomp-

son et al 2010 MacAllister et al 2011) The conjugate S-

formyl GSH is hydrolyzed by a thiolase to generate formate

and GSH (Teng et al 2001 Harris et al 2003 MacAllister

et al 2011) Unlike ADH3 the reaction catalyzed by

ALDH2 is a single-step GSH-independent process (Teng

et al 2001 MacAllister et al 2011) Since ADH3 has a

very low KM-value for S-hydroxymethyl GSH (less than

10 lM) compared to that of ALDH2 for formaldehyde (02 ndash

05 mM) (Casanova-Schmitz et al 1984 Heck et al 1990)

ADH3 is likely to be especially important for the oxidation

of low concentrations of formaldehyde

The formate generated by formaldehyde oxidation can

undergo further oxidization to carbon dioxide in a metabolic

pathway involving tetrahydrofolate (THF) wherein formateis 1047297rst converted to 10-formyl THF (Fig 1) in an ATP-

dependent reaction (Skrzydlewska 2003 Krupenko 2009

Krupenko et al 2010) This reaction is catalyzed either by

the cytosolic methylene tetrahydrofolate dehydrogenase

(MTHFD) 1 or by its mitochondrial isoform MTHFD1L

(Tibbetts and Appling 2010) 10-formyl THF is subsequently

oxidized by the cytosolic 10-formyl THF dehydrogenase

also known as ALDH1L1 or its mitochondrial isoform

ALDH1L2 to carbon dioxide Both enzymes use NADP+ as a

co-factor and regenerate THF (Skrzydlewska 2003 Kru-

penko 2009 Krupenko et al 2010) Although formate

oxidation takes place predominantly by the THF-dependent

pathway catalase-mediated oxidation of formate has also

been reported (Cook et al 2001 Skrzydlewska 2003)

Formaldehyde metabolism (Fig 1) is best studied for the

liver (Skrzydlewska 2003 Tibbetts and Appling 2010) but it

is very likely that other organs including the brain will also

use the enzymatic pathways that are well known for

formaldehyde metabolism in liver In brain at least all the

enzymes required for complete formaldehyde oxidation are

expressed (Table 1)

Differences in the rate of formaldehyde metabolism have

been described between species for the formaldehyde

metabolism For example formate is metabolized at a slower

rate in the liver of monkeys and humans compared to ratspartly because rats have a higher hepatic THF content

(Tephly 1991 Skrzydlewska 2003) Also species-speci1047297c

differences in the kinetic parameters of the enzymes involved

in formaldehyde metabolism may contribute to the different

rates of formaldehyde oxidation observed and subsequently

may determine the consequences of an exposure to formal-

dehyde andor it metabolites

Generation and oxidation of formaldehydein brain cells

Several reports have demonstrated that the enzymes required

to produce or metabolize formaldehyde are expressed in the

brain on the mRNA or protein level (Table 1) Of these

enzymes only the expression of ADH1 in the brain has been

controversially discussed since this dehydrogenase was not

detected in brain by some investigators (Julia et al 1987

Galter et al 2003) Despite the presence of ADH1 mRNA in

cultured neural cells methanol generation was not found for

formaldehyde-exposed cultured brain cells (Tulpule and

Dringen 2012 Tulpule et al 2013) suggesting that oxida-

tion to formate is the preferred pathway of formaldehyde

metabolism in brain cells Cultured astrocytes and neurons

contain the mRNAs for SSAO and LSD1 as well as for the


Formaldehyde in brain 9



enzymes involved in formaldehyde metabolism (Tulpule and

Dringen 2012 Tulpule et al 2013) These studies indicate

that formaldehyde may be produced locally in the brain and

that among the different types of brain cells at least astrocytes

and neurons have the potential to generate and oxidize

formaldehyde

Acute formaldehyde exposure in concentrations of up to

1 mM for up to 3 h does not cause severe toxicity in cultured

astrocytes or neurons (Song et al 2010 Tulpule and Dringen2011 2012 Tulpule et al 2013) A rapid metabolism of

cellular formaldehyde may contribute to the resistance of

cultured brain cells to formaldehyde toxicity since formal-

dehyde has been reported to be more cytotoxic than its

metabolites methanol and formate (Oyama et al 2002 Lee

et al 2008) Both cultured astrocytes and neurons clear

exogenously applied formaldehyde with a similar rate of

around 02 lmol(h 9 mg) (Tulpule and Dringen 2012

Tulpule et al 2013) which is about 20 of the formaldehyde

oxidation rate reported for liver cells (Dicker and Cederbaum

1984) The K M-value for formaldehyde clearance by cultured

astrocytes is around 019 mM suggesting that both the

cytosolic ADH3 and mitochondrial ALDH2 could contribute

to formaldehyde oxidation (Tulpule and Dringen 2012)

Although cultured astrocytes and neurons have compara-

ble rates of formaldehyde clearance the metabolic fate of the

disposed formaldehyde differs between these two types of

neural cells Although astrocytes convert the majority

(gt 90) of formaldehyde to formate that is subsequently

exported from the cells (Tulpule and Dringen 2012) only

about 25 of the formaldehyde cleared by cultured neurons

is detected as extracellular formate (Tulpule et al 2013) The

underlying reason for this difference might be a poor export

of formate from cultured neurons andor a higher capacity of

these cells to further oxidize formate to carbon dioxide

(Fig 1) Although the putative formate exporters GABA-

gated channels (Mason et al 1990) and monocarboxylate

transporter (MCT) 1 (Moschen et al 2012) are expressed in

both astrocytes and neurons (Debernardi et al 2003 Olsen

and Sieghart 2009 Lee et al 2011 Velez-Fort et al 2011)

the expression level of MCT1 in neurons has been reported

to be very low (Debernardi et al 2003) However if poor

export of formate would be the only reason behind the lower extracellular accumulation of this metabolite in cultured

neurons these cells should accumulate large amounts of

formaldehyde-derived formate which is not the case (Tulp-

ule et al 2013) Thus the lower extracellular accumulation

of formaldehyde-derived formate in cultured neurons com-

pared to cultured astrocytes is likely to be predominantly

caused by oxidation of formaldehyde-derived cellular

formate to carbon dioxide The enzymes involved in the

oxidation of 10-formyl THF require NADP+ as electron

acceptor (Krupenko 2009 Krupenko et al 2010) and the

availability of NADP+ in cytosol and mitochondria depends

on the pathways involved in NADPH consumption and

NADPH regeneration As such pathways differ between

astrocytes and neurons (Dringen et al 2007) the NADP+

availability could also contribute to the differences observed

in formate release from astrocytes and neurons that were

exposed to formaldehyde (Tulpule and Dringen 2012

Tulpule et al 2013)

Alterations of the metabolism of braincells upon exposure to formaldehyde

A large number of adverse consequences have been reported

for an exposure of brain cells to formaldehyde in vivo and

Table 1 Formaldehyde-producing and formaldehyde-metabolizing enzymes in the brain

Enzymes

Species

Rat Mouse Human

Formaldehyde generation

ADH1 Martinez et al (2001)

Catalase Zimatkin and Lindros (1996) Schad et al (2003) Meinerz et al (2013) van Horssen et al (2008)

SSAOVAP1 Obata and Yamanaka (2000) Ferrer et al (2002) Unzeta et al (2007)

Valente et al (2012)

LSD1 Zibetti et al (2010) Zhang et al (2010) Zibetti et al (2010)

JHDM Wolf et al (2007) Fukuda et al (2011) Wolf et al (2007)

Formaldehyde oxidation

ADH3 Julia et al (1987) Iborra et al (1992)

Galter et al (2003)

Galter et al (2003) Galter et al (2003)

ALDH2 Guo et al (2013) Alnouti and Klaassen (2008) Stewart et al (1996)

Formate oxidation

MTHFD1 Thigpen et al (1990) MacFarlane et al (2009) Fountoulakis et al (2003)

MTHFD1L Prasannan et al (2003)

ALDH1L1 Neymeyer et al (1997) Anthony and Heintz (2007) Cahoy et al (2008) Oldham et al (2008)

ALDH1L2 Krupenko et al (2010)





in vitro (Table 2) Recently it was demonstrated that

formaldehyde in the concentration range between 01 mM

and 1 mM strongly affects basal metabolic properties of

cultured astrocytes and neurons that is formaldehyde

stimulates glycolytic 1047298ux and the export of the antioxidative

tripeptide GSH from brain cells

Formaldehyde-stimulated glycolysisAstrocytes are more glycolytic than neurons (Bola~nos et al

2010) a feature which has been attributed to expression of

the glycolysis-promoting enzyme PFKFB3 in astrocytes

(Herrero-Mendez et al 2009) an inhibited pyruvate dehy-

drogenase complex (Halim et al 2010) and a low rate of

NADH shuttling into mitochondria in astrocytes (Berkich

et al 2007 Neves et al 2012) Despite the differences in

basal rates of glucose consumption and lactate release in

cultured astrocytes and neurons application of formaldehyde

signi1047297cantly increases these rates in both types of brain cells

(Tulpule and Dringen 2012 Tulpule et al 2013) However

the extent of stimulation of glycolytic 1047298ux in formaldehyde-

exposed cells compared to the basal condition differs

between the culture types investigated For example at a

formaldehyde concentration of 05 mM the lactate release

and glucose consumption rates were doubled in cultured

neurons (Tulpule et al 2013) while this concentration of

formaldehyde did not affect glycolysis in cultured astrocytes

(Tulpule and Dringen 2012) Astrocytes had to be exposed to

1 mM formaldehyde to elevate glycolysis by 50 (Tulpule

and Dringen 2012)

The accelerated glycolysis in formaldehyde-exposed neu-

ral cells is likely to be caused by the formaldehyde-derived

formate which is known to inhibit mitochondrial cytochrome

c oxidase (Nicholls 1975 Wallace et al 1997) This view is

supported by the observation that incubation of astrocytes

with formaldehyde for 90 min is required for the accelerated

lactate release to persist even after removal of formaldehyde

(Tulpule and Dringen 2012) This long delay most likely

re1047298ects the slow mitochondrial accumulation of formalde-

hyde-derived formate to concentrations that are suf 1047297cient to

inactivate respiration as most of the formate is ef 1047297cientlyexported from astrocytes Moreover the persistent lactate

release of astrocytes exposed to formaldehyde was not

further enhanced by application of azide an inhibitor of

mitochondrial cytochrome c oxidase (Tulpule and Dringen

2012) Thus formaldehyde-derived formate is likely to

stimulate glycolytic 1047298ux as a consequence of an inhibited

respiration as also other inhibitors of respiratory chain

complexes stimulate glycolytic lactate production in cultured

astrocytes and neurons (Pauwels et al 1985 Scheiber and

Dringen 2011)

