Methylmercury (MeHg) 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. This competitive renewal application describes a 5 year plan aimed at examining the long-term neurotoxic effects of in utero MeHg exposure using the nonhuman primate and rodent animal model. During the initial 3 years of the plan, operant testing of two groups of adult macaca fascicularis: one exposed in utero to MeHg, the other unexposed controls will take place at the University of Washington to test 2 hypotheses related to the effects of early MeHg exposure on adult memory and visual function. At this time, studies of rodents will be carried out at the University of Rochester to test the hypothesis that lesions induced by in utero exposure to MeHg are exacerbated by CNS changes associated with normal aging. At the end of the three years, the results of the behavioral tests of the primates and the neuroanatomical studies of rodents will be reviewed to direct further studies of the primate colony. For the present plan, the primate colony will be sacrificed at the end of year 3 and studies to test 5 hypotheses related to the long-term neuroanatomical and neurochemical effects of in utero MeHg will be conducted during years 4 and 5. All of the hypotheses that will be tested are based on the results developmental assessments of the MeHg exposed and control macaca fascicularis from our laboratory and from the laboratory of Rice et al. (1989). To test the primate neurobehavioral hypotheses, assessments of Delayed Spatial Alteration, Delayed Nonmatch-to-Sample, and Spatial-and Temporal-Visual Contrast Sensitivity will be used. The primate and rodent neuroanatomical hypotheses will be tested by quantifying brains for cell numbers, cell density, and tissue volume; immunocytochemistry will be used to identify growth-controlling cells and astrocytes, and dendritic development will be assessed biochemically by assays of MAP2 (primates only) and morphometrically for dendritic pattern and extent. Finally, the primate neurochemical hypotheses will be tested using autoradiographic techniques to evaluate cholinergic neurotransmission in cortical and subcortical areas related to specific memory pathways and catecholaminergic neurotransmission in the hypothalamic-pituitary axis related to the regulation of growth. While previous studies have reported immediate effects following early MeHg exposure in rodents, macaques, and humans, little is currently known regarding the long-term effects of in utero MeHg exposure on adult and aged animals or humans. The proposed nonhuman primate studies make the best use of the valuable monkey colony, because the studies focus on a set of strongly-supported hypotheses using procedures that are readily available for use with humans. The rodent studies will provide the first results regarding the influence of aging on MeHg neuropathology; results that can be used to direct subsequent studies of the primate colony.
