scpa610 cellular and molecular pathology from
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SCPA610–Cellular and molecular pathology from
chemical and physical injuries
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Associate Professor Dr. Wannee Jiraungkoorskul
Department of Pathobiology, Faculty of Science, Mahidol University
Tel: 02-201-5563, E-mail: wannee.jir@mahidol.ac.th
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Objectives
• Explain the definition and classification of
environmental hazard.
• Discuss the cellular and molecular mechanism of lead
metal.
• Discuss the cellular and molecular effect of ultraviolet
radiation.
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Environmental hazard : Definition
• An environmental hazard is a substance, state or event which has
the potential to threaten the surrounding natural environment / or
adversely affect people's health, including pollution and natural
disasters such as storms and earthquakes.
• Any single or combination of toxic chemical, biological, or physical
agents in the environment, resulting from human activities or
natural processes, that may impact the health of exposed subjects,
including pollutants such as heavy metals, pesticides, biological
contaminants, toxic waste, industrial and home chemicals.
• Hazards can be categorized in four types:
• Chemical
• Physical
• Biological
• Psychosocial
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Environmental hazard : Classification
Chemical hazard• Chemical hazards are defined in the Globally Harmonized
System and in the European Union chemical regulations.
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• Anthrax
• Antibiotic agents in animals destined
for human consumption
• Arsenic - a contaminant of fresh water
sources (water wells)
• Asbestos - carcinogenic
• DDT
• Carcinogens
• dioxins
• Endocrine disruptors
• Explosive material
• Fungicides
• Furans
• Heavy metals
• Herbicides
• Hormones in animals destined for
human consumption
• Lead in paint
• Mercury
• Mutagens
• Pesticides
• Polychlorinated biphenyls
• Radon and other natural sources
of radioactivity
• Soil pollution
• Tobacco smoking
• Toxic waste
• Radon
Physical hazard
• A physical hazard is a type of occupational hazard that involves
environmental hazards that can cause harm with or without contact.
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• Cosmic rays
• Earthquake
• Electromagnetic fields
• E-waste
• Floods
• Fog
• Lightning
• Noise pollution
• Quicksand
• Ultraviolet light
• vibration
• X-rays
Biological hazard
• Biological hazards, also known as biohazards, refer to biological
substances that pose a threat to the health of living organisms,
primarily that of humans. This can include medical waste or
samples of a microorganism, virus or toxin (from a biological
source) that can affect human health.
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• Allergies
• Arbovirus
• Avian influenza
• Bovine spongiform
encephalopathy (BSE)
• Cholera
• Ebola
• Food poisoning
• Malaria
• Molds
• Pollen for allergic people
• Rabies
• Severe acute respiratory
syndrome (SARS)
• Sick building syndrome
Psychosocial hazard
• Psychosocial hazards are basically causing stress to a worker or
workplace stressors.
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Heavy metal
• A heavy metal is defined as trace element that has a
relatively high density (≥ 3g/cm3 ).
Copper Lead Arsenic Mercury
http://en.wikipedia.org/wiki/Heavy_metal_(chemistry) 9
http://www.elementsdatabase.com/10
• Heavy metals generate oxidizing radicals •OH (hydroxyl radicals)
from H2O2 (hydrogen peroxide) and superoxide (•O2-) leading to
metal-induced carcinogenesis.
Heavy metal reaction
The reduction of ferric ion to ferrous
Fe3+ + •O2− → Fe2+ + O2
Fe2+ + H2O2 → Fe3+ + OH− + •OH
•O2- + H2O2 → •OH + OH- + O2
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Lead• Lead symbol Pb (Latin: plumbum) and atomic number 82.
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• Lead paint
• Food container
• Petrol (tetraethyl lead)
• Toy and Jewelry
• Herbal remedy
Uses and sources of lead
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Lead in Klity Creek, Kanchanaburi
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Lead in shrimp
(Thairat newspaper 20 Feb 2002)
Lead in fish
(Thairat newspaper 12 May 2002)
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http://www.epa.nsw.gov.au/leadsafe/body.htm
Lead Lines
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Basophilic stippling
Microcytic, hypochromic hemolytic anemia
• Basophilic stippling refers to erythrocytes display small dots at the periphery.
• These dots represent accumulations of rRNA and is associated with several conditions, including:anemia, lead poisoning, beta thalassemia
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• Lead poisoning (Latin plumbum, lead ; plumbism, colica
pictonum, saturnism, Devon colic, or painter's colic) is a medical
condition caused by increased levels of the heavy metal lead in the
body.
• Radiodense “lead lines” in children, due to interference with
normal remodeling of calcified cartilage
• “Lead lines” of gums also seen - hyperpigmentation due to excess
lead
Lead toxicity
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Lead lines
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ALA = Aminolevulinic acidZn PP = Zinc protoporphyrin Lead toxicity
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Environ mental Health Perspectives 1974; 7: 121–127.
