endocrine disrupting compounds

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Endocrine Disrupting Compounds Any exogenous agent that causes adverse health effects in an intact organism, or its progeny, consequent to changes in endocrine function.

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Endocrine Disrupting Compounds. Any exogenous agent that causes adverse health effects in an intact organism, or its progeny, consequent to changes in endocrine function. Specifically…. - PowerPoint PPT Presentation

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Page 1: Endocrine Disrupting Compounds

Endocrine Disrupting Compounds

Any exogenous agent that causes adverse health effects in an intact organism, or its

progeny, consequent to changes in endocrine

function.

Page 2: Endocrine Disrupting Compounds

Specifically….

Any exogenous chemical that interferes with the production, release, transport, binding, action, or elimination of natural hormones responsible for the maintenance of homeostasis and regulation of developmental processes.

Page 3: Endocrine Disrupting Compounds

Chemicals: Wide Variety -

Pesticides Herbicides Fungicides Plasticizers Surfactants Organometals Halogenated

PAHs Phytoestrogens

At Least 4 Modes of Action

1. Serving as steroid receptor ligands.

2. Modifying steroid hormone-metabolizing enzymes.

3. Perturbing hypothalamic pituitary release of trophic hormones.

4. Miscellaneous or unknown. Interactions with the

functions of estrogens, androgens, and thyroid hormones have been the most highly studied.

Page 4: Endocrine Disrupting Compounds

Prototypical Exoestrogens: Note the Diverse Chemical Structures

Page 5: Endocrine Disrupting Compounds
Page 6: Endocrine Disrupting Compounds

Nuclear Receptor Super Family

Steroid Receptors

Androgen R. Progesterone R. Glucocorticoid R. Mineralocorticoid R.

Estrogen Receptors

Thyroid Receptors

Thyroid Hormone R. Retinoic Acid R. RXR Vitamin D R.

Page 7: Endocrine Disrupting Compounds
Page 8: Endocrine Disrupting Compounds

Mechanisms of Endocrine Disruption

Binding and activating the estrogen receptor (thereby acting as an estrogen)

  Binding but not activating the

estrogen receptor (thereby acting as an anti-estrogen

Page 9: Endocrine Disrupting Compounds

Mechanisms (Continued)

Binding other receptors (e.g., androgen receptors in males) activating the receptor thereby acting

like an androgen not activating the receptor thereby

acting like an anti-androgen Modifying the metabolism of

natural hormones

Page 10: Endocrine Disrupting Compounds

Mechanisms (Continued)

Modifying the number of hormone receptors in a cell (reduce or increase the number)

Modify the production of natural hormones

Interactions with steroid binding proteins

Page 11: Endocrine Disrupting Compounds

Individual Mechanisms

Binding and activating the estrogen receptor (thereby acting as an estrogen) Exogenous estrogens can bind to the

estrogen receptor but the affinity with which these exogenous estrogens bind to the receptor is usually only a fraction of the binding affinity of 17 B-estradiol.

Page 12: Endocrine Disrupting Compounds

Xenobiotics may affect transcription and signal transduction.

Can act through both i) receptor-mediated and non-receptor-mediated mechanisms.e.g., genistein is a weak est receptor agonist, but can also modulate the activity of tyr kinases and DNA topoisomerases.

Page 13: Endocrine Disrupting Compounds

Estrogen Receptor (Continued) Compounds may act as either estrogens

or anti-estrogens depending on the cellular environment. Certain hydroxylated PCBs are able to bind

the estrogen receptor and activiate gene transcription at high concentrations.

However, these PCB metabolites are weak agonists at appropriate concentrations, and they may have the potential to interfere by competing with endogenous estrogens for binding sites.

Page 14: Endocrine Disrupting Compounds
Page 15: Endocrine Disrupting Compounds

Estrogen Receptor (cont’d) We have additive effects: several

chemicals binding and activating the estrogen receptor – their combined effects will be additive.e.g., butylbenzyl phthalate and di-n-butyl phthalate can add their effects to any natural estrogen present.

Synergism, however, has not yet been demonstrated.

Page 16: Endocrine Disrupting Compounds

Estrogen Receptor (Continued) Hydroxylated PCBs: altered temperature

dependent sex determination in turtles. It has been suggested that PCBs and other

combinations of weak environmental estrogens such as the insecticides dieldrin and toxaphene, have synergistic activities that are mediated by the estrogen receptor.

