IMMUNE AND BRAIN STUDIES

Project: Research project

Description