Formaldehyde-accelerated glutathione export

GSH is an important antioxidant (Lushchak 2012 Schmidt

and Dringen 2012 Lu 2013) that is also involved in the

formaldehyde oxidation catalyzed by ADH3 (Fig 1) Under

basal conditions cultured astrocytes and neurons as well as

cells of the oligodendroglial cell line OLN-93 export GSH

although with variable rates (Tulpule and Dringen 2011

Tulpule et al 2012 2013) Formaldehyde treatment stimu-

lated GSH export from all three types of cultured neural cells

without severely altering the ratio of GSH to glutathione

disul1047297de (GSSG) (Tulpule and Dringen 2011 Tulpule et al

2012 2013) This accelerated GSH export from formalde-

hyde-treated neural cells is mediated by multidrug resistance

Table 2 Consequences of a formaldehyde exposure of rodent brain cells in vivo and in vitro

References

In vivo

Decrease in the number of neuron Gurel et al (2005) Aslan et al (2006) Sarsilmaz et al (2007)Decreased level of GSH Lu et al (2008)

Lowered levels of superoxide dismutase and catalase Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)

Songur et al (2008)

Increase in levels of nitric oxide malondialdehyde

and protein carbonyls

Gurel et al (2005) Zararsiz et al (2006 2007 2011) Lu et al (2008)

Songur et al (2008)

Increase in apoptotic events Zararsiz et al (2006 2007)

De1047297cit in memory and learning Pitten et al (2000) Usanmaz et al (2002) Malek et al (2003)

Sorg et al (2004) Lu et al (2008) Turkoglu et al (2008)

Tong et al (2011 2013a b)

In vitro

Elevated glycolysis in neurons and astrocytes Tulpule and Dringen (2012) Tulpule et al (2013)

Mrp1-stimulated GSH export from neurons and astrocytes Tulpule and Dringen (2011) Tulpule et al (2013)

Decreased gl utamate uptake in cultured astrocytes Song et al (2010)

Lower expression of neuronal NMDA receptor subunits Tong et al (2013a)

The articles by Lu et al (2008) Usanmaz et al (2002) and Tong et al (2011) describe data that have been obtained on mice whereas all other

studies were performed on rats or rat brain cells





protein (Mrp) 1 (Tulpule and Dringen 2011 Tulpule et al

2012 2013) Mrp1 is a member of ATP-binding cassette

transporters and transports besides GSH a wide array of

substrates including GSSG and GSH conjugates (Keppler

2011 Yin and Zhang 2011) The potential of formaldehydeto accelerate GSH export differs between different brain cell

culture types For example exposure to 05 mM formalde-

hyde increased the respective GSH export rates of cultured

astrocytes neurons and OLN-93 cells by 10- 5- and 20-fold

respectively (Tulpule and Dringen 2011 Tulpule et al 2012

2013) However half-maximal cellular GSH depletions were

observed at similar incubation parameters for all types of

neural cells after incubation for 1 h with 03 mM formalde-

hyde (Tulpule and Dringen 2011 Tulpule et al 2012 2013)

Formaldehyde exposure does not impair the capacity of

neural cells to synthesize GSH At least formaldehyde-treated

neurons restored their cellular GSH levels after application of

amino acid precursors for GSH synthesis (Tulpule et al

2013)

The molecular mechanism involved in the formaldehyde-

accelerated Mrp1-mediated GSH export from neural cells is

not resolved so far Since the stimulation of GSH export is

observed within minutes after formaldehyde application

(Tulpule and Dringen 2011 Tulpule et al 2012 2013)

de novo synthesis of Mrp1 is unlikely to explain the

stimulated GSH ef 1047298ux Furthermore the 1047297nding that removal

of formaldehyde instantly decelerates the stimulated GSH

export (Tulpule and Dringen 2011 Tulpule et al 2012

2013) indicates that the mechanism responsible for formal-

dehyde-accelerated GSH export is quickly reversibleAssuming that cellular GSH is the transported Mrp1

substrate (Fig 2a) formaldehyde could stimulate GSH

export by a reversible covalent activation of this transporter

Alternatively a formaldehyde-induced recruitment of intra-

cellular Mrp1 molecules into the cell membrane could

explain the accelerated GSH export Such a reversible

translocation of Mrp1 from the Golgi to the cell surface

has been reported for cultured astrocytes treated with

bilirubin (Gennuso et al 2004)

Mrp1 ef 1047297ciently exports GSH conjugates (Keppler 2011

Yin and Zhang 2011) As the formaldehyde metabolism in

neural cells involves the generation of the GSH conjugatesS-hydroxymethyl GSH and S-formyl GSH (Fig 1) these

conjugates could also serve as substrates of Mrp1 (Fig 2b)

Since both conjugates are known to be labile (Ahmed and

Ahmed 1978 Uotila 1981) they are likely to disintegrate

into GSH and formaldehyde or formate immediately after

being exported

Direct experimental evidence that discriminates between

the potential two mechanisms (Fig 2) that may be involved

in the formaldehyde-induced accelerated GSH export via

Mrp1 is missing so far However determination of the

kinetic parameters for the GSH export from astrocytes

revealed that the K M-values of the basal as well as the

formaldehyde-accelerated GSH export from astrocytes are

identical (about 100 nmolmg or 25 mM) but that the

V max-value for the stimulated GSH export is eightfold higher

than that for the basal GSH export (Tulpule et al 2012)

These data suggest that at least for formaldehyde-treated

astrocytes GSH rather than a GSH conjugate is exported via

Mrp1 since the K M-values of Mrp1 for its substrate GSH are

normally higher than 5 mM while that for GSH conjugates

are below 1 mM (Burg et al 2002 Cole and Deeley 2006

Deeley and Cole 2006)

Application of formaldehyde does not deprive the cells

completely of their GSH and about 5 residual GSH still

remains within neural cells (Tulpule and Dringen 2011Tulpule et al 2012 2013) In cultured astrocytes this low

cellular GSH content represents a residual GSH concentra-

tion of about 04 mM (Dringen and Hamprecht 1998) which

will be suf 1047297cient to drive ADH3-catalyzed GSH-dependent

formaldehyde oxidation since the K M-value of ADH3 for

S-hydroxymethyl GSH is less than 10 lM (Casanova-

Schmitz et al 1984 Heck et al 1990) and this reaction

(a) (b)

Fig 2 Potential mechanisms involved in

formaldehyde-stimulated glutathione (GSH)

export from brain cells (a) Formaldehyde

directlystimulatesMrp1-mediatedGSH export

(b) The GSH conjugates S-hydroxymethyl

GSH andor S-formyl GSH which are

intermediates of cellular formaldehyde

metabolism are exported by Mrp1 The

labile conjugates immediately disintegrate

after export to generate GSH





involves recycling of GSH (Fig 1) Thus the stimulated

GSH export is unlikely to compromise GSH-dependent

formaldehyde oxidation

Evidence for the role of formaldehyde in pathology

In healthy individuals the formaldehyde concentration in the

blood has been reported to be around 01 mM (Heck and

Casanova 2004) while that in the brain is about 02 mM

(hippocampus) and 04 mM (cortex) (Tong et al 2013a)

These levels of formaldehyde represent the normal phy-

siological balance between formaldehyde-generating and

formaldehyde-disposing processes However an increased

activity of formaldehyde-generating enzymes or an acute

exposure to high amounts of exogenous formaldehyde

without a concurrent elevation in the capacity to clear

formaldehyde will raise formaldehyde level in the body and

will lead to formaldehyde stress (He et al 2010) Indeed an

increased expressionactivity of the formaldehyde-generating

enzymes VAP1SSAO LSD1 and JHDM has been reported

for various diseases (Table 3) While a broad spectrum of

pathological conditions are associated with elevated levels of

VAP1SSAO an increase in the expression of the histone

demethylases has especially been observed in different types

of cancer (Table 3) The elevated expression of formalde-

hyde-generating enzymes is accompanied by increased

formaldehyde levels in diabetic rats (Tong et al 2013a) in

cancer tissue (Tong et al 2010) and in some human cancer

cell lines (Kato et al 2001 Tong et al 2010)

Increased expression of formaldehyde-generating enzymes

(Table 3) as well as elevated formaldehyde levels have also

been reported in brains of patients suffering from neurode-

generative diseases like Alzheimer rsquos disease (AD) or multi-

ple sclerosis (MS) (Khokhlov et al 1989 cited in Miao andHe 2012 Tong et al 2011 2013a) Some hypotheses have

been postulated that link the increase in formaldehyde level

to neuropathology For example some human subjects who

suffered from methanol poisoning developed symptoms of

MS which has been discussed to be an effect of methanol

oxidation to formaldehyde and the subsequent modi1047297cation

of proteins resulting in an immune reaction (Schwyzer and

Henzi 1983 Henzi 1984) Along that line it was discussed

that formaldehyde methylates proteins like tau (in AD) or

myelin basic protein (in MS) which in turn elicits an immune

response by the body that is characteristic for these diseases

(Monte 2010 Lu et al 2013) Also inhibition of SSAO in a

murine model of MS has been shown to reduce the incidence

and severity of this disease (Wang et al 2006) which could

at least partly be the consequence of a lowered formaldehyde

generation Moreover formaldehyde exposure has been

implicated to be a risk factor for the development of

amyotrophic lateral sclerosis (Weisskopf et al 2009) a

disease that is characterized by degeneration of motor

neurons (Kiernan et al 2011)

Formaldehyde-induced alterations in neuralmetabolism as potential contributors toneurodegeneration

Figure 3 summarizes the current knowledge on formalde-

hyde metabolism and on formaldehyde-induced alterations in

the glucose and GSH metabolism of neural cells The

potential of cultured brain cells to ef 1047297ciently metabolize

formaldehyde suggests that also the cells in brain deal quite

well with the moderate amounts of formaldehyde that are

generated under physiological conditions Similar to liver

cells brain cells are likely to use both cytosolic and

mitochondrial pathways for formaldehyde oxidation to

formate and further to carbon dioxide (Figs 1 and 3)

Cultured brain cells ef 1047297ciently produce and export glyco-

lytically generated lactate and also release GSH into the

medium although the basal rates of glycolysis and GSH

export differ between different types of neural cells (Tulpule

and Dringen 2011 2012 Tulpule et al 2012 2013) These

pathways are not affected by low concentrations of formal-

dehyde but as soon as formaldehyde levels are increased in

pathological conditions an accelerated generation of formate

is likely to stimulate glycolytic 1047298ux by inhibition of the

mitochondrial respiration (Fig 3) In addition an excess of

formaldehyde deprives brain cells of GSH by stimulating

Mrp1-mediated GSH export (Fig 3) Although caution should

be exercised while extrapolating in vitro data to the situation

in the brain a speculation on potential consequences of

Table 3 Elevation in expression or activity of formaldehyde-generat-

ing enzymes in human diseases

Enzyme Disease References

SSAOVAP1 Alzheimer rsquos disease Ferrer et al (2002) del Mar

Hernandez et al (2005)