160 to 1600 x more potent than either of the individual chemicals alone

other studies just suggest additive interactions / Still a controversy on this subject.

Page 17: Endocrine Disrupting Compounds

Estrogen Receptor (cont’d) PCBs: learning and locomotor deficits

in juvenile rodents and monkeys.e.g., Arochlor 1254

hypothyroidism and testes weight and sperm production in rats

Stunted growth Cognitive deficits Delayed eye opening Hyperactivity Auditory deficits

Page 18: Endocrine Disrupting Compounds

Individual Mechanisms Binding but not activating the

estrogen receptor (thereby acting as an anti-estrogen = ______________?

E.g., Est receptor: tamoxifen is an anti-breast cancer drug, but is an agonist in preservation of bone mineral density.

E.g., Androgen receptor antagonists (some insecticides) cause demasculinizing traits.

Page 19: Endocrine Disrupting Compounds

Individual Mechanisms E.g., Glucocorticoid receptor:

antagonists adversely affect growth and development.

Mixed agonists/antagonists. Binding and activation or lack

of activation depends on the: Affinity for the receptor Receptor number [xenoagonist] [endogenous hormone]

Page 20: Endocrine Disrupting Compounds

The effects are predicted to be summed.

Page 21: Endocrine Disrupting Compounds

Individual Mechanisms Binding other receptors (e.g., androgen

receptors in males) DDT: has been reported to induce

reproductive abnormalities, particularly in wildlife species such as the American alligator, birds, and laboratory rodents.

The breakdown product of DDT, DDE, is able to act as an anti-androgen by blocking the testosterone receptor and producing effects that are phenotypically similar to those caused by estrogens.

Page 22: Endocrine Disrupting Compounds

Other Receptors (Continued) Retinoid X receptor forms heterodimers

with either the thyroid hormone receptor or with the peroxisome proliferator activated receptor and these heterodimers can bind to the estrogen response elements on DNA.

While these heterodimers are capable of binding to the estrogen response elements on DNA they are not capable of increasing gene expression.

Page 23: Endocrine Disrupting Compounds

Other Receptors (Continued) Instead, binding of the heterodimers to

the estrogen response elements results in decreased transcription due to competition with the estrogen receptor for the estrogen response elements.

The heterodimers may act as a specific inhibitor of estrogen receptor mediated gene transcription and ER-mediated signal transduction.

Page 24: Endocrine Disrupting Compounds

Other Receptors (cont’d)

All of this suggests that there is receptor cross-reactivity of the appropriate response elements.

Exogenous compounds have great broad receptor specificity across the nuclear receptor superfamily.

Page 25: Endocrine Disrupting Compounds

Individual Mechanisms Modifying the metabolism of natural

hormones Endocrine disrupters may affect homeostasis

through alterations in steroid synthesis or metabolism. Therefore, any substance that modifies either the enzymes involved in steroid biosynthesis and/or metabolism of steroids could be classified as an endocrine disrupter.

A number of compounds acting through the Ah receptor have demonstrated anti-estrogenic activities. TCDD is one of these compounds.

Page 26: Endocrine Disrupting Compounds

Individual Mechanisms:Modifying the metabolism of

natural hormones

Some chemicals, e.g., lindane and atrazine, can affect the metabolic pathway of estradiol producing more estrogenic metabolites.

Page 27: Endocrine Disrupting Compounds

Individual Mechanisms:Modifying the metabolism of natural

hormones

Effects of EDCs on Hormone Synthesis and Metabolism:A cpd may adversely affect the levels of critical endogenous hormones by inducing or inhibiting biosynthetic or metabolic enzyme activity.e.g., phytoestrogens can interact with 17-β-DH, which regulates levels of 17-β-estradiol or estrone.

Page 28: Endocrine Disrupting Compounds

Individual Mechanisms:Modifying the metabolism of natural

hormones

phytoestrogens can modulate overall estrogen levels in addition to acting as a ligand for the estrogen receptor.

E.g., perchlorate competitively inhibits thyroid I uptake disrupts thyroid hormone synthesis.

Page 29: Endocrine Disrupting Compounds

Timing of Exposure Sensitivity of an individual to

gonadal steroids depends on where (s)he is temporally in life.

Thus, a chemical may have little-to-no impact on a young/older adult, but may have profound development-disrupting effects if exposure occurs in utero or during puberty.

Page 30: Endocrine Disrupting Compounds

Timing of Exposure (cont’d)

E.g., PCBs and dioxin affect development more during gestational than during lactational exposure.

