Calcium-mediated cytotoxicity[edit]

Lead pipes are common sources of ingested lead.

Lead[edit]
Lead is a potent neurotoxin whose toxicity has been recognized for at least thousands of years.
[95]
Though neurotoxic effects for lead are found in both adults and young children, the developing
brain is particularly susceptible to lead-induced harm, effects which can include apoptosis and
excitotoxicity.[95] An underlying mechanism by which lead is able to cause harm is its ability to be
transported by calcium ATPase pumps across the BBB, allowing for direct contact with the fragile
cells within the central nervous system.[96] Neurotoxicity results from leads ability to act in a similar
manner to calcium ions, as concentrated lead will lead to cellular uptake of calcium which disrupts
cellular homeostasis and induces apoptosis.[44] It is this intracellular calcium increase that
activates protein kinase C (PKC), which manifests as learning deficits in children as a result of
early lead exposure.[44] In addition to inducing apoptosis, lead inhibits interneuron signaling
through the disruption of calcium-mediated neurotransmitter release. [97]

Neurotoxins with multiple effects[edit]

Ethanol[edit]
As a neurotoxin, ethanol has been shown to induce nervous system damage and affect the body
in a variety of ways. Among the known effects of ethanol exposure are both transient and lasting
consequences. Some of the lasting effects include long-term reduced neurogenesis in
the hippocampus,[98][99] widespread brain atrophy,[100] and induced inflammation in the brain.[101] Of
note, chronic ethanol ingestion has additionally been shown to induce reorganization of cellular
membrane constituents, leading to a lipid bilayer marked by increased membrane concentrations
of cholesterol and saturated fat.[46] This is important as neurotransmitter transport can be impaired
through vesicular transport inhibition, resulting in diminished neural network function. One
significant example of reduced inter-neuron communication is the ability for ethanol to
inhibit NMDA receptors in the hippocampus, resulting in reduced long-term potentiation (LTP) and
memory acquisition.[45] NMDA has been shown to play an important role in LTP and consequently
memory formation.[102] With chronic ethanol intake, however, the susceptibility of these NMDA
receptors to induce LTP increases in the mesolimbic dopamine neurons in an inositol 1,4,5-
triphosphate (IP3) dependent manner.[103] This reorganization may lead to neuronal cytotoxicity
both through hyperactivation of postsynaptic neurons and through induced addiction to
continuous ethanol consumption. It has, additionally, been shown that ethanol directly reduces
intracellular calcium ion accumulation through inhibited NMDA receptor activity, and thus reduces
the capacity for the occurrence of LTP.[104]
In addition to the neurotoxic effects of ethanol in mature organisms, chronic ingestion is capable
of inducing severe developmental defects. Evidence was first shown in 1973 of a connection
between chronic ethanol intake by mothers and defects in their offspring. [105] This work was
responsible for creating the classification of fetal alcohol syndrome; a disease characterized by
common morphogenesis aberrations such as defects in craniofacial formation, limb development,
and cardiovascular formation. The magnitude of ethanol neurotoxicity in fetuses leading to fetal
alcohol syndrome has been shown to be dependent on antioxidant levels in the brain such
as vitamin E.[106] As the fetal brain is relatively fragile and susceptible to induced stresses, severe
deleterious effects of alcohol exposure can be seen in important areas such as the hippocampus
and cerebellum. The severity of these effects is directly dependent upon the amount and
frequency of ethanol consumption by the mother, and the stage in development of the fetus. [107] It
is known that ethanol exposure results in reduced antioxidant levels, mitochondrial dysfunction
(Chu 2007), and subsequent neuronal death, seemingly as a result of increased generation
of reactive oxidative species (ROS).[29] This is a plausible mechanism, as there is a reduced
presence in the fetal brain of antioxidant enzymes such as catalase and peroxidase.[108] In support
of this mechanism, administration of high levels of dietary vitamin E results in reduced or
eliminated ethanol-induced neurotoxic effects in fetuses.[8]