Unzeta et al (2007)

Multiple sclerosis Airas et al (2006)

Heart disease Boomsma et al (2000 2005)

Diabetes mellitus

and diabetic

complications

Meszaros et al (1999)

Gr euroonvall-Nordquist

et al (2001) Karadi et al(2002) Boomsma et al

(2005) Obata (2006)

Chronic liver disease Kurkijarvi et al (2000)

LSD1JHDM Sarcoma Schildhaus et al (2011)

Bennani-Baiti et al (2012)

Peripheral nerve

sheath tumor

Schildhaus et al (2011)

Neuroblastoma Schulte et al (2009)

Bladder cancer Hayami et al (2010 2011)

Breast cancer Lim et al (2010)

Prost ate cancer Kahl et al (2006) Xiang

et al (2007)





elevated formaldehyde levels in brain on the cellular metab-

olism is tempting especially since the formaldehyde concen-trations that have been shown to alter metabolic properties of

cultured brain cells (01 ndash 1 mM) are in the concentration

range reported for the normal brain (02 ndash 04 mM) Thus mild

elevations in brain formaldehyde concentrations could already

strongly affect energy and GSH metabolism of this organ

The potential pathological implications of metabolic

changes exerted by excess of formaldehyde in the brain are

shown in Fig 4 Astrocytes and neurons in brain are likely to

ef 1047297ciently metabolize an excess of formaldehyde as also

reported for brain homogenates (Iborra et al 1992) Subse-

quently the formate generated from formaldehyde is either

released from brain cells or inactivates mitochondrial cyto-

chrome c oxidase An inhibition of the mitochondrialrespiratory chain will stimulate glycolytic 1047298ux in the brain

cells to at least transiently meet their energy demand

However prolonged exposure to formaldehyde is likely to

result in energy crisis that in turn will disrupt the functions of

brain cells This may also be the underlying mechanism of

the neurotoxicity of formate in hippocampal brain slices

(Kapur et al 2007) Besides this impairment of energy

metabolism formaldehyde-induced accumulation of both

formate and lactate in the brain would cause cerebral acidosis

(Skrzydlewska 2003 Rose 2010) which would subsequently

induce astrocytic swelling impairment of neuronal signal

Fig 3 Metabolic consequences of a formaldehyde exposure in

cultured brain cells Exogenous formaldehyde is entering brain cells

most likely by diffusion through the cell membrane and is oxidized

within the cell to formate either in a glutathione (GSH)-dependent

reaction that is mediated by cytosolic alcohol dehydrogenase (ADH) 3

or by the mitochondrial aldehyde dehydrogenase (ALDH) 2 Part of the

generated formate is exported while a fraction is further oxidized to

carbon dioxide Remaining cellular formate is likely to inhibit mito-

chondrial cytochrome c oxidase which leads to accelerated glycolytic

1047298ux Formaldehyde also induces a rapid Mrp1-mediated GSH export

from brain cells Small black squares indicate transporters that are

required for membrane transport of the indicated metabolites

Fig 4 Potential consequences of an

excess of formaldehyde in brain Presence

of excess of formaldehyde or formaldehyde-

derived metabolites will acutely modulate

metabolic pathways of brain cells (light gray

squares) which are likely to cause delayed

indirect consequences (dark gray squares)

that 1047297nally lead to the adverse effects

reported for formaldehyde exposure





transmission and neurological de1047297cits (Staub et al 1993 Li

et al 2011 Zhao et al 2011)

Exposure to high levels of formaldehyde will cause GSH

depletion in brain cells together with GSH accumulation in

the extracellular space As GSH is involved in important cellular functions in the brain like protection against reactive

oxygen species and detoxi1047297cation of xenobiotics (Lushchak

2012 Schmidt and Dringen 2012 Lu 2013) GSH depletion

may contribute to the severe oxidative stress reported for

brain after prolonged exposure to formaldehyde (Zararsiz

et al 2006 2007 2011 Songur et al 2008) A loss in

cellular GSH would under normal conditions be compen-

sated by increased GSH synthesis However lactacidosis

caused by the formaldehyde-induced production of lactate

(Skrzydlewska 2003 Rose 2010) impairs GSH synthesis

(Lewerenz et al 2010) and cellular GSH levels are likely to

remain low Thus chronic exposure to formaldehyde may

render brain cells incapable of fully restoring their cellular

GSH levels

The formaldehyde-induced accumulation of extracellular

GSH in brain can also be detrimental since GSH has been

suggested to act as a neurotransmitter and neuromodulator at

glutamate receptors (Janaky et al 2007) which play impor-

tant roles in memory and learning (Davis et al 2013

Mukherjee and Manahan-Vaughan 2013) Also accelerated

extracellular GSH hydrolysis by the astrocytic ectoenzyme

c-GT (Dringen et al 1997) caused by the increased extra-

cellular GSH concentration would generate the neurotrans-

mitter glutamate (Fernandez-Fernandez et al 2012 Schmidt

and Dringen 2012) Thus excessive accumulation of extra-cellular GSH as well as GSH-derived glutamate may cause

excitotoxicity which has at least been demonstrated in vitro

(Regan and Guo 1999a b)

To address the molecular mechanisms that are involved in

the development of adverse neural effects of an elevated

concentration of formaldehyde it has to be discriminated

between direct and indirect consequences of formaldehyde

exposure Acute exposure of neural cells to formaldehyde

andor the rapid generation of formaldehyde-derived metab-

olites will directly affect basal metabolic parameters (Fig 4

light gray squares) which may subsequently lead to indirect

delayed consequences (Fig 4 dark gray squares) Little is

known so far on the mechanisms that link acute direct

consequences of a formaldehyde exposure such as acceler-

ated glycolysis or GSH export to the known adverse effects

of formaldehyde on neural cells (Table 2) Activation of

signaling cascades as well as alterations in protein expression

are likely to be involved in the development of the delayed

indirect effects of an exposure to excess of formaldehyde

For example formaldehyde-exposed neuronal PC12 cells

show endoplasmic reticulum stress decreased levels of the

antioxidant proteins thioredoxin and paraoxonase 1 (Tang

et al 2011 Luo et al 2012) and a decreased expression of

the anti-apoptotic protein Bcl-2 while the expression of pro-

apoptotic Bax protein increases (Tang et al 2012) Also the

expression of the rate-limiting enzyme in dopamine synthesis

tyrosine hydroxylase is lowered in PC12 cells after exposure

to formaldehyde (Lee et al 2008) Further studies are now

required to investigate the signaling pathways that link theacute formaldehyde-induced metabolic alterations to the

known brain pathology of an excess of formaldehyde

(Table 2)

Conditions such as aging and diseases like MS and AD

which are associated with increased levels of formaldehyde

in brain (Khokhlov et al 1989 cited in Miao and He 2012

Tong et al 2011 2013a b) show impaired mitochondrial

function (Sullivan and Brown 2005 Mahad et al 2008

Boumezbeur et al 2010 Leuner et al 2012) together with

an increase in brain lactate content (Parnetti et al 2000 Ross

et al 2010 Paling et al 2011) Moreover ageing MS and

AD have been connected with oxidative stress in the brain

(Haider et al 2011 van Horssen et al 2011 Belkacemi

and Ramassamy 2012 Sohal and Orr 2012 Steele and

Robinson 2012) These reports strengthen the view that

formaldehyde may at least to some extent have a role in the

initiation andor progression of pathological symptoms of

neurodegenerative conditions (Yu 2001 Monte 2010) An

adequate supply of lactate to neurons has been shown to

foster memory formation (Suzuki et al 2011) while GSH

depletion in the brain has been demonstrated to result in

behavioral changes (Steullet et al 2010) Thus the formal-

dehyde-induced alterations in glucose and GSH metabolism

may contribute to the de1047297cits in behavior cognition and

learning observed in formaldehyde-exposed animals (Pittenet al 2000 Malek et al 2003 Lu et al 2008 Tong et al

2011 2013a b)

Conclusions and future perspectives

In conclusion elevation of brain formaldehyde levels is

likely to alter brain cell metabolism which may affect the

function of this vital organ Although some studies have

correlated that neurodegenerative conditions are associated

with increased levels of formaldehyde in the brain and others

have connected such diseases with impaired energy metab-

olism and oxidative stress a direct causal link between

formaldehyde impaired metabolism and oxidative stress

remains to be demonstrated Interestingly resveratrol which

is known to be neuroprotective for AD (Richard et al 2011

Li et al 2012) is a formaldehyde scavenger (Tyihak and

Kir aly-Veghely 2008) suggesting that the bene1047297cial effects

of resveratrol could also include removal of excess formal-

dehyde Further studies that will combine the quanti1047297cation

of formaldehyde levels in post-mortem brains with metab-

olite pro1047297les and analysis of oxidative stress markers are now

required to provide further experimental evidence for a direct

contribution of formaldehyde in the pathology of neurode-

generative disorders





Conflict of interest

The authors have no con1047298ict of interest to declare

References

Ahmed A E and Ahmed M W (1978) Metabolism of dihalomethanes

to formaldehyde and inorganic halide II Studies on the mechanism

of the reaction Biochem Pharmacol 27 2021 ndash 2025

Airas L Mikkola J Vainio J M Elovaara I and Smith D J (2006)

Elevated serum soluble vascular adhesion protein-1 (VAP-1) in

patients with active relapsing remitting multiple sclerosis

J Neuroimmunol 177 132 ndash 135

Alnouti Y and Klaassen C D (2008) Tissue distribution ontogeny and

regulation of aldehyde dehydrogenase (Aldh) enzymes mRNA by

prototypical microsomal enzyme inducers in mice Toxicol Sci

101 51 ndash 64

Anthony T E and Heintz N (2007) The folate metabolic enzyme

ALDH1L1 is restricted to the midline of the early CNS suggesting

a role in humanneural tubedefects J Comp Neurol 500 368 ndash 383Aslan H Songur A Tunc A T Ozen O A Bas O Yagmurca M

