Developmental arsenic exposure produces cognitive impairments

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DESCRIPTION (provided by applicant): Millions of people throughout the world are suffering from chronic arsenic poisoning due to the consumption of contaminated drinking water. Although it is well known that adults experience neurotoxicity when they are acutely exposed to high doses, the developmental neurotoxicity of arsenic is poorly understood. This data gap is alarming because the toxic effects that result from exposure during critical periods of brain development are often permanent and are expressed later in life as behavioral impairments. The proposed research will fill this void by examining a series of reflexive, motor, attention, and learning behaviors following developmental exposure to trivalent arsenic (the most toxic form) in drinking water. These behavioral endpoints will be examined in the C57BL6 inbred mouse strain. Both male and female mice will be examined to identify sex-specific responses. The behavioral tests were carefully selected because each is dependent on the integrity of dopamine or norepinephrine systems in the frontal cortex, hippocampus, basal ganglia, or cerebellum. Previous research has shown that arsenic can increase or decrease catecholamine levels in the brain depending on the dose. It is hypothesized that arsenic exposure during development produces long-term effects on forebrain catecholamine systems. A second objective of the proposed research is to use immunohistochemistry and confocal microscopy to examine the effects of arsenic on the distribution and density of catecholamine neurons in the adult brain. A reduction of the number of neurons in the adult brain may be due to early changes. In vitro studies have shown that arsenic increases neuronal apoptosis. Therefore, it is hypothesized that arsenic exposure during development increases apoptosis in forebrain catecholamine systems. A third objective for this research is to use the TUNEL staining technique to label apoptotic neurons in the neonatal frontal cortex, hippocampus, basal ganglia, or cerebellum. Millions of people worldwide consume arsenic-contaminated drinking water. Some of the affected individuals are pregnant women and the developing fetus is particularly sensitive to arsenic toxicity. The proposed research is designed to determine how inorganic arsenic impairs cognitive function following gestational exposure.