1-1974
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• Objective: In vitro study of lead inclusion bodies in renal tubular cells of
rat.
• Results: The inclusion bodies are insoluble in physiological media but
dissolved in urea and sodium deoxycholate.
• They contain about 40-50 µg of lead/mg protein but only about 10% of
this is tightly bound. They also contain calcium, iron, zinc, copper, and
cadmium.
• The protein has a molecular weight of 27,500 and is rich in glutamic and
aspartic acids, glycine and cystine.
• Rat proximal tubule with intranuclear inclusion body characterized by dense
central core and fibrillary margin. A small inclusion body is located within
invaginated nuclear membrane.
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Journal of Biological Chemistry 1982; 257: 11802–11807.
2-1982
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• Objective: To investigate the characteristic of lead intranuclear
inclusion bodies from rat kidney.
• Results: It has the protein molecular weight of 32,000 and an
isoelectric point of 6.3
• It has been suggested that the inclusion bodies have a protective
effect in lead-intoxicated animals.
• TEM from a rat fed a diet including
1% lead acetate for 13 weeks reveals a
large inclusion body in kidney.
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• Three intranuclear inclusion bodies.
• The largest one surrounded by a fibrous cortex.
• L = nuclear pore complex-lamina
• M = mitochondria
• C = collagen fibers
• H = homogeneous material which appears in
the shape of circles and ribbons
Biological Trace Element Research 1999; 75: 245–251.
3-1999
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• Objective: To study the histological and histochemical techniques
on the lead intranuclear bodies in rat kidney.
• Results: The intranuclear bodies proved to be lead lipoprotein
complexes containing sulfyhydryl groups and are basic in nature
with orthochromatic, eosinophilic, argyrophilic, osmophilic,
fuchsinophilic and sudanophilic characteristics.
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4-2004
Histology Histopathology 2004; 19: 69-76.
• Objective: To investigate 24 h subcytotoxic doses of lead nitrate
(EC10 = effective concentration 10%) in renal cell line.
• Results: Inclusion bodies in the form of irregular granules of
varying size in both cytoplasm and lysosomes.
• Increase number of phagolysosomes and myeline figures
Control Buffalo Green Monkey renal cells have variable number of microvilli, spherical or oval mitochondria, abundant chromatin in nucleus
BGM-Non-lead expose
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a = inclusion bodies in lysosomes b = free in the cytoplasmic matrix c = ring-shaped inclusion bodies and myelin figures d = loss of mitochondrial cristae e = intranuclear inclusion
BGM-Lead expose
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a = inclusion bodies in lysosomes b = free in the cytoplasmic matrix c = ring-shaped inclusion bodies and myelin figures d = loss of mitochondrial cristae e = intranuclear inclusion
BGM-Lead expose
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a = ring-shaped intracytoplasmic inclusion bodies in lysosomes b = free in the cytoplasmic matrix and myelin figures c and d = intranuclear inclusion
VERO-Lead expose
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a = ring-shaped intracytoplasmic inclusion bodies in lysosomes b = free in the cytoplasmic matrix and myelin figures c and d = intranuclear inclusion
VERO-Lead expose
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5-2008
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• Lead’s movement through the blood brain barrier. Lead ions are able to permeate the blood brain barrier via ion channels. Lead interferes in the communication between astrocytes and endothelial cells
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6-2009
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Abstract• Objective: To investigate chronic lead intoxication (500 ppm in
drinking water) during 7 months on the structure, function and
biochemical properties of rat proximal tubule.
• Results: Increased lead concentration in kidney, Reduction of
calcium and amino acids uptake, Oxidative damage, Glucosuria,
proteinuria, hematuria and reduced urinary pH.
• Inclusion bodies were found in the cytoplasm and in mitochondria.
• Loss of apical microvillae, decrement of the luminal space,
formation of atypical intercellular contacts and adhesion structure.
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tl = tubular lumen mt = mitochondria am = apical membrane n = nuclei d = detritus
Proximal tubule: Non-lead expose Lead expose
Reduction of lumen, microvillus and lost of the brush border of renal proximal tubules
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Micrographs show alteration in the morphology of cellular organelles (mitochondrial swelling).
Lead expose
tl = tubular lumen am = apical membrane bm = basal membrane mt = mitochondria n = nuclei d = detritus
Proximal tubule: Non-lead expose
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Micrographs show nuclei with intranuclear inclusion bodies .
mt = mitochondria n = nuclei ib = inclusion bodies
Lead expose Proximal tubule: Non-lead expose
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Inclusion bodies in nucleus (a), mitochondria and cytoplasm (b) of proximal tubule cells of rats with intraperitoneal administration of lead (subacute intoxication).
Mitochondria (mt); nuclei (n); inclusion bodies (ib)
Lead expose Lead expose
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(a) Lost of apical microvillus and changes in membrane integrity.
Lead expose Lead expose
tubular lumen (tl); basal membrane (bm); nuclei (n)
(b) Collapse of tubule structure with intercellular apposition.