Turgut M Sarsilmaz M and Kaplan S (2006) Effects of

formaldehyde exposure on granule cell number and volume of

dentate gyrus a histopathological and stereological study Brain

Res 1122 191 ndash 200

Belkacemi A and Ramassamy C (2012) Time sequence of oxidative

stress in the brain from transgenic mouse models of Alzheimer rsquos

disease related to the amyloid-b cascade Free Radic Biol Med

52 593 ndash 600

Bennani-Baiti I M Machado I Llombart-Bosch A and Kovar H

(2012) Lysine-speci1047297c demethylase 1 (LSD1KDM1AAOF2

BHC110) is expressed and is an epigenetic drug target in

chondrosarcoma Ewingrsquos sarcoma osteosarcoma and

rhabdomyosarcoma Hum Pathol 43 1300 ndash 1307

Berkich D A Ola M S Cole J Sweatt A J Hutson S M andLaNoue K F (2007) Mitochondrial transport proteins of the brain

J Neurosci Res 85 3367 ndash 3377

Bola~nos J P Almeida A and Moncada S (2010) Glycolysis a

bioenergetic or a survival pathway Trends Biochem Sci 35 145 ndash

149

Boomsma F de Kam P J Tjeerdsma G van den Meiracker A H and

van Veldhuisen D J (2000) Plasma semicarbazide-sensitive amine

oxidase (SSAO) is an independent prognostic marker for mortality

in chronic heart failure Eur Heart J 21 1859 ndash 1863

Boomsma F Hut H Bagghoe U van der Houwen A and van den

Meiracker A (2005) Semicarbazide-sensitive amine oxidase

(SSAO) from cell to circulation Med Sci Monit 11 RA122 ndash

RA126

Boumezbeur F Mason G F de Graaf R A Behar K L Cline G W

Shulman G I Rothman D L and Petersen K F (2010) Alteredbrain mitochondrial metabolism in healthy aging as assessed by

in vivo magnetic resonance spectroscopy J Cereb Blood Flow

Metab 30 211 ndash 221

Burg D Wielinga P Zelcer N Saeki T Mulder G J and Borst P

(2002) Inhibition of the multidrug resistance protein 1 (MRP1) by

peptidomimetic glutathione-conjugate analogs Mol Pharmacol

62 1160 ndash 1166

Cahoy J D Emery B Kaushal A et al (2008) A transcriptome

database for astrocytes neurons and oligodendrocytes a new

resource for understanding brain development and function

J Neurosci 28 264 ndash 278

Casanova-Schmitz M David R M and Heck H D (1984) Oxidation of

formaldehyde and acetaldehyde by NAD+-dependent dehydrogenases

in rat nasal mucosal homogenates Biochem Pharmacol 33 1137 ndash

1142

Cheng X and Zhang X (2007) Structural dynamics of protein lysine

methylation and demethylation Mutat Res 618 102 ndash 115

Cloos P A Christensen J Agger K and Helin K (2008) Erasing the

methyl mark histone demethylases at the center of cellular differentiation and disease Genes Dev 22 1115 ndash 1140

Cole S P C and Deeley R G (2006) Transport of glutathione and

glutathione conjugates by MRP1 Trends Pharmacol Sci 27 438 ndash

446

Cook R J Champion K M and Giometti C S (2001) Methanol

toxicity and formate oxidation in NEUT2 mice Arch Biochem

Biophys 393 192 ndash 198

Davis M J Iancu O D Acher F C Stewart B M Eiwaz M A

Duvoisin R M and Raber J (2013) Role of mGluR4 in acquisition

of fear learning and memory Neuropharmacology 66 365 ndash 372

Debernardi R Pierre K Lengacher S Magistretti P J and Pellerin L

(2003) Cell-speci1047297c expression pattern of monocarboxylate

transporters in astrocytes and neurons observed in different

mouse brain cortical cell cultures J Neurosci Res 73 141 ndash 155

Deeley R G and Cole S P (2006) Substrate recognition and transport by multidrug resistance protein 1 (ABCC1) FEBS Lett 580 1103 ndash

1111

Dhareshwar S S and Stella V J (2008) Your prodrug releases

formaldehyde should you be concerned No J Pharm Sci 97

4184 ndash 4193

Dicker E and Cederbaum A I (1984) Inhibition of the oxidation of

acetaldehyde and formaldehyde by hepatocytes and mitochondria

by crotonaldehyde Arch Biochem Biophys 234 187 ndash 196

Dringen R and Hamprecht B (1998) Glutathione restoration as indicator

for cellular metabolism of astroglial cells Dev Neurosci 20 401 ndash

407

Dringen R Kranich O and Hamprecht B (1997) The c-glutamyl

transpeptidase inhibitor acivicin preserves glutathione released by

astroglial cells in culture Neurochem Res 22 727 ndash 733

Dringen R Hoepken H H Minich T and Ruedig C (2007) Pentosephosphate pathway and NADPH metabolism in Handbook of

Neurochemistry and Molecular Neurobiology (Dienel G and

Gibson G S eds) pp 41 ndash 62 Neural Energy Utilization Springer

Heidelberg

Fernandez-Fernandez S Almeida A and Bola~nos J P (2012)

Antioxidant and bioenergetic coupling between neurons and

astrocytes Biochem J 443 3 ndash 12

Ferrer I Lizcano J M Hernandez M and Unzeta M (2002)

Overexpression of semicarbazide sensitive amine oxidase in the

cerebral blood vessels in patients with Alzheimer rsquos disease and

cerebral autosomal dominant arteriopathy with subcortical infarcts

and leukoencephalopathy Neurosci Lett 321 21 ndash 24

Forneris F Battaglioli E Mattevi A and Binda C (2009) New roles of

1047298avoproteins in molecular cell biology histone demethylase LSD1

and chromatin FEBS J 276 4304 ndash 4312Fountoulakis M Gulesserian T and Lubec G (2003) Overexpression of

C1-tetrahydrofolate synthase in fetal Down syndrome brain

J Neural Transm Suppl 67 85 ndash 93

Franks S J (2005) A mathematical model for the absorption and

metabolism of formaldehyde vapour by humans Toxicol Appl

Pharmacol 206 309 ndash 320

Friedenson B (2011) A common environmental carcinogen unduly

affects carriers of cancer mutations carriers of genetic mutations in

a speci1047297c protective response are more susceptible to an

environmental carcinogen Med Hypotheses 77 791 ndash 797

Fukuda T Tokunaga A Sakamoto R and Yoshida N (2011) Fbxl10

Kdm2b de1047297ciency accelerates neural progenitor cell death and

leads to exencephaly Mol Cell Neurosci 46 614 ndash 624





Galter D Carmine A Buervenich S Duester G and Olson L (2003)

Distribution of class I III and IV alcohol dehydrogenase mRNAs

in the adult rat mouse and human brain Eur J Biochem 270

1316 ndash 1326

Gennuso F Fernetti C Tirolo C et al (2004) Bilirubin protects

astrocytes from its own toxicity by inducing up-regulation andtranslocation of multidrug resistance-associated protein 1 (Mrp1)

Proc Natl Acad Sci USA 101 2470 ndash 2475

Gr euroonvall-Nordquist J L Backlund L B Garpenstrand H Ekblom J

Landin B Yu P H Oreland L and Rosenqvist U (2001) Follow-

up of plasma semicarbazide-sensitive amine oxidase activity and

retinopathy in type 2 diabetes mellitus J Diabetes Complications

15 250 ndash 256

de Groot A C Flyvholm M A Lensen G Menne T and Coenraads P

J (2009) Formaldehyde-releasers Relationship to formaldehyde

contact allergy Contact allergy to formaldehyde and inventory of

formaldehyde-releasers Contact Derm 61 63 ndash 85

de Groot A White I R Flyvholm M A Lensen G and Coenraads P

J (2010) Formaldehyde-releasers in cosmetics relationship to

formaldehyde contact allergy Part 2 Patch test relationship

to formaldehyde contact allergy experimental provocationtests amount of formaldehyde released and assessment of risk

to consumers allergic to formaldehyde Contact Derm 62

18 ndash 31

Guo J M Liu A J Zang P et al (2013) ALDH2 protects against

stroke by clearing 4-HNE Cell Res 2013 1 ndash 16

Gurel A Coskun O Armutcu F Kante M and Ozen O A (2005)

Vitamin E against oxidative damage caused by formaldehyde in

frontal cortex and hippocampus biochemical and histological

studies J Chem Neuroanat 29 173 ndash 178

Haider L Fischer M T Frischer J M Bauer J Hoftberger R Botond

G Esterbauer H Binder C J Witztum J L and Lassmann H

(2011) Oxidative damage in multiple sclerosis lesions Brain 134

1914 ndash 1924

Halim N D McFate T Mohyeldin A et al (2010) Phosphorylation

status of pyruvate dehydrogenase distinguishes metabolicphenotypes of cultured rat brain astrocytes and neurons Glia 58

1168 ndash 1176

Harris C Wang S W Lauchu J J and Hansen J M (2003) Methanol

metabolism and embryotoxicity in rat and mouse conceptuses

comparisons of alcohol dehydrogenase (ADH1) formaldehyde

dehydrogenase (ADH3) and catalase Reprod Toxicol 17 349 ndash

357

Hayami S Yoshimatsu M Veerakumarasivam A et al (2010)

Overexpression of the JmjC histone demethylase KDM5B in

human carcinogenesis involvement in the proliferation of cancer

cells through the E2FRB pathway Mol Cancer 9 59

Hayami S Kelly J D Cho H S et al (2011) Overexpression of LSD1

contributes to human carcinogenesis through chromatin regulation

in various cancers Int J Cancer 128 574 ndash 586

He R Lu J and Miao J (2010) Formaldehyde stress Sci China LifeSci 53 1399 ndash 1404

Heck H D and Casanova M (2004) The implausibility of leukemia

induction by formaldehyde a critical review of the biological

evidence on distant-site toxicity Regul Toxicol Pharmacol 40

92 ndash 106

Heck H D Casanova-Schmitz M Dodd P B Schachter E N Witek

T J and Tosun T (1985) Formaldehyde (CH2O) concentrations in

the blood of humans and Fischer-344 rats exposed to CH2O under

controlled conditions Am Ind Hyg Assoc J 46 1 ndash 3

Heck H D Casanova M and Starr T B (1990) Formaldehyde toxicity -

new understanding Crit Rev Toxicol 20 397 ndash 426

Hedberg J J Backlund M Stromberg P Lonn S Dahl M L

Ingelman-Sundberg M and Hoog J O (2001) Functional

polymorphism in the alcohol dehydrogenase 3 (ADH3) promoter

Pharmacogenetics 11 815 ndash 824

Henzi H (1984) Chronic methanol poisoning with the clinical and

pathologic-anatomical features of multiple sclerosis Med

Hypotheses 13 63 ndash 75

Herrero-Mendez A Almeida A Fernandez E Maestre C Moncada S

and Bola~nos J P (2009) The bioenergetic and antioxidant status of

neurons is controlled by continuous degradation of a key glycolytic

enzyme by APCC ndash Cdh1 Nat Cell Biol 11 747 ndash 752

van Horssen J Schreibelt G Drexhage J Hazes T Dijkshtra C D

van der Valk P and de Vries H E (2008) Severe oxidative

damage in multiple sclerosis lesions coincides with enhanced

antioxidant enzyme expression Free Radic Biol Med 45 1729 ndash

1737

van Horssen J Witte M E Schreibelt G and de Vries H E (2011)

