Methyl mercury continues to be a major global environmental problem. The International Program of Chemical Safety lists mercury as one of the six most dangerous chemicals to the world's environment. The purpose of the proposal studies is to examine the neuroanatomical and neurochemical effects of early MeHg exposure using two groups of adult macaca fascicularis: one group exposed in utero to MeHg (15 animals), the other unexposed controls (14 animals). The hypotheses to be tested are based on the developmental assessment of these animals from birth to adulthood, which indicates cognitive deficits related to two neuroanatomically separable memory systems, and postnatal growth deficits related to neuroendocrine control of growth. The five hypotheses that will be tested are 1). MeHg exposure alters the structure of the memory pathway from temporal cortex to amygdala to dorsomedial thalamus to ventromedial prefrontal cortex, which mediates visual recognition memory. 2). MeHg exposure alters the structure of the memory pathway from hippocampus to anterior nuclei of thalamus to dorsolateral prefrontal cortex, which mediates object permanence. 3). MeHg exposure alters the structure of the hypothalamic-pituitary axis which mediates the rate of physical growth. 4). The memory pathways described in hypothesis 1 and 2, rich in cholinergic neurons, will exhibit alterations in cholinergic neurotransmission due to MeHg exposure, and 5). The hypothalamic-pituitary axis, rich in catecholaminergic neurons, will exhibit alterations in catecholaminergic neurotransmission due to MeHg exposure. Brains will be quantified for cell numbers, cell density, and tissue volume in the regions of interest. Immunocytochemistry will be used to identify growth-controlling cells in the hypothalamus and pituitary, and astrocytes in hypothalamus, thalamus, hippocampus, amygdala, and cortical samples. Dendritic development will be assessed biochemically by assays of MAP2 in a set of cortical regions, and the most-affected regions will then be evaluated morphometrically for dendritic pattern and extent. The evaluation of the cholinergic and catecholaminergic systems will include studies of related enzyme systems and receptors, as well as assays of the transmitters themselves. These studies make the best use of the available monkey tissue, because they focus on hypotheses generated from these animals, and in the case of the cognitive-memory system studies, they investigate hypotheses which can be tested only in primates. The methods proposed are quantitative, and should be more sensitive to teratologic effects than traditional qualitative pathological evaluations.
