This application seeks to determine the nature and mechanisms of developmentally mediated perturbations of the primate immune, nervous, and neuroendocrine systems, caused by low doses of lead. The proposed studies seek to 1) extend, in a nonhuman primate species, earlier observations made in the laboratory rat and 2) test the hypothesis that early, low-level lead exposure will alter immune, neuroendocrine and neurochemical function. A particular strength of this proposal is the availability of a population of monkeys (Macaca fasicularis) whose blood-lead levels and age at exposure are similar to those of rodents used in independently-funded research. In addition, early lead exposure in these monkeys has resulted in subtle but significant behavioral changes in cognitive function. The experimental subjects are 20 monkeys which were dosed orally from birth with 1.5 mg/kg/day of lead using one of four (n=5) dosing regimes: Group 1, vehicle only; Group 2, lead from birth onward; Group 3, lead from birth to 400 days of age and vehicle thereafter; Group 4, vehicle from birth to 300 days of age and lead thereafter. One hypothesis, based on our rodent data, is that monkeys will show similar permanent changes in drinking behavior, as well as increases in dipsogenic effects of lithium. This effect is hypothesized to be due to alterations in dopaminergic function, particularly in lateral hypothalamus, amygdala and/or globus pallidus. A second hypothesis supported by the literature is that low doses of lead alter immune, and possibly, neuroendocrine function. A final hypothesis is that alterations in non-spatial discrimination reversal tasks are due, in part, to alterations in specific cholinergic and/or dopaminergic pathways. These hypotheses will be tested by first determining, in vivo, if the lead- treated monkeys have alterations in discrete components of water consumption, before or after lithium administration. Cell-mediated immunity will be studied by characterizing immunological cell phenotype and conducting blastogenic assays following mitogen stimulation. Neuroendocrine function will be examined by radioimmunoassay of stress- related hormones. Following these in vivo studies (year 01), the monkeys will be sacrificed, and in vitro experiments will be conducted on post- mortem tissue. Neurochemical studies will focus on selected central monoaminergic pathways measuring the concentration of monoamines and their metabolites in microdissected brain nuclei. Receptor binding studies (using quantitative autoradiography and homogenate assays) will evaluate potential alterations in the density and affinity of monoamine and cholinergic receptors. After determination of the chemical and anatomical locus of lead-induced changes, morphological studies using immunocytochemical techniques will be initiated. Because these studies will occur concomitantly with independently funded studies in rats, comparisons across genera will be possible, as will testing of new hypotheses derived from the rodent studies. Finally, careful archiving of monkey brains will permit future testing of post hoc hypotheses by us or other investigators.
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| Gilmore, J H; Lawler, C P; Eaton, A M et al. (1993) Postmortem stability of dopamine D1 receptor mRNA and D1 receptors. Brain Res Mol Brain Res 18:290-6 |