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(c) Formation of intercellular adhesion junctions between apposed cells.
Lead expose Lead expose
Tubular lumen (tl); nuclei (n). Arrows indicate the cell adhesion structures in abnormal junctions.
(d) Abnormal junction apical-apical membrane with formation of intercellular junctions.
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(e) Lost of lumen and sealing of apical membranes. basal membrane (bm). Arrows indicate the cell adhesion structures in abnormal junctions.
Lead expose
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7-2012
50Interdiscrplinary Toxicology 2012; 5: 47-58.
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Ultraviolet light : Definition
• Ultraviolet (UV) is an electromagnetic radiation with a wavelength
from 10 nm to 400 nm, shorter than that of visible light but longer
than X-rays.
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Ultraviolet light
• It is also produced by electric arcs and specialized lights, such
as mercury-vapor lamps, tanning lamps, and black lights.
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Mercury vapor street light
Electric arcs
Black light tubes
Health effects of UV radiation
56https://sites.google.com/site/uvraysallyouneedtoknow/_/rsrc/1291158047136/general-information-1/uv_ray_graphic_560w.jpg
UVA = Aging ray
UVB = Burning ray
Case study
• Unilateral Dermatoheliosis
• New England Journal of
Medicine 2012; 366:e25
• A 69-year-old man presented
with a 25-year history of
gradual, asymptomatic
thickening and wrinkling of
the skin on the left side of his
face.
• The physical examination
showed hyperkeratosis with
accentuated ridging, multiple
open comedones, and areas of
nodular elastosis.57
• Histopathological analysis showed an accumulation of elastolytic
material in the dermis and the formation of milia within the vellus hair
follicles.
• Findings were consistent with the Favre–Racouchot syndrome of
photodamaged skin, known as dermatoheliosis.
• The patient reported that he had driven a delivery truck for 28 years.
• Ultraviolet A (UVA) rays transmit through window glass, penetrating
the epidermis and upper layers of dermis.
• Chronic UVA exposure can result in thickening of the epidermis and
stratum corneum, as well as destruction of elastic fibers.
• This photoaging effect of UVA is contrasted with photocarcinogenesis.
• Although exposure to ultraviolet B (UVB) rays is linked to a higher
rate of photocarcinogenesis, UVA has also been shown to induce
substantial DNA mutations and direct toxicity, leading to the formation
of skin cancer.
• The use of sun protection and topical retinoids and periodic monitoring
for skin cancer were recommended for the patient.58
The Translational Basis of Human Cutaneous Photoaging
• Comparison between youthful skin (as normal), skin from an older
individual showing loss of rete ridges and thinning of dermal collagen
bundles, and photodamaged skin with superimposed aggregates of
amorphous, pale blue-gray elastin in the superficial dermis.
59The American Journal of Pathology, Vol. 174, No. 2, February 2009
Histology of photoaged skin
• The predominant
histological finding of
photodamaged skin is
solar elastosis, which is
basophilic degeneration of
elastotic fibers in the
dermis.
• Solar elastosis separates
from the epidermis by a
narrow band of normal-
appearing collagen (grenz
zone) with collagen fibers
arranged horizontally.
60https://www.intechopen.com/books/molecular-mechanisms-of-the-aging-process-and-rejuvenation/molecular-mechanisms-of-skin-aging-and-rejuvenation
Possible Involvement of Basement Membrane Damage in
Skin Photoaging
• Basement membrane (BM) structure at the dermal–epidermal junction (DEJ) and
damaged BM structure. The DEJ is visualized at stepwise magnification from light
microscopic scale to transmission electron microscopic scale.
• Hemidesmosome (HD), anchoring filament (af), lamina densa, and anchoring fibrils (AF)
are observed and form a special anchoring complex for the attachment of epidermis to
dermis.
61Journal of Investigative Dermatology 2009; 4: 2-7.
Possible Involvement of Basement Membrane Damage in
Skin Photoaging
• DEJ of human skin: Disruption and reduplication of the lamina densa can be seen at the
DEJ in the sun-exposed cheek skin of a 30-year-old woman, whereas neither duplication
nor disruption can be observed in the sun-protected abdomen skin of a 34-year-old
woman.
62Journal of Investigative Dermatology 2009; 4: 2-7.
63https://www.intechopen.com/books/molecular-mechanisms-of-the-aging-process-and-rejuvenation/molecular-mechanisms-of-skin-aging-and-rejuvenation
Schematic representation of pathogenesis of
premature/extrinsic skin aging
ROS: reactive oxygen species, AhR: arylhydrocarbon receptor, NF-kB: nuclear factor kappa‐B, IL-1:
interleukin‐1, TNF-α: tumor necrosis factor, CCN1: cysteine-rich protein 61, MAPK: mitogen‐activated
protein kinase, AP‐1: activator protein 1, and MMPs: matrix metalloproteinases.
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Reference
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