Toxicology Concepts (Lecture derma, neuro, endocrine, heavy metals, heamo)

What are oligodendrocytes?

• a type of glial cell found in the central nervous system (CNS)

• main function is to produce the myelin sheath, a fatty layer that wraps around the axons of neurons.

What are ependymal cells?

• Specialized ependymal cells in structures called the choroid plexus secrete CSF, which cushions the brain and spinal cord and helps maintain a stable environment

What do Schwann and satellite cells do?

• Each Schwann cell wraps around a single segment of one axon, forming the myelin sheath.

• Regulate the chemical environment around neurons (similar to astrocytes in the CNS).

Symptoms of neurodegenrative disorders

• memory loss

• cognitive impairment

• neuronal inflammation

• mitochondrial dysfunction

• oxidative stress

neuron diagram

Afferent vs Efferent neurons

Afferent neurons: innervated tissue to CNS

Efferent neurons: CNS to innervated tissue

Mechanisms of protein oxidation

• Carbonylation: Addition of carbonyl groups (–CO) to amino acid side chains (especially lysine, arginine, proline, threonine)

• Disulfide bond formation: Between cysteine residues

• Oxidation of methionine or tryptophan

• Fragmentation or aggregation of proteins

6 common ROS and RNS

•superoxide (O2•−),

•hydrogen peroxide (H2O2),

•hydroxyl radical (HO•),

•hypochlorous acid (HOCl),

•nitric oxide (NO) and

•peroxynitrite (ONOO-)

What enzymes produce ROS extracellulary?

NADPH oxidases (NOX)

myeloperoxidase (MPO)

xanthine oxidase (XO)

NADPH oxidases (NOX)

• Transfer electrons from NADPH to oxygen (O₂) to form superoxide (O₂•⁻)

• Found in phagocyte membranes

myeloperoxidase (MPO)

• Uses hydrogen peroxide (H₂O₂) to produce hypochlorous acid (HOCl)

• Granules of neutrophils and monocytes.

Xanthine Oxidase

• Catalyzes the oxidation of hypoxanthine to xanthine, and then xanthine to uric acid, producing superoxide (O₂•⁻) and hydrogen peroxide (H₂O₂) in the process.

• Mainly in liver and vascular endothelial cells.

What does nitric oxide synthase make?

Nitric Oxide

Functions of Nitric Oxide

🫀 1. Vasodilation (Blood Vessel Relaxation)

🧠 2. Neurotransmission (Brain Signaling)

3. Immune Defense

⚠ 4. Cell Signaling and Regulation

⛔ 5. Pathological Roles

Functions of Nitric Oxide (vasodilation, neurotransmission, immune defense)

🫀 1. Vasodilation (Blood Vessel Relaxation)

• It activates guanylate cyclase in smooth muscle cells → increases cGMP → causes vasodilation.

🧠 2. Neurotransmission (Brain Signaling)

• It diffuses freely across membranes and modulates neural activity without needing receptors.

🧫 3. Immune Defense

• Produced by inducible nitric oxide synthase (iNOS) in macrophages and other immune cells.

• NO reacts with superoxide (O₂•⁻) to form peroxynitrite (ONOO⁻), a powerful molecule that helps kill bacteria, viruses, and tumor cells.

Functions of Nitric Oxide (Cell signalling, Pathological roles)

⚠ 4. Cell Signaling and Regulation

• Regulates platelet aggregation (prevents unwanted blood clotting).

• Influences inflammation, apoptosis, and cell proliferation.

⛔ 5. Pathological Roles

• Too little NO: can contribute to hypertension, atherosclerosis, and erectile dysfunction.

• Too much NO (especially from iNOS): can cause inflammation, tissue damage, and contribute to neurodegenerative diseases (e.g., Parkinson’s, Alzheimer’s).

