Tox 9

Objective 1: Identify and describe the major toxicant effects in the nervous system.
- **Major toxic effects include:
- Neuronopathy**: Generalized damage to nerve cells, primarily affecting the nerve cell body, leading to cell death (apoptosis/necrosis) and irreversible loss of neurons.
- Synaptic Dysfunction: Interference with signaling processes by activating or inhibiting neurotransmitter receptors or altering neurotransmitter availability.
- Neuroinflammation: Chronic sustained cycles of injury and response; the cumulative effects of immunological activation contribute to neurodestructive effects.
Objective 2: Provide evidence for neurotoxicity and mechanism of action of methylmercury, lead, and organophosphate pesticides.
Objective 3: Understand the cell type specificity of the action of some neurotoxicants, illustrated by the MPTP story, which targets dopaminergic neurons.
Objective 4: Describe Gulf War Illness (GWI), highlighting its differences from classic organophosphate pesticide-induced neurotoxicity.

In 2014, leading scientists identified a dozen chemicals responsible for widespread behavioral and cognitive issues.
Dr. David Bellinger reported a collective loss of 41 million IQ points among Americans due to lead, mercury, and organophosphate pesticides.

The nervous system (NS) rapidly controls body functions and coordinates information gathering and responses (e.g., fight or flight, rest and digest).

Neurons: The fundamental unit responsible for receiving input and sending output (e.g., axon terminals release neurotransmitters into the synapse).

Cellular Features:
- Long cellular processes supported by a cell body.
- Excitable membranes that require maintenance for de/repolarization.
- High metabolic rate necessitating significant ATP production.
- Synaptic communication, where loss of a neuron in the central nervous system (CNS) is irreversible.

The nervous system includes components beyond neurons:
- Oligodendrocytes: Wrap myelin around axons.
- Astrocytes: Extend to blood vessels and synapses, playing crucial supportive roles.
- Microglial Cells: Act as immune cells, crucial for response and repair mechanisms.
Glial Cells: Comprise 90% of the nervous system's cellular makeup.

Myelination: 20-200 layers of myelin sheath speed up conduction of electrical signals and conserve energy
Blood-Brain Barrier (BBB): Protects from foreign substances/toxicants and maintains a stable environment within the CNS.
Microglia Functions:
- Survey territory for distressed neurons and pathogens.
- Activated forms proliferate and migrate to sites of infection/injury, phagocytosing pathogens and debris.

Neuronopathy: Generalized damage to nerve cells, leading to cell death and irreversible loss.
Axonopathy: Primarily affects the axon; degeneration of the axon and myelin occurs while the cell body remains intact. Only peripheral nervous system (PNS) axons can regenerate.
Myelinopathy: Involves separation or degeneration of myelin; efficient remyelination is limited to the PNS.

Organic vs. Inorganic Mercury:
- Inorganic Mercury: Associated with autoimmune disease, nephrotoxicity, and gastrointestinal issues.
- Organic Mercury (Methylmercury): Highly neurotoxic with a 90% oral absorption rate from seafood and capable of crossing the blood-brain barrier (BBB).
- Half-life: Approximately 30-60 days.
Minamata Disease: A historical example of methylmercury poisoning in a fish-eating population, leading to severe neurological issues.

Transport Mechanism: Methylmercury mimics methionine to cross the BBB and placenta, allowing it to reach the brain and fetus.
Neurotoxic Effects: Reports from studies indicate reduced brain size, irreversible developmental impairments, and severe cortical damage in infants exposed prenatally.

Routes of Exposure:
- Inhalation, dermal, and oral, with particular risks in children due to increased absorption rates.
Distribution and Storage: 94% of lead body burden is stored in bones.
Toxicity: Lead is a multi-organ toxicant, significantly affecting the developing nervous system. No threshold for neurotoxicity has been established.

Historical observations detail leads connection with cognitive deficits and neurological disorders,
Lead's mechanisms include substitution for essential cations (Ca2+, Zn2+) affecting biochemical processes crucial in neurodevelopment such as neurotransmitter systems.

Cholinergic Syndrome: Caused by acetylcholinesterase (AChE) inhibition, leading to neuronal overstimulation.
Signs and Symptoms: Increased sweating, gastrointestinal symptoms, respiratory failure can occur due to acute poisoning.

Chronic neuroinflammation involves cycles of neuronal injury and immune response contributions, leading to sustained effects.
GWI presents itself in veterans with diverse symptoms, including cognitive dysfunction and chronic pain related to environmental exposures (e.g., pesticides).

Neurotoxic injury manifests as various disorders, including sensory, movement, learning, and memory disorders, alongside neuroinflammation and synaptic dysfunction.
Neurons' high energy needs and limited self-repair capabilities underscore their vulnerability to toxicants, emphasizing the irreversibility of CNS neuron loss after injury.