Generally, sensitivity to EDCs is greater during fetal and perinatal exposure than during adulthood.

However, sometimes, fetal serum-binding proteins may protect the fetus from harmful EDCs (lower sensitivity).

e.g., α-fetoprotein binding 17-β-estradiol protects the fetal male rat from maternal estrogens.

Page 31: Endocrine Disrupting Compounds

Timing of Exposure (cont’d)

IMPORTANT: Estrogen levels are NOT feedback regulated in a typical homeostatic mechanism (- feedback).

RATHER, there is a feed-forward mechanism (+ feedback)

[estradiol] throughout most of pregnancy in rodents and humans.

Page 32: Endocrine Disrupting Compounds

Timing of Exposure (cont’d)

Thus, an exogenous dose of any estrogen agonist will be additive to the endogenous level, be cause there is NO (-) feedback to endogenous hormone production in a compensatory way.

Page 33: Endocrine Disrupting Compounds

Timing of Exposure (cont’d)

Also, in rodents and humans, the specific estradiol binding proteins, α-fetoprotein, test/estradiol binding protein also steadily during pregnancy to protect the fetus from the high levels of circulating estrogens;

C.f., rodent littermates influenced by neighbors’ gender.

Page 34: Endocrine Disrupting Compounds

Timing of Exposure (cont’d)

Xenoestrogens that fail to bind to these proteins have increased bioavailability and therefore, increased receptor-binding ability. But…,

E.g., DES has ~100-fold lower affinity for est receptor than does E2.

E.g., Fungal estrogen, zearalenone, is ~0.66% as potent as E2 for the uterotrophic responses in humans; 5% in rats.

Page 35: Endocrine Disrupting Compounds

Individual Mechanisms:Modifying the metabolism of natural

hormones

Other chemicals activate enzymes, which accelerate the metabolism of hormones, thereby disrupting their natural state.

E.g., the testes contain specific enzymes to metabolize estrogens to a metabolite, which can no longer bind the estrogen receptor.

Page 36: Endocrine Disrupting Compounds

Individual Mechanisms:Modifying the metabolism of natural

hormones

However, these enzymes are compromised by a xenoestrogen, metabolism , exposure of the testes to estrogen problems during fetal development.

Page 37: Endocrine Disrupting Compounds

Metabolism (Continued) A number of genes have been shown to

be induced by the Ah receptor including CYP1A1, CYP1A2, and CYP1B1, all of which are involved in the oxidative metabolism of 17B-estradiol.

Therefore, decreased estrogen bio-availability due to increased estrogen metabolism may explain some of the anti-estrogenic activities observed with Ah receptor ligands.

Page 38: Endocrine Disrupting Compounds

Individual Mechanisms Modifying the number of hormone receptors

in a cell (reduce or increase the number) Following TCDD pretreatment, cells in culture

display decreased estrogen receptor levels. Retinoids have also been shown to down-regulate estrogen receptor levels.

Therefore, any mechanism that significantly decreases estrogen receptor levels within the cell may limit the magnitude or duration of exposure.

Page 39: Endocrine Disrupting Compounds

Modifying the production of natural hormones

Chemicals can interfere with this process in the thyroid, immune, and nervous systems.

Page 40: Endocrine Disrupting Compounds

Individual Mechanisms Interactions with steroid binding proteins

Proteins such as serum albumin, sex hormone binding globulin, and alpha-fetoprotein bind estrogens.

These proteins could play a role by decreasing the bio-availability of endocrine disrupters or, alternatively, by increasing the bio-availability of more potent estrogens through displacement of the endogenous hormones by the endocrine disrupter.

Page 41: Endocrine Disrupting Compounds

Specific Examples of Endocrine Disruption

Tributyltin: Causes imposex and intersex in

gastropod mollusks Neogastropods have separate sexes

but it was observed that many female dogwhelk from certain areas of the United Kingdom had a penis-like structure behind the right tentacle.

Page 42: Endocrine Disrupting Compounds

Tributyltin (Continued) This was also seen later in other gastropod

species in the eastern United States. These gastropods also had a vas deferens (sperm duct) and a convoluted gonoduct. The term “imposex” was coined to describe the superimposition of male characters onto females.

It was demonstrated that levels of imposex were elevated close to marinas, a feature attributed to the presence of anti-fouling paints.