Radical changes in multiple sclerosis pathogenesis Biochim

Biophys Acta 1812 141 ndash 150

Hou H and Yu H (2010) Structural insights into histone lysine

demethylation Curr Opin Struct Biol 20 739 ndash 748

Iborra F J Renau-Piqueras J Portoles M Boleda M D Guerri C and

Pares X (1992) Immunocytochemical and biochemicaldemonstration of formaldehyde dehydrogenase (class III alcohol

dehydrogenase) in the nucleus J Histochem Cytochem 40 1865 ndash

1878

Izzo A and Schneider R (2010) Chatting histone modi1047297cations in

mammals Brief Funct Genomics 9 429 ndash 443

Jalkanen S and Salmi M (2001) Cell surface monoamine oxidases

enzymes in search of a function EMBO J 20 3893 ndash 3901

Jalkanen S and Salmi M (2008) VAP-1 and CD73 endothelial cell

surface enzymes in leukocyte extravasation Arterioscler Thromb

Vasc Biol 28 18 ndash 26

Janaky R Cruz-Aguado R Oja S S and Shaw C A (2007)

Glutathione in the nervous system roles in neural function and

health and implications for neurological disease in Handbook of

Neurochemistry (Oja S S Schousboe A and Saransaari P eds)

pp 347 ndash 399 Amino Acids and Peptides in the Nervous SystemSpringer Heidelberg

Julia P Farres J and Pares X (1987) Characterization of three

isoenzymes of rat alcohol-dehydrogenase - tissue distribution

and physical and enzymatic-properties Eur J Biochem 162

179 ndash 189

Kahl P Gullotti L Heukamp L C et al (2006) Androgen receptor

coactivators lysine-speci1047297c histone demethylase 1 and four and a

half LIM domain protein 2 predict risk of prostate cancer

recurrence Cancer Res 66 11341 ndash 11347

Kapur B M Vandenbroucke A C Adamchik Y Lehotay D C and

Carlen P L (2007) Formic acid a novel metabolite of chronic

ethanol abuse causes neurotoxicity which is prevented by folic

acid Alcohol Clin Exp Res 31 2114 ndash 2120

Karadi I Meszaros Z Csanyi A Szombathy T Hosszufalusi N

Romics L and Magyar K (2002) Serum semicarbazide-sensitiveamine oxidase (SSAO) activity is an independent marker of carotid

atherosclerosis Clin Chim Acta 323 139 ndash 146

Kato S Burke P J Koch T H and Bierbaum V M (2001)

Formaldehyde in human cancer cells detection by preconcentration-

chemical ionization mass spectrometry Anal Chem 73 2992 ndash

2997

Keppler D (2011) Multidrug resistance proteins (MRPs ABCCs)

importance for pathophysiology and drug therapy Handb Exp


Khokhlov A P Zavalishin I A Savchenko I N and Dziuba A N

(1989) Disorders of formaldehyde metabolism and its metabolic

precursors in patients with multiple sclerosis Zh Nevropatol

Psikhiatr Im S S Korsakova 89 45 ndash 48





Kiernan J A (2000) Formaldehyde formalin paraformaldehyde and

glutaraldehyde what they are and what they do Microsc Today 1

8 ndash 12

Kiernan M C Vucic S Cheah B C Turner M R Eisen A Hardiman

O Burrell J R and Zoing M C (2011) Amyotrophic lateral

sclerosis Lancet 377 942 ndash 955Kilburn K H Seidman B C and Warshaw R (1985a) Neurobehavioral

and respiratory symptoms of formaldehyde and xylene exposure in

histology technicians Arch Environ Health 40 229 ndash 233

Kilburn K H Warshaw R Boylen C T Johnson S J Seidman B

Sinclair R and Takaro T Jr (1985b) Pulmonary and

neurobehavioral effects of formaldehyde exposure Arch

Environ Health 40 254 ndash 260

Krupenko S A (2009) FDH an aldehyde dehydrogenase fusion enzyme

in folate metabolism Chem Biol Interact 178 84 ndash 93

Krupenko N I Dubard M E Strickland K C Moxley K M Oleinik

N V and Krupenko S A (2010) ALDH1L2 is the mitochondrial

homolog of 10-formyltetrahydrofolate dehydrogenase J Biol

Chem 285 23056 ndash 23063

Kurkijarvi R Yegutkin G G Gunson B K Jalkanen S Salmi M and

Adams D H (2000) Circulating soluble vascular adhesion protein1 accounts for the increased serum monoamine oxidase activity in

chronic liver disease Gastroenterology 119 1096 ndash 1103

Laitinen J Makela M Mikkola J and Huttu I (2010) Fire 1047297ghting

trainersrsquo exposure to carcinogenic agents in smoke diving

simulators Toxicol Lett 192 61 ndash 65

Lee E S Chen H Hardman C Simm A and Charlton C (2008)

Excessive S-adenosyl-L-methionine-dependent methylation

increases levels of methanol formaldehyde and formic acid in rat

brain striatal homogenates possible role in S-adenosyl-

L-methionine-induced Parkinsonrsquos disease-like disorders Life

Sci 83 821 ndash 827

Lee M Schwab C and McGeer P L (2011) Astrocytes are GABAergic

cells that modulate microglial activity Glia 59 152 ndash 165

Leuner K Muller W E and Reichert A S (2012) From mitochondrial

dysfunction to amyloid beta formation novel insights into thepathogenesis of Alzheimer rsquos disease Mol Neurobiol 46 186 ndash

193

Lewerenz J Dargusch R and Maher P (2010) Lactacidosis modulates

glutathione metabolism and oxidative glutamate toxicity

J Neurochem 113 502 ndash 514

Li F Liu X Su Z and Sun R (2011) Acidosis leads to brain

dysfunctions through impairing cortical GABAergic neurons

Biochem Biophys Res Commun 410 775 ndash 779

Li F Gong Q Dong H and Shi J (2012) Resveratrol a neuroprotective

supplement for Alzheimer rsquos disease Curr Pharm Des 18 27 ndash 33

Lim S Janzer A Becker A Zimmer A Schule R Buettner R and

Kirfel J (2010) Lysine-speci1047297c demethylase 1 (LSD1) is highly

expressed in ER-negative breast cancers and a biomarker

predicting aggressive biology Carcinogenesis 31 512 ndash 520

Lu S C (2013) Glutathione synthesis Biochim Biophys Acta 18303143 ndash 3153

Lu Z Li C M Qiao Y Yan Y and Yang X (2008) Effect of inhaled

formaldehyde on learning and memory of mice Indoor Air 18 77 ndash

83

Lu J Li C Su T Liu Y and He R (2013) Formaldehyde induces

hyperphosphorylation and polymerization of Tau protein both

in vitro and in vivo Biochim Biophys Acta 1830 4102 ndash 4116

Luo F C Zhou J Lv T Qi L Wang S D Nakamura H Yodoi J and

Bai J (2012) Induction of endoplasmic reticulum stress and the

modulation of thioredoxin-1 in formaldehyde-induced

neurotoxicity Neurotoxicology 33 290 ndash 298

Lushchak V I (2012) Glutathione homeostasis and functions potential

targets for medical interventions J Amino Acids 2012 736837

MacAllister S L Choi J Dedina L and OrsquoBrien P J (2011) Metabolic

mechanisms of methanolformaldehyde in isolated rat hepatocytes

Carbonyl-metabolizing enzymes versus oxidative stress Chem

Biol Interact 191 308 ndash 314

MacFarlane A J Perry C A Girnary H H Gao D Allen R H

Stabler S P Shane B and Stover P J (2009) Mthfd1 is anessential gene in mice and alters biomarkers of impaired one-

carbon metabolism J Biol Chem 284 1533 ndash 1539

Mahad D Ziabreva I Lassmann H and Turnbull D (2008)

Mitochondrial defects in acute multiple sclerosis lesions Brain

131 1722 ndash 1735

Malek F A Moritz K U and Fanghanel J (2003) A study on speci1047297c

behavioral effects of formaldehyde in the rat J Exp Anim Sci 42

160 ndash 170

del Mar Hernandez M Esteban M Szabo P Boada M and Unzeta M

(2005) Human plasma semicarbazide sensitive amine oxidase

(SSAO) b-amyloid protein and aging Neurosci Lett 384183 ndash 187

Martinez S E Vaglenova J Sabria J Martinez M C Farres J and

Pares X (2001) Distribution of alcohol dehydrogenase mRNA in

the rat central nervous system - consequences for brain ethanol and

retinoid metabolism Eur J Biochem 268 5045 ndash 5056Mason M J Mattsson K Pasternack M Voipio J and Kaila K (1990)

Postsynaptic fall in intracellular pH and increase in surface pH

caused by ef 1047298ux of formate and acetate anions through GABA-

gated channels in cray1047297sh muscle-1047297bers Neuroscience 34 359 ndash

368

Meinerz D F Comprasi B Allebrandt J et al (2013) Sub-acute

administration of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido)

succinate induces toxicity and oxidative stress in mice unexpected

effects of N-acetylcysteine Springerplus 2 182

Meszaros Z Szombathy T Raimondi L Karadi I Romics L and

Magyar K (1999) Elevated serum semicarbazide-sensitive amine

oxidase activity in non-insulin-dependent diabetes mellitus

correlation with body mass index and serum triglyceride

Metabolism 48 113 ndash 117

Metz B Kersten G F Hoogerhout P et al (2004) Identi1047297cation of formaldehyde-induced modi1047297cations in proteins reactions with

model peptides J Biol Chem 279 6235 ndash 6243

Metz B Kersten G F Baart G J de Jong A Meiring H ten Hove J

van Steenbergen M J Hennink W E Crommelin D J and

Jiskoot W (2006) Identi1047297cation of formaldehyde-induced

modi1047297cations in proteins reactions with insulin Bioconjug

Chem 17 815 ndash 822

Miao J and He R (2012) Chronic formaldehyde-mediated impairments

and age-related dementia in Neurodegeneration (Martin L M and

Loh S H Y eds) pp 59 ndash 76 InTech doi 10577234949

Monte W C (2010) Methanol a chemical Trojan horse as the root of the

inscrutable U Med Hypotheses 74 493 ndash 496

Moschen I Broer A Galic S Lang F and Broer S (2012) Signi1047297cance

of short chain fatty acid transport by members of the

monocarboxylate transporter family (MCT) Neurochem Res 372562 ndash 2568

Mukherjee S and Manahan-Vaughan D (2013) Role of metabotropic

glutamate receptors in persistent forms of hippocampal plasticity

and learning Neuropharmacology 66 65 ndash 81

Nazarian A Hermannsson B J Muller J Zurakowski D and Snyder

B D (2009) Effects of tissue preservation on murine bone

mechanical properties J Biomech 42 82 ndash 86

Neves A Costalat R and Pellerin L (2012) Determinants of brain

cell metabolic phenotypes and energy substrate utilization unraveled

with a modeling approach PLoS Comput Biol 8 e1002686

Neymeyer V Tephly T R and Miller M W (1997) Folate and 10-

formyltetrahydrofolate dehydrogenase (FDH) expression in the

central nervous system of the mature rat Brain Res 766 195 ndash 204





Nicholls P (1975) Formate as an inhibitor of cytochrome c oxidase


Nishimura M and Naito S (2006) Tissue-speci1047297c mRNA expression

pro1047297les of human phase I metabolizing enzymes except for

cytochrome P450 and phase II metabolizing enzymes Drug

Metab Pharmacokinet 21 357 ndash 374Obata T (2006) Diabetes and semicarbazide-sensitive amine oxidase

(SSAO) activity a review Life Sci 79 417 ndash 422

Obata T and Yamanaka Y (2000) Evidence for existence of

immobilization stress-inducible semicarbazide-sensitive amine

oxidase inhibitor in rat brain cytosol Neurosci Lett 296 58 ndash 60

Oldham M C Konopka G Iwamoto K Langfelder P Kato T

Horvath S and Geschwind D (2008) Functional organization of

the transcriptome in the human brain Nat Neurosci 11 1271 ndash

1282

Olsen R W and Sieghart W (2009) GABAA receptors subtypes provide

diversity of function and pharmacology Neuropharmacology 56

141 ndash 148

OrsquoSullivan J Unzeta M Healy J OrsquoSullivan M I Davey G and

Tipton K F (2004) Semicarbazide-sensitive amine oxidases

enzymes with quite a lot to do Neurotoxicology 25 303 ndash 315Oyama Y Sakai H Arata T Okano Y Akaike N Sakai K and Noda

K (2002) Cytotoxic effects of methanol formaldehyde and

formate on dissociated rat thymocytes a possibility of aspartame

toxicity Cell Biol Toxicol 18 43 ndash 50

Paling D Golay X Wheeler-Kingshott C Kapoor R and Miller D

(2011) Energy failure in multiple sclerosis and its investigation

using MR techniques J Neurol 258 2113 ndash 2127

Parnetti L Reboldi G P and Gallai V (2000) Cerebrospinal 1047298uid

pyruvate levels in Alzheimer rsquos disease and vascular dementia

Neurology 54 735 ndash 737

Pauwels P J Opperdoes F R and Trouet A (1985) Effects of

antimycin glucose deprivation and serum on cultures of neurons

astrocytes and neuroblastoma cells J Neurochem 44 143 ndash 148

Pitten F A Kramer A Herrmann K Breme I and Koch S (2000)

Formaldehyde neurotoxicity in animal experiments Pathol ResPract 196 193 ndash 198

Prasannan P Pike S Peng K Shane B and Appling D R (2003)

Human mitochondrial C1-tetrahydrofolate synthase gene structure

tissue distribution of the mRNA and immunolocalization in

Chinese hamster ovary cells J Biol Chem 278 43178 ndash 43187

Regan R F and Guo Y P (1999a) Extracellular reduced glutathione

increases neuronal vulnerability to combined chemical hypoxia and

glucose deprivation Brain Res 817 145 ndash 150

Regan R F and Guo Y P (1999b) Potentiation of excitotoxic injury by

high concentrations of extracellular reduced glutathione

Neuroscience 91 463 ndash 470

Richard T Pawlus A D Iglesias M L Pedrot E Waffo-Teguo P

Merillon J M and Monti J P (2011) Neuroprotective properties

of resveratrol and derivatives Ann N Y Acad Sci 1215 103 ndash

108Rose C F (2010) Increase brain lactate in hepatic encephalopathy cause

or consequence Neurochem Int 57 389 ndash 394

Ross J M Oberg J Brene S et al (2010) High brain lactate is a

hallmark of aging and caused by a shift in the lactate

dehydrogenase AB ratio Proc Natl Acad Sci USA 107

20087 ndash 20092

Salthammer T Mentese S and Marutzky R (2010) Formaldehyde in the

indoor environment Chem Rev 110 2536 ndash 2572

Sarsilmaz M Kaplan S Songur A Colakoglu S Aslan H Tunc A T

Ozen Q A Turgut M and Bas O (2007) Effects of postnatal

formaldehyde exposure on pyramidal cell number volume of cell

layer in hippocampus and hemisphere in the rat a stereological

study Brain Res 1145 157 ndash 167

Sasseville D (2004) Hypersensitivity to preservatives Dermatol Ther

17 251 ndash 263

Schad A Fahimi H D Volkl A and Baumgart E (2003) Expression

of catalase mRNA and protein in adult rat brain detectionby nonradioactive in situ hybridization with signal ampli1047297cation

by catalyzed reporter deposition (ISH-CAR D) and

immunohistochemistry (IHC)immuno1047298uorescence (IF) J

Histochem Cytochem 51 751 ndash 760

Scheiber I F and Dringen R (2011) Copper accelerates glycolytic 1047298ux

in cultured astrocytes Neurochem Res 36 894 ndash 903

Schildhaus H U Riegel R Hartmann W et al (2011) Lysine-speci1047297c

demethylase 1 is highly expressed in solitary 1047297brous tumors

synovial sarcomas rhabdomyosarcomas desmoplastic small round

cell tumors and malignant peripheral nerve sheath tumors Hum

Pathol 42 1667 ndash 1675

Schmidt M M and Dringen R (2012) GSH synthesis and metabolism

in Advances in Neurobiology (Gruetter R and Choi I Y eds) pp

1029 ndash 1050 Neural Metabolism in vivo Springer New York

Schulte J H Lim S Schramm A et al (2009) Lysine-speci1047297cdemethylase 1 is strongly expressed in poorly differentiated

neuroblastoma implications for therapy Cancer Res 69 2065 ndash

2071

Schwyzer R U and Henzi H (1983) Multiple sclerosis plaques caused

by 2-step demyelination Med Hypotheses 12 129 ndash 142

Skrzydlewska E (2003) Toxicological and metabolic consequences of

methanol poisoning Toxicol Mech Methods 13 277 ndash 293

Smith D J and Vainio P J (2007) Targeting vascular adhesion protein-

1 to treat autoimmune and in1047298ammatory diseases Ann N Y Acad

Sci 1110 382 ndash 388

Sohal R S and Orr W C (2012) The redox stress hypothesis of aging

Free Radic Biol Med 52 539 ndash 555

Song M S Baker G B Dursun S M and Todd K G (2010) The

antidepressant phenelzine protects neurons and astrocytes

against formaldehyde-induced toxicity J Neurochem 1141405 ndash 1413

Songur A Sarsilmaz M Ozen O A Sahin S Koken R Zararsiz I and

Ilhan N (2008) The effects of inhaled formaldehyde on oxidant and

antioxidant systems of rat cerebellum during the postnatal

development process Toxicol Mech Methods 18 569 ndash 574

Songur A Ozen O A and Sarsilmaz M (2010) The toxic effects of

formaldehyde on the nervous system Rev Environ Contam

Toxicol 203 105 ndash 118

Sorg B A Swindell S and Tschirgi M L (2004) Repeated low level

formaldehyde exposure produces enhanced fear conditioning to

odor in male but not female rats Brain Res 1008 11 ndash 19

Staab C A Alander J Morgenstern R Grafstrom R C and Hoog J O

(2009) The janus face of alcohol dehydrogenase 3 Chem Biol

Interact 178 29 ndash 35

Staub F Peters J Kempski O Schneider G H Schurer Land Baethmann A (1993) Swelling of glial cells in lactacidosis

and by glutamate signi1047297cance of Cl ndash transport Brain Res 610 69 ndash

74

Steele M L and Robinson S R (2012) Reactive astrocytes give neurons

less support implications for Alzheimer rsquos disease Neurobiol

Aging 33 423e1 ndash 423e13

Steullet P Cabungcal J H Kulak A Kraftsik R Chen Y Dalton T

P Cuenod M and Do K Q (2010) Redox dysregulation affects

the ventral but not dorsal hippocampus impairment of

parvalbumin neurons gamma oscillations and related behaviors






Stewart M J Malek K and Crabb D W (1996) Distribution of

messenger RNAs for aldehyde dehydrogenase 1 aldehyde

dehydrogenase 2 and aldehyde dehydrogenase 5 in human

tissues J Investig Med 44 42 ndash 46

Sullivan P G and Brown M R (2005) Mitochondrial aging and

dysfunction in Alzheimer rsquos disease Prog Neuropsychopharmacol

Biol Psychiatry 29 407 ndash 410

Suzuki A Stern S A Bozdagi O Huntley G W Walker R H

Magistretti P J and Alberini C M (2011) Astrocyte-neuron

lactate transport is required for long-term memory formation Cell

144 810 ndash 823

Tang X Bai Y Duong A Smith M T Li L and Zhang L (2009)

Formaldehyde in China production consumption exposure levels

and health effects Environ Int 35 1210 ndash 1224

Tang X Q Ren Y K Chen R Q et al (2011) Formaldehyde induces

neurotoxicity to PC12 cells involving inhibition of paraoxonase-1

expression and activity Clin Exp Pharmacol Physiol 38 208 ndash

214

Tang X Q Ren Y N Zhou C F et al (2012) Hydrogen sul1047297de

prevents formaldehyde-induced neurotoxicity to PC12 cells by

attenuation of mitochondrial dysfunction and pro-apoptoticpotential Neurochem Int 61 16 ndash 24

