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Submitted to Dr, kps gowda sir Hod and asso professorDept of pharmacology

DEVELOPMENTAL NEUROTOXICITY

Contents :Introduction.Syndrome of neurotoxicity.Sign of central and peripheral

neuropathy.Why is the Brain Particularly

Vulnerable to Injury.Causes of neurotoxicity.Types.Neurotoxicology of heavy metal.

Cells of the Nervous System

Neurons Signal integration/generation; direct

control of skeletal muscle (motor axons)

Supporting Cells (Glia cells) Astrocytes (CNS – blood brain barrier) Oligodendrocytes (CNS – myelination)

Schwann cells (PNS – myelination) Microglia (activated astrocytes)

Developmental neurotoxicity (DNT) is probably the least tested health effect of chemicals: only about 150 substances have been subjected to the internationally agreed guideline studies.The lack DNT data for almost all chemicals, including environmental pollutants, industrial chemicals, drugs, consumer .

Epidemiological studies in this field can hardly prove causal

relationships unless effects are dramatic; only a handful of compounds, therefore, have been established as definitive DNToxicants in man methyl mercury, lead, arsenic, toluene, and ethanol. This group was recently expanded to include six additional developmental neurotoxicants – manganese, fluoride, chlorpyrifos, dichlorodiphenyltrichloroethane,

• Brain in children and fetuses is much more vulnerable to chemical perturbation than the adult brain, leads to major concerns about deficient DNT data. The high sensitivity of the developing brain is due to the still immature blood/brain-barrier, increased absorption versus low body weight, and diminished ability to detoxify exogenous chemicals

Moreover, CNS development is a complex process involving many different events, such as differentiation of progenitor cells, proliferation and cell migration, synaptogenesis, myelination, cell death, synthesis of neurotransmitters, and formation of receptors. these events occur within strictly controlled timeframes and, therefore, each event creates a different window of vulnerability to xenobiotic exposure

Once neurodevelopment is disturbed there is little potential for repair

Why is the Brain Particularly Vulnerable to

Injury? Neurons are post-mitotic cells High dependence on oxygen Little anaerobic capacity Brief hypoxia/anoxia-neuron cell death Dependence on glucose Sole energy source (no glycolysis) Brief disruption of blood flow-cell death

Many substances go directly to the brain via inhalation

Blood-brain Barrier

Anatomical Characteristics Capillary endothelial cells are tightly joined – no pores

between cells Capillaries in CNS surrounded by astrocytes Active ATP-dependent transporter – moves chemicals into the

brain.

Not an absolute barrier Caffeine (small), nicotine Methylmercury cysteine complex Lipids (barbiturate drugs and alcohol) Susceptible to various damages

BBB can be broken down by

Hypertension: high blood pressure opens the BBB

Hyperosmolarity: high concentration of solutes can open the BBB.

Infection: exposure to infectious agents can open the BBB.

Trauma, Ischemia, Inflammation, Pressure: injury to the brain can open the BBB.

Development: the BBB is not fully formed at birth.

What causes neurotoxicity? Chemical

Physical

Toxicants and Exposure

Inhalation (e.g. solvents CS2 , 1,1,1‐trichloroethane, nicotine, nerve gases)

Ingestions (e.g. lead, alcohol, drugs such as MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).

Skin (e.g. pesticides, nicotine). Physical (e.g. load noise, trauma).

Types Of Neurotoxicity

Neuropathies Axonopathies Myelinopathies Neurotransmission-associated

abnormalities

NEURONOPATHIES

Injury or death to neurons. Irreversible loss. Initial injury followed by apoptosis or

necrosis. Caused by CO, ethanol, carbon

tetrachloride, methyl mercury, lead.

AXONOPATHIES

Primary site of toxicity is axon Degeneration of axon, surrounding

myelin, but cell body remains intact Irreversible in CNS, but reversible in

PNS Caused by CS2, acrylamide, gold,

organophosphorus esters

PATHWAY OF AXOPATHOPATHIES

MYELINOPATHIES

Intramyelinic edema Demyelination Remyelination in CNS occurs to a limited

extent Remyelination in PNS done by Schwann

cells Caused by amiodarone, disulfiram,Pb

NEUROTRANSMISSION-ASSOCIATED ANOMALITIES

Interruption of impulse transmission Blockade of transsynaptic

communication Inhibition of neurotransmitter uptake Interference with second-messenger

systems Caused by nicotine, amphetamines,

cocaine

Neurotoxicology

Heavy Metals Lead – environmental exposure

(paint, fuels) Mercury – exposure via diet

(bioaccumulation in fish

Lead Neurotoxicity Developmental Neurotoxicity Reduced IQ Impaired learning and memory Life-long effects Related to effects on calcium

permeable channels (NMDA, Ca++ channels)

Overview of Glutamate and Excitotoxicity

Lead neurotoxicity CENTRAL: Cerebral edema Apoptosis of neuronal cells Necrosis of brain tissue Glial proliferation around blood vessels PERIPHERAL: Demyelination Reversible changes in nerve conduction

velocity (NCV) Irreversible axonal degeneration

Toxicity of Mercury

Organic mercury (methylmercury) is the form in fish tuna and swordfish, bioaccumulates to high levels.

Organic mercury from fish is the most significant source of human exposure.

Brain and nervous system toxicity: High fetal exposures: mental retardation,

seizures, blindness. Low fetal exposures: memory, attention,

language disturbances.

References

Google .com Slideshare.com Authorstream.com Lena s, Helena T. Marcel L , and

Thomas H. Developmental Neurotoxicity – Challenges

in the 21st Century and In Vitro Opportunities.2014 altrex :page 129-156.