Page 43: Endocrine Disrupting Compounds

Tributyltin Results of experimental exposure of

gastropods to TBT confirmed this idea. The initial stages of imposex appear at a TBT

[ ] of 1.0 ng/L and the syndrome is irreversible.

At [ ]s exceeding 5 ng/L vas deferens formation progresses further, overgrowing the genital papilla blocking the vulva and invading the oviduct. Females in this condition are sterile because egg capsules cannot be expelled.

Page 44: Endocrine Disrupting Compounds

Tributyltin

In some species, the appearance of a penis and sperm duct appears to cause little interference with reproductive activity of the affected female.

In other species the structure of the oviduct may be so modified that breeding is inhibited resulting in population decline and extinction.

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Mechanism of TBT Action Mollusks contain vertebrate-like

steroids, and molluskan steroidogenesis is also similar to the vertebrate plan. Cholesterol -----------

Androstenedione------------ testosterone or estrone

Testosterone can also be converted to 17-β-estradiol

It is hypothesized that TBT causes imposex and intersex in gastropods by interfering with steroid biosynthesis.

Page 46: Endocrine Disrupting Compounds

Mechanism (Continued)

Inhibition of CYP19A1 hypothesis: In a study of gastropods exposed to

TBT where the steroids were measured in the body, estrogen levels were not affected but testosterone levels were greatly increased. Inhibition of conversion of testosterone to 17-β-estradiol.

NET EFFECT: Testosterone

Page 47: Endocrine Disrupting Compounds

Mechanism (Continued) Probably a competitive type of inhibition

and not a total inhibition of the CYP enzyme. TBT and testosterone compete for the same

CYP. With increased levels of TBT in the body, less testosterone is converted to 17-β-estradiol and more testosterone remains causing the imposex condition.

Using a known inhibitor of CYP19A1 also causes imposex in tested species.

NET EFFECT: Testosterone

Page 48: Endocrine Disrupting Compounds

Mechanisms (Continued)

Second Hypothesis Another hypothesis says that TBT

metabolites compete with testosterone for sulfur conjugation (phase II reaction) and therefore less testosterone is excreted. Testosterone builds up in the body because of less sulphate conjugation and less excretion.

NET EFFECT: Testosterone

Page 49: Endocrine Disrupting Compounds

Effects of PCBs on sex determination in Rainbow Trout:

Hatchling fish were exposed to Arochlor 1260 in 1, 5, and 20 mg/L solutions. Animals in the 1 and 20 mg/L treatments

accumulated the same amount of PCBs in the body (~ 2.1 to 2.5 μg/g tissue).

No effect of treatment on survival was observed and although more females were produced in the treatment groups compared to the control groups, the difference was not statistically significant.

Page 50: Endocrine Disrupting Compounds

PCBs (Continued) Treatment groups did have a

significantly greater proportion of grossly visible gonad abnormalities in females compared to controls (Lack of oocyte development).

Tissue concentrations of 2.1 to 2.5 μg/g tissue are typically found in nature and concentrations can reach 10 μg/g tissue near point sources of PCB exposure.

Page 51: Endocrine Disrupting Compounds

General Sexual Disruption in Fish:

Rivers and estuaries throughout the world are repositories for enormous amounts of industrial and domestic waste containing thousands of chemicals, both natural and human-made.

Page 52: Endocrine Disrupting Compounds

Sex Disruption (Continued) In fish, exposure to estrogens and their mimics

has been shown to cause the synthesis and secretion of vitellogenin, a female-specific protein, in male fish.

Male fish, which do not usually express the vitellogenin gene and hence have no vitellogenin in their plasma, were held in cages placed in effluent channels of sewage treatment works close to where effluent entered the river, and at various distances downstream, including sites where water was extracted for domestic use.

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Sex Disruption (Continued)

After only one week in effluent, plasma vitellogenin concentrations had risen one thousand-fold or more, and by three weeks the concentrations were in the tens of mg/ml. At this time vitellogenin was the major blood protein comprising more than 50% of total plasma protein.

Page 54: Endocrine Disrupting Compounds

Second Study on Fish Jobling et al. 1998 used wild populations of

roach, a river fish found in the UK. Sampled fish both upstream and downstream of sewage treatment works on each of eight rivers. Control sites were lakes or canals that did not receive treated sewage.

Histological examination of the fish showed a large proportion of the males were in fact intersex, as defined by the simultaneous presence of both male and female gonad characteristics.

Incidence ranged from 4% in a laboratory group and at one control site to 100% at two effluent downstream sites.