Teng S Beard K Pourahmad J Moridani M Easson E Poon R and

OrsquoBrien P J (2001) The formaldehyde metabolic detoxi1047297cation

enzyme systems and molecular cytotoxic mechanism in isolated rat

hepatocytes Chem Biol Interact 130 ndash 132 285 ndash 296

Tephly T R (1991) The toxicity of methanol Life Sci 48 1031 ndash

1041

Thigpen A E West M G and Appling D R (1990) Rat C1-

tetrahydrofolate synthase cDNA isolation tissue-speci1047297c levels of

the mRNA and expression of the protein in yeast J Biol Chem

265 7907 ndash 7913

Thompson C M Ceder R and Grafstrom R C (2010) Formaldehyde

dehydrogenase beyond phase I metabolism Toxicol Lett 193

1 ndash 3

Tibbetts A S and Appling D R (2010) Compartmentalization of mammalian folate-mediated one-carbon metabolism Annu Rev

Nutr 30 57 ndash 81

Tong Z Luo W Wang Y et al (2010) Tumor tissue-derived

formaldehyde and acidic microenvironment synergistically induce

bone cancer pain PLoS ONE 5 e10234

Tong Z Zhang J Luo W et al (2011) Urine formaldehyde level is

inversely correlated to mini mental state examination scores in

senile dementia Neurobiol Aging 32 31 ndash 41

Tong Z Han C Luo W Wang X Li H Luo H Zhou J Qi J and He

R (2013a) Accumulated hippocampal formaldehyde induces age-

dependent memory decline Age (Dordr) 35 583 ndash 596

Tong Z Han C Luo W et al (2013b) Aging-associated excess

formaldehyde leads to spatial memory de1047297cits Sci Rep 3 1807

Tulpule K and Dringen R (2011) Formaldehyde stimulates Mrp1-

mediated glutathione deprivation of cultured astrocytes J Neurochem 116 626 ndash 635

Tulpule K and Dringen R (2012) Formate generated by cellular

oxidation of formaldehyde accelerates the glycolytic 1047298ux in

cultured astrocytes Glia 60 582 ndash 593

Tulpule K Schmidt M M Boecker K Goldbaum O Richter-

Landsberg C and Dringen R (2012) Formaldehyde induces rapid

glutathione export from viable oligodendroglial OLN-93 cells

Neurochem Int 61 1302 ndash 1313

Tulpule K Hohnholt M C and Dringen R (2013) Formaldehyde

metabolism and formaldehyde-induced stimulation of lactate

production and glutathione export in cultured neurons


Turkoglu A O Sarsilmaz M Ogeturk M Kus I and Songur A (2008)

Bene1047297cial effects of caffeic acid phenethyl ester on formaldehyde-

induced learning and memory disabilities a labyrinth test

performance study Erciyes Med J 30 211 ndash 217

Tyihak E and Kir aly-Veghely Z (2008) Interaction of trans-resveratrol

with endogenous formaldehyde as one basis of its diversebene1047297cial biological effects Bull de I rsquoOIV 81 65 ndash 74

Unzeta M Sole M B oada M and Hernandez M (2007)

Semicarbazide-sensitive amine oxidase (SSAO) and its possible

contribution to vascular damage in Alzheimer rsquos disease J Neural

Transm 114 857 ndash 862

Uotila L (1981) Thioesters of glutathione Methods Enzymol 77 424 ndash

430

Usanmaz S E Akarsu E S and Vural N (2002) Neurotoxic effects of

acute and subacute formaldehyde exposures in mice Environ

Toxicol Pharmacol 11 93 ndash 100

Valente T Gella A Sole M Durany N and Unzeta M (2012)

Immunohistochemical study of semicarbazide-sensitive amine

oxidasevascular adhesion protein-1 in the hippocampal

vasculature pathological synergy of Alzheimer rsquos disease and

diabetes mellitus J Neurosci Res 90 1989 ndash 1996Velez-Fort M Audinat E and Angulo M C (2011) Central role of

GABA in neuron-glia interactions Neuroscientist 18 237 ndash 250

Wallace K B Eells J T Madeira V M Cortopassi G and Jones D P

(1997) Mitochondria-mediated cell injury Symposium overview

Fundam Appl Toxicol 38 23 ndash 37

Wang R S Nakajima T Kawamoto T and Honma T (2002) Effects of

aldehyde dehydrogenase-2 genetic polymorphisms on metabolism

of structurally different aldehydes in human liver Drug Metab

Dispos 30 69 ndash 73

Wang E Y Gao H F Salter-Cid L Zhang J Huang L Podar E M

Miller A Zhao J J OrsquoRourke A and Linnik M D (2006)

Design synthesis and biological evaluation of semicarbazide-

sensitive amine oxidase (SSAO) inhibitors with anti-in1047298ammatory

activity J Med Chem 49 2166 ndash 2173

Weisskopf M G Morozova N OrsquoReilly E J McCullough M LCalle E E Thun M J and Ascherio A (2009) Prospective study

of chemical exposures and amyotrophic lateral sclerosis J Neurol

Neurosurg Psychiatry 80 558 ndash 561

Wolf S S Patchev V K and Obendorf M (2007) A novel variant of the

putative demethylase gene s-JMJD1C is a coactivator of the AR

Arch Biochem Biophys 460 56 ndash 66

Xiang Y Zhu Z Han G et al (2007) JARID1B is a histone H3 lysine

4 demethylase up-regulated in prostate cancer Proc Natl Acad

Sci USA 104 19226 ndash 19231

Yin J and Zhang J (2011) Multidrug resistance-associated protein 1

( MRP1ABCC1) polymorphism from discovery to clinical

application J Cent South Univ 36 927 ndash 938

Yu P H (2001) Involvement of cerebrovascular semicarbazide-sensitive

amine oxidase in the pathogenesis of Alzheimer rsquos disease and

vascular dementia Med Hypotheses 57 175 ndash 179Yu P H Wright S Fan E H Lun Z R and Gubisne-Harberle D

(2003) Physiological and pathological implications of

semicarbazide-sensitive amine oxidase Biochim Biophys Acta

1647 193 ndash 199

Zararsiz I Kus I Akpolat N Songur A Ogeturk M and Sarsilmaz M

(2006) Protective effects of x-3 essential fatty acids against

formaldehyde-induced neuronal damage in prefrontal cortex of

rats Cell Biochem Funct 24 237 ndash 244

Zararsiz I Kus I Ogeturk M Akpolat N Kose E Meydan S and

Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced

neurotoxicity in prefrontal cortex of rats An immunohistochemical

and biochemical study Cell Biochem Funct 25 413 ndash 418





Zararsiz I Meydan S Sarsilmaz M Songur A Ozen O A and Sogut

S (2011) Protective effects of omega-3 essential fatty acids against

formaldehyde-induced cerebellar damage in rats Toxicol Ind

Health 27 489 ndash 495

Zhang Y Z Zhang Q H Ye H Zhang Y Luo Y M Ji X M and Su

Y Y (2010) Distribution of lysine-speci1047297c demethylase 1 in thebrain of rat and its response in transient global cerebral ischemia

Neurosci Res 68 66 ndash 72

Zhao H Cai Y Yang Z He D and Shen B (2011) Acidosis leads

to neurological disorders through overexciting cortical

pyramidal neurons Biochem Biophys Res Commun 415 224 ndash

228

Zibetti C Adamo A Binda C Forneris F Toffolo E Verpelli C

Ginelli E Mattevi A Sala C and Battaglioli E (2010) Alternative

splicing of the histone demethylase LSD1KDM1 contributes to the

modulation of neurite morphogenesis in the mammalian nervoussystem J Neurosci 30 2521 ndash 2532

Zimatkin S M and Lindros K O (1996) Distribution of catalase in rat

brain aminergic neurons as possible targets for ethanol effects

Alcohol Alcohol 31 167 ndash 174





formaldehyde (01 ndash 04 mM) that are found in body 1047298uids

and tissues under normal and pathological conditions (Heck

and Casanova 2004 Tong et al 2013a)

Endogenous and exogenous sources of formaldehyde

Formaldehyde exposure is caused by the generation of this

aldehyde within the body and can also be a consequence of

contact with elevated levels of environmental formaldehyde

(Fig 1) Some of the endogenous enzymatic reactions that

generate formaldehyde as well as exogenous sources of

formaldehyde are described below

Formaldehyde is the oxidation product of methanol This

alcohol can be generated within the body by hydrolysis of

protein carboxymethyl esters either non-enzymatically or

catalyzed by methylesterases (Lee et al 2008) In addition

accidental or intentional intake of methanol will further

expose the body to this alcohol In cells methanol is oxidized

to formaldehyde by alcohol dehydrogenase (ADH) 1 by

catalase or by a non-enzymatic reaction of methanol with

hydroxyl radicals (Harris et al 2003 MacAllister et al

2011) In humans and primates ADH1 appears to be

predominately responsible for methanol oxidation while

the majority of methanol oxidation in rats has been reported

to be mediated by catalase (Tephly 1991 Skrzydlewska

2003)

Another endogenous source of formaldehyde are semicar-

bazide-sensitive amine oxidases (SSAO) which represent agroup of copper-containing amine oxidases that are inhibited

by semicarbazide and most of them contain topa-quinone at

their catalytic centre (Jalkanen and Salmi 2001 Yu et al

2003) Oxidative deamination of methylamine by SSAO

generates formaldehyde together with ammonia and hydro-

gen peroxide (Yu et al 2003 OrsquoSullivan et al 2004) In

mammals SSAO are either membrane-associated or circulate

in a soluble form in the vascular system (Jalkanen and Salmi

2001) Among the SSAO the vascular adhesion protein

(VAP) 1 is one of the most extensively studied members of

this group of enzymes (Smith and Vainio 2007 Jalkanen and

Salmi 2008)

Formaldehyde is also generated as by-product of reactions

catalyzed by lysine-speci1047297c demethylase (LSD) 1 and JmjC

domain-containing histone demethylases (JHDM) (Cloos

et al 2008 Hou and Yu 2010) These enzymes remove

methyl groups from lysine residues in histones thereby

altering the chromatin structure (Cheng and Zhang 2007

Cloos et al 2008 Hou and Yu 2010 Izzo and Schneider

2010) LSD1 is a 1047298avin-containing enzyme that selectively

demethylates the mono- or dimethylated lysine residue in

position 4 of histone H3 (Forneris et al 2009 Hou and Yu

2010) On the other hand JHDM can remove methyl groups

from mono- di- or trimethylated lysine residues and require

Fe2+

and a-ketoglutarate as cofactors (Cloos et al 2008 Houand Yu 2010)

In addition to endogenous sources the body can also

encounter environmental formaldehyde since a number of

commonly used products contain either formaldehyde or

formaldehyde-releasing substances (Sasseville 2004

de Groot et al 2009) Some examples of such products are

construction materials agricultural fertilizers fumigants

paints cosmetics antiperspirants polish cleaning agents

and toiletries (Sasseville 2004 de Groot et al 2009 2010)

In addition formaldehyde can be produced and released from

burning of wood coal tobacco natural gas and kerosene

(de Groot et al 2009 Laitinen et al 2010) Moreover foods

like coffee cod1047297sh meat poultry and maple syrup naturally

contain formaldehyde (Dhareshwar and Stella 2008 de

Groot et al 2009) Thus this ubiquitously present compound

can enter the human body by inhalation ingestion or entry

through the skin

One pertinent question is whether exogenous formalde-

hyde can pose a big threat to the central nervous system by

entering the blood and ultimately reaching the brain after

crossing the blood ndash brain barrier In healthy individuals the

formaldehyde concentration in the blood is around 01 mM

(Heck and Casanova 2004) and that in the brain is

02 ndash 04 mM (Tong et al 2013a) Inhalation of moderate

Fig 1 Endogenous and exogenous sources of formaldehyde (HCHO)

and pathways involved in cellular formaldehyde disposal For details

see text ADH alcohol dehydrogenase ALDH aldehyde dehydroge-

nase cy cytosolic JHDM JmjC domain-containing histone demeth-

ylases LSD lysine-speci1047297c demethylase mt mitochondrial MTHFD

methylene tetrahydrofolate dehydrogenase SSAO semicarbazide-

sensitive amine oxidases VAP vascular adhesion protein


























formaldehyde





















































expressed (Table 1)


































formaldehyde




















































Tulpule et al 2013)





Enzymes

Species

Rat Mouse Human










Galter et al (2003)



Formate oxidation



































and Dringen 2012)




















Dringen 2011)















References

In vivo



Songur et al (2008)




Songur et al (2008)





In vitro




























2013)



























being exported


























(a) (b)
































































































Unzeta et al (2007)



Diabetes mellitus

and diabetic

complications




(2005) Obata (2006)




Peripheral nerve

sheath tumor






et al (2007)







































































GSH levels









































(Table 2)























2011 2013a b)



























References











101 51 ndash 64







Res 1122 191 ndash 200




52 593 ndash 600










149








RA126








62 1160 ndash 1166








1142







446












1111



4184 ndash 4193






407







Heidelberg































1316 ndash 1326








15 250 ndash 256










18 ndash 31










1914 ndash 1924



1168 ndash 1176





357












92 ndash 106






















1737









1878
















179 ndash 189















2997














8 ndash 12















Chem 285 23056 ndash 23063

















193
















83



















131 1722 ndash 1735



160 ndash 170











368






















































1282



141 ndash 148




































20087 ndash 20092









17 251 ndash 263


















2071







Sci 1110 382 ndash 388





















74























144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228

































formaldehyde





















































expressed (Table 1)


































formaldehyde




















































Tulpule et al 2013)





Enzymes

Species

Rat Mouse Human










Galter et al (2003)



Formate oxidation



































and Dringen 2012)




















Dringen 2011)















References

In vivo



Songur et al (2008)




Songur et al (2008)





In vitro




























2013)



























being exported


























(a) (b)
































































































Unzeta et al (2007)



Diabetes mellitus

and diabetic

complications




(2005) Obata (2006)




Peripheral nerve

sheath tumor






et al (2007)







































































GSH levels









































(Table 2)























2011 2013a b)



























References











101 51 ndash 64







Res 1122 191 ndash 200




52 593 ndash 600










149








RA126








62 1160 ndash 1166








1142







446












1111



4184 ndash 4193






407







Heidelberg































1316 ndash 1326








15 250 ndash 256










18 ndash 31










1914 ndash 1924



1168 ndash 1176





357












92 ndash 106






















1737









1878
















179 ndash 189















2997














8 ndash 12















Chem 285 23056 ndash 23063

















193
















83



















131 1722 ndash 1735



160 ndash 170











368






















































1282



141 ndash 148




































20087 ndash 20092









17 251 ndash 263


















2071







Sci 1110 382 ndash 388





















74























144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228

















formaldehyde




















































Tulpule et al 2013)





Enzymes

Species

Rat Mouse Human










Galter et al (2003)



Formate oxidation



































and Dringen 2012)




















Dringen 2011)















References

In vivo



Songur et al (2008)




Songur et al (2008)





In vitro




























2013)



























being exported


























(a) (b)
































































































Unzeta et al (2007)



Diabetes mellitus

and diabetic

complications




(2005) Obata (2006)




Peripheral nerve

sheath tumor






et al (2007)







































































GSH levels









































(Table 2)























2011 2013a b)



























References











101 51 ndash 64







Res 1122 191 ndash 200




52 593 ndash 600










149








RA126








62 1160 ndash 1166








1142







446












1111



4184 ndash 4193






407







Heidelberg































1316 ndash 1326








15 250 ndash 256










18 ndash 31










1914 ndash 1924



1168 ndash 1176





357












92 ndash 106






















1737









1878
















179 ndash 189















2997














8 ndash 12















Chem 285 23056 ndash 23063

















193
















83



















131 1722 ndash 1735



160 ndash 170











368






















































1282



141 ndash 148




































20087 ndash 20092









17 251 ndash 263


















2071







Sci 1110 382 ndash 388





















74























144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228






































and Dringen 2012)




















Dringen 2011)















References

In vivo



Songur et al (2008)




Songur et al (2008)





In vitro




























2013)



























being exported


























(a) (b)
































































































Unzeta et al (2007)



Diabetes mellitus

and diabetic

complications




(2005) Obata (2006)




Peripheral nerve

sheath tumor






et al (2007)







































































GSH levels









































(Table 2)























2011 2013a b)



























References











101 51 ndash 64







Res 1122 191 ndash 200




52 593 ndash 600










149








RA126








62 1160 ndash 1166








1142







446












1111



4184 ndash 4193






407







Heidelberg































1316 ndash 1326








15 250 ndash 256










18 ndash 31










1914 ndash 1924



1168 ndash 1176





357












92 ndash 106






















1737









1878
















179 ndash 189















2997














8 ndash 12















Chem 285 23056 ndash 23063

















193
















83



















131 1722 ndash 1735



160 ndash 170











368






















































1282



141 ndash 148




































20087 ndash 20092









17 251 ndash 263


















2071







Sci 1110 382 ndash 388





















74























144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228





























2013)



























being exported


























(a) (b)
































































































Unzeta et al (2007)



Diabetes mellitus

and diabetic

complications




(2005) Obata (2006)




Peripheral nerve

sheath tumor






et al (2007)







































































GSH levels









































(Table 2)























2011 2013a b)



























References











101 51 ndash 64







Res 1122 191 ndash 200




52 593 ndash 600










149








RA126








62 1160 ndash 1166








1142







446












1111



4184 ndash 4193






407







Heidelberg































1316 ndash 1326








15 250 ndash 256










18 ndash 31










1914 ndash 1924



1168 ndash 1176





357












92 ndash 106






















1737









1878
















179 ndash 189















2997














8 ndash 12















Chem 285 23056 ndash 23063

















193
















83



















131 1722 ndash 1735



160 ndash 170











368






















































1282



141 ndash 148




































20087 ndash 20092









17 251 ndash 263


















2071







Sci 1110 382 ndash 388





















74























144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228





























































































Unzeta et al (2007)



Diabetes mellitus

and diabetic

complications




(2005) Obata (2006)




Peripheral nerve

sheath tumor






et al (2007)







































































GSH levels









































(Table 2)























2011 2013a b)



























References











101 51 ndash 64







Res 1122 191 ndash 200




52 593 ndash 600










149








RA126








62 1160 ndash 1166








1142







446












1111



4184 ndash 4193






407







Heidelberg































1316 ndash 1326








15 250 ndash 256










18 ndash 31










1914 ndash 1924



1168 ndash 1176





357












92 ndash 106






















1737









1878
















179 ndash 189















2997














8 ndash 12















Chem 285 23056 ndash 23063

















193
















83



















131 1722 ndash 1735



160 ndash 170











368






















































1282



141 ndash 148




































20087 ndash 20092









17 251 ndash 263


















2071







Sci 1110 382 ndash 388





















74























144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228














































































GSH levels









































(Table 2)























2011 2013a b)



























References











101 51 ndash 64







Res 1122 191 ndash 200




52 593 ndash 600










149








RA126








62 1160 ndash 1166








1142







446












1111



4184 ndash 4193






407







Heidelberg































1316 ndash 1326








15 250 ndash 256










18 ndash 31










1914 ndash 1924



1168 ndash 1176





357












92 ndash 106






















1737









1878
















179 ndash 189















2997














8 ndash 12















Chem 285 23056 ndash 23063

















193
















83



















131 1722 ndash 1735



160 ndash 170











368






















































1282



141 ndash 148




































20087 ndash 20092









17 251 ndash 263


















2071







Sci 1110 382 ndash 388





















74























144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228














References











101 51 ndash 64







Res 1122 191 ndash 200




52 593 ndash 600










149








RA126








62 1160 ndash 1166








1142







446












1111



4184 ndash 4193






407







Heidelberg































1316 ndash 1326








15 250 ndash 256










18 ndash 31










1914 ndash 1924



1168 ndash 1176





357












92 ndash 106






















1737









1878
















179 ndash 189















2997














8 ndash 12















Chem 285 23056 ndash 23063

















193
















83



















131 1722 ndash 1735



160 ndash 170











368






















































1282



141 ndash 148




































20087 ndash 20092









17 251 ndash 263


















2071







Sci 1110 382 ndash 388





















74























144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228















1316 ndash 1326








15 250 ndash 256










18 ndash 31










1914 ndash 1924



1168 ndash 1176





357












92 ndash 106






















1737









1878
















179 ndash 189















2997














8 ndash 12















Chem 285 23056 ndash 23063

















193
















83



















131 1722 ndash 1735



160 ndash 170











368






















































1282



141 ndash 148




































20087 ndash 20092









17 251 ndash 263


















2071







Sci 1110 382 ndash 388





















74























144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228














8 ndash 12















Chem 285 23056 ndash 23063

















193
















83



















131 1722 ndash 1735



160 ndash 170











368






















































1282



141 ndash 148




































20087 ndash 20092









17 251 ndash 263


















2071







Sci 1110 382 ndash 388





















74























144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228

























1282



141 ndash 148




































20087 ndash 20092









17 251 ndash 263


















2071







Sci 1110 382 ndash 388





















74























144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228






















144 810 ndash 823







214









1041




265 7907 ndash 7913



1 ndash 3


Nutr 30 57 ndash 81




































430






























Sci USA 104 19226 ndash 19231









1647 193 ndash 199























228






















228










journal of neurochemistry

Documents