Three types of NOS

• endothelial NOS

• inducible NOS

• neuronal NOS

endothelial NOS

• Location: Endothelial cells lining blood vessels

• Type: Constitutive (always present), calcium/calmodulin-dependent

• Function:

  • Produces low levels of NO for vasodilation

  • Maintains vascular tone and blood pressure

  • Inhibits platelet aggregation and leukocyte adhesion

• Protective Role: eNOS-derived NO is anti-atherogenic (prevents atherosclerosis)

Neuronal NOS

• Location: Neurons in the brain, spinal cord, and peripheral nerves

• Type: Constitutive, calcium/calmodulin-dependent

• Function:

  • Produces NO as a neurotransmitter/neuromodulator

  • Regulates synaptic plasticity, learning, memory, and neurovascular coupling

• Also found in: Skeletal muscle, where it may regulate blood flow during muscle activity

Inducible NOS (iNOS or NOS2)

• Location: Macrophages, neutrophils, and other immune or damaged cells

• Type: Inducible (not normally present; expression triggered by inflammation, cytokines like TNF-α or IFN-γ)

• Function:

  • Produces large amounts of NO as part of the immune response

  • NO combines with superoxide (O₂•⁻) to form peroxynitrite (ONOO⁻), which kills pathogens and tumor cells

• Unregulated iNOS activity: Can cause tissue damage and contribute to chronic inflammation

diagram of oxidative stress pathway

pro-oxidants

Pro-oxidants are substances that promote oxidation in cells by either generating reactive oxygen species (ROS) or inhibiting antioxidant systems.

Define lipid peroxidation

is a free radical oxidation of polyunsaturated fatty acids such as linoleic acid or arachidonic acid.

What products arise from lipid peroxidation?

How do reactive aldehydes hurt us?

1. Protein modification

• Aldehydes form covalent adducts with amino acid side chains (especially cysteine, histidine, lysine).

• This changes protein structure, function, and stability.

• Leads to loss of enzyme activity, misfolding, or aggregation (linked to diseases like Alzheimer’s).

2. DNA damage

• Reactive aldehydes can form DNA adducts → base modifications or mutations.

• MDA and acrolein can cause frameshifts, cross-links, or strand breaks.

• May contribute to cancer initiation and progression.

3. Membrane damage

• Lipid aldehydes further disrupt membrane integrity, increasing permeability and ion imbalance.

• This affects mitochondrial function, potentially triggering cell death.

Key features of Alzheimers disease

1. Amyloid-β plaques (extracellular)

• Clumps of amyloid-beta (Aβ) peptides, especially Aβ42, accumulate between neurons.

• These plaques disrupt cell communication and trigger inflammation.

• Amyloid comes from the cleavage of amyloid precursor protein (APP).

2. Neurofibrillary tangles (intracellular)

• Made of hyperphosphorylated tau protein, which normally stabilizes microtubules.

• In AD, tau detaches and forms twisted tangles, leading to neuronal transport failure and cell death.

Cefepine is a _______ known to cause neurotoxicity

cephalosporin

_____ can be used for APAP overdose

Coconut oil

_____ protects against neurotoxicity and endocrine disruption caused by paracetemol

betanine

What disease is linked to organochlorines?

Pakinsons

The elasticity of the skin is due to ______ & other extracellular matrix components secreted by _______, the main cell type of the dermis.

elastin

fibroblasts

diagram of skin layers

Explain the movement of keratinocytes

• Keratinocytes make up ~90% of the epidermis.

• They are born in the stratum basale and migrate upward through the layers, undergoing a differentiation process.

• As they move up, they:

  • Produce keratin (a tough protein)

  • Lose their nucleus and organelles

  • Become corneocytes (dead, flattened cells)

• These corneocytes are embedded in a lipid matrix (fats), forming a protective barrier against water loss, pathogens, and chemicals.

What cells are found in the epidermis?

Melanocytes

protecting the skin from UV

radiation through the production

of melanosomes (melanin) that are

transferred to keratinocytes to protect their

nuclei (preventing DNA damage ).

Merkel cells:

are epithelial neuroendocrine cells. rare and are found

in the basal layer of the epidermis and around the bulge region

of hair follicles.

Dendritic cells

are specialized, migratory antigen presenting cells --- able to regulate immune

reactions. ----- sensitive to signals derived from microbes, allergens, and the airway tissue

microenvironment. central role in the establishment of long-lasting adaptive immunity

Types of cutaenous toxicity

Contact dermatitis. ...

• Photosensitive dermatitis. ...

• Chemical-induced acne. ...

• Pigmentary disturbance. ...

• Drug rash (cutaneous reaction) ...

• Hair disturbance. ...

• Nail disturbance.

Contact Dermitis

Contact Dermatitis

• Cause: Direct contact with an irritant (e.g., detergent, acid) or allergen (e.g., nickel, poison ivy).

• Symptoms: Redness, itching, swelling, sometimes blisters.

• Types:

  • Irritant contact dermatitis (non-immune)

  • Allergic contact dermatitis (immune-mediated)

Photosensitive dermatitis

. Photosensitive Dermatitis

• Cause: Exposure to sunlight + certain drugs or chemicals (e.g., tetracyclines, perfumes).

• Symptoms: Redness, itching, rash in sun-exposed areas.

• Types:

  • Phototoxic: direct damage from sunlight + substance.

  • Photoallergic: immune reaction triggered by sun + substance.

Chemical-induced acne

3. Chemical-Induced Acne

• Cause: Long-term exposure to oils, tar, chlorinated compounds.

• Symptoms: Acne-like eruptions (comedones, papules).

• Example: "Chloracne" from industrial chemicals like dioxins

Pigmentary Disturbance

🎨 4. Pigmentary Disturbance

• Cause: Drugs or chemicals that affect melanocytes or pigment production.

• Types:

  • Hyperpigmentation: e.g., from minocycline, antimalarials

  • Hypopigmentation: e.g., from phenol or corticosteroids

Drug Rash

💊 5. Drug Rash (Cutaneous Drug Reaction)

• Cause: Allergic or toxic response to medications.

• Symptoms: Range from mild rashes to severe (e.g., Stevens-Johnson syndrome).

• Common culprits: antibiotics, NSAIDs, anticonvulsants.

Hair disturbance

💇‍♂ 6. Hair Disturbance

• Cause: Medications, hormones, or toxic chemicals.

• Types:

  • Hair loss (alopecia): e.g., chemotherapy, retinoids

  • Excess hair growth (hypertrichosis): e.g., steroids, minoxidil

Nail disturbance

💅 7. Nail Disturbance

• Cause: Drugs, systemic illness, or toxic exposure.

• Examples:

  • Beau’s lines: grooves across nails (seen after chemotherapy)

  • Onycholysis: nail separates from bed (e.g., from tetracycline + sun)

Effects of pollutants on skin (melanin/sebum)

1. Melanin and Sebum Modifications

• Melanin: The skin may produce more melanin in response to pollutants and UV (causing pigmentation irregularities or dark spots).

• Sebum: Pollutants can oxidize sebum (the skin's natural oil), leading to inflammation, clogged pores, or acne-like symptoms.

Effects of pollutants on skin (skin erythmea)

🌡 2. Skin Erythema

• Erythema = abnormal redness of the skin, due to increased blood flow in response to irritation or inflammation.

• UV + pollutants trigger inflammatory responses, causing visible redness and sensitivity.

Effects of pollutants on skin (trans epidermal water loss)

💧 3. Increased Trans-Epidermal Water Loss (TEWL)

• TEWL is the loss of water through the skin, normally controlled by the skin barrier.

• Pollutants weaken the skin barrier, allowing more water to escape, leading to dryness, dehydration, and rough texture.

Polycyclic hydrocarbons are linked to_____

inflammatry skin disease

SDBS caused damage to ______

gills, skin, and blood of fish

Heavy metals

A metal having an atomic weight greater

than sodium, a density greater than 5 g/cm3

Arsenic 5.7; cadmium 8.65; lead 11.34;

Properties of heavy metals

1. High Density and Atomic Weight

2. Metallic Luster and Malleability

3. Variable Oxidation States

4. Low Reactivity (in some cases)

Toxic exposure to metals and metallic elements depends on

• The type of exposure (inhalation, dermal absorption, or ingestion)

• The species (salt, element, vapor)

• Dose and duration.

• Host-based factors that can impact metal toxicity include (age at exposure, gender, and capacity for biotransformation)

• Young: sensitive, consume more food, higher absorption in GI, rapid growth

• Lifestyle factors such as smoking or alcohol ingestion may have direct or indirect impacts on the level of metal intoxication.

How are metals naturally distributed?

Rainwater dissolves rocks and transports materials, including metals, to rivers & underground water (e.g, arsenic), depositing and stripping materials from adjacent soil and transporting these substances to the ocean to b precipitated as sediment or taken up into forming rainwater to be relocated elsewhere

Overview of metal toxicity

What does absorption of heavy metals depend on?

• Solubility of metal in fluids of the intestinal tract

• Chemical forms of metal (lipid soluble methyl mercury is completely absorbed compare to inorganic mercury –poorly absorbed)

• Presence and composition of other materials in GI tract

• Composition for absorption sites between similar metals (zinc & cadmium or calcium & lead)

• Physiological state of the person exposed (Vitamin D enhance the absorption of lead)

Metals in blood plasma are bound to

__________ and ___________

plasma proteins and amino acids

Metals bound to low molecular weight proteins and amino acids are filtered in __________ into fluid of the renal tubule

glomerulous

Some metals (Cd & Zn) are effectively resorbed by _________ before they reach the urinary bladder where very little resorption occur

tubular epithelia

Absorbed metal may also excreted into intestinal tract in ___, ____, or _____

bile, pancreatic secretion or saliva

What is chelation therapy

Chelating agents (such as EDTA, dimercaprol, or DMSA) bind to metals in the bloodstream, forming stable complexes. These are then excreted via urine.

Common chelating agents

EDTA	Lead, calcium overload

Dimercaprol (BAL)

Arsenic, mercury poisoning

DMSA	Lead, mercury (oral form)

Deferoxamine

Iron overload

Requirements of being a chelator

a) Should have minimal risks involved with their therapeutic use.

b) Complex should be water soluble to enhance elimination through the kidneys without causing additional toxicity.

c) Oral administration is desirable, especially for treatment of chronic metal toxicity.

Table of chelators and their properties

Occurrence of lead

• batteries and in sheathing electric cables

• protective shielding from X rays and radiation from nuclear reactors

• pigments in paint, until it was banned as an environmental pollutant in the United States in the 1970s.

Sources of lead exposure

• Soil and dust

• Paint chips

• Contaminated water

• Parents lead-related occupation

• Folk remedies

• Congenital exposure

Mechanism of lead toxicity (STUDY LATER)

Doses of lead and effects

Diagnosis of Lead Poisoning

• Evaluation of clinical symptoms and signs

• CBC

• Serum iron levels, TIBC, ferritin

• Abdominal radiographs (for recent ingestion of lead-containing

• material)

• Whole blood lead level

• X-ray fluorescence (XRF)- to asses body burden

APP70 increase, SOD1, prdx6 APP 695 decrease is associated with what?

lead exposure

Endocrine glands consist of:

• The adenohypophysis produces and secretes a majority of the hormones of the pituitary gland

• Toxicants can influence the synthesis, storage, and release of hypothalamic-releasing hormones, adenohypophyseal-releasing hormones, and the endocrine gland–specific hormones.

Corticotropin-releasing hormone (CRH) is secreted by the _________

hypothalamus

Corticotropin-releasing hormone travels through the _______________

hypophyseal portal system (a capillary and vein network linking the hypothalamus to the anterior pituitary, or adenohypophysis).

In the anterior pituitary, CRH stimulates the cleavage of __________

pro-opiomelanocortin (POMC).

POMC is a prohormone that gives rise to

• Adrenocorticotropic hormone (ACTH)

• Melanocyte-stimulating hormone (MSH)

• Beta-endorphins

• ACTH enters the bloodstream and targets the _________

• It stimulates the synthesis and release of _______, a key stress hormone.

adrenal cortex

cortisol

How does cortisol regulate it’s pathway?

• The hypothalamus (reducing CRH)

• The anterior pituitary (reducing ACTH)

What are prohormones?

biologically inactive precursor molecules that are converted into active hormones through enzymatic processing. They are part of the body's hormone regulation system, ensuring that hormones are activated only when and where needed.

GH effects on hormones

1. Stimulates Protein Synthesis

   • Increases transcription and translation of genes involved in cell growth.

2. Increases Amino Acid Uptake

   • Enhances the transport of amino acids into cells, promoting muscle and tissue growth.

GH stimulates the GH to produce _________

somatomedins, mainly:

• Somatomedin C, also known as Insulin-like Growth Factor 1 (IGF-1)

Functions of IGF-1

• Enhance T-cell proliferation

• Increase in the absorption of calcium from the intestines and decreases

the loss from urinary excretion

• Stimulates hepatic glycogenolysis to raise levels of glucose in the blood

• Increase in the growth of soft and skeletal tissues

• Increase uptake of non-esterified fatty acids by the muscle.

Function of TSH

to stimulate the thyroid gland to produce and release:

• Triiodothyronine (T3)

• Thyroxine (T4)

Describe the regulation of TSH secretion

• Initiation:

  • The hypothalamus secretes Thyrotropin-Releasing Hormone (TRH).

• Portal System Transport:

  • TRH travels through the hypophyseal portal system to the anterior pituitary (adenohypophysis).

• Stimulation:

  • TRH stimulates thyrotrophic (thyrotrope) cells in the anterior pituitary to secrete TSH.

• Thyroid Activation:

  • TSH travels via the bloodstream to the thyroid gland, where it promotes:

    • Iodine uptake

    • Synthesis of thyroglobulin

    • Release of T3 and T4

Explain the negative feedback loop of TSH

Elevated levels of T3 and T4 inhibit:

• TRH release from the hypothalamus

• TSH secretion from the anterior pituitary

What is an endocrine disruptor?

• Mimic natural hormones (e.g., estrogen), binding to receptors and triggering inappropriate responses.

• Block hormone receptors, preventing the real hormone from binding.

• Alter hormone production, metabolism, or elimination, leading to hormone imbalances.

Sources of endocrine disruptors

• pesticides/herbicides

• personal care products

• pharma drugs

• industrial chemicals

What endocrine disruptors are in personal care products

• Triclosan

• Phthalates

• DEHP Bis-2-ethylhexyphthalate

Triclosan:

where

Linked to

• Antibacterial soaps

• Toothpaste

• Cosmetics

• Toys Furniture

• Endocrine disruption

• Breast cancer

• Resistant bacteria

• Bioaccumulation

Endorcine distuptors: pesticides/herbicides/fungicides

• endosulfan

• DDT

• Vinclosan

Endosulfan is an ________

organochlorine

what endocrine disorders are pesticides associated with?

endometriosis, early puberty, cervical cancer

What is antiandrogernic?

substance that keeps androgens (male sex hormones) from binding to proteins called androgen receptors

What is a teratogen?

any substance that can interfere with normal prenatal development, potentially causing birth defects or other abnormalities in a developing fetus

What endocrince disruptors aresynthetic/naturally occurring hormones?

• phytoestrogens

• diethylstilbisterol

• xenoestrogens

Food with the most phytoestrogens are ______

soya, wheat, pulses

how does diethylstilbisterol disrupt endocrines

Diethylstilbestrol (DES) is a synthetic estrogen that disrupts the endocrine system by:

1. Mimicking estrogen – It binds strongly to estrogen receptors, overstimulating estrogenic pathways.

2. Altering gene expression – It causes long-lasting epigenetic changes, especially when exposure happens in the womb.

3. Disrupting hormone balance – It interferes with feedback loops in the reproductive hormone system.

Effects of endocrine disruptors on humans

🧠 1. Neurodevelopmental Disorders

• Interference with thyroid hormones (essential for brain development)

• Linked to:

  • Reduced IQ

  • Attention Deficit Hyperactivity Disorder (ADHD)

  • Autism Spectrum Disorders (ASD)

🧬 2. Reproductive and Developmental Effects

• In females:

  • Early puberty (linked to BPA, phthalates)

  • Irregular menstrual cycles

  • Increased risk of polycystic ovarian syndrome (PCOS)

• In males:

  • Lower sperm count

  • Testicular dysgenesis

  • Cryptorchidism (undescended testes)

  • Hypospadias (abnormal urethral opening)

🩺 3. Hormone-Related Cancers

• Endocrine disruptors can mimic estrogen or testosterone, promoting tumor growth.

  • Breast cancer

  • Prostate cancer

  • Testicular cancer

🧠 4. Metabolic Disorders

• Disruption of insulin and other metabolic hormones

• Linked to:

  • Obesity

  • Type 2 diabetes

  • Non-alcoholic fatty liver disease (NAFLD)

🧬 5. Thyroid Dysfunction

• Disruption of thyroid hormone synthesis or signaling

• May cause:

  • Hypothyroidism

  • Goiter

  • Impaired growth and brain development in children

Why are hematopoeitic cells particular sensitive target?

cytoreductive drugs (reduce cell count):

Methothrexate, Hydroxyurea

antimitotic agents (block cell division):

Paclitaxel, Colchicine

Consequences of direct or indirect damage to blood cells

• Hemolysis from toxins

• infections

• mechanical damage

• bone marrow failure

• tachycardia

Primary toxicity

• Toxic effects that result directly from a substance's interaction with target cells or organs

• Direct cellular or biochemical interaction (e.g., DNA damage, enzyme inhibition)

• Usually rapid or predictable from known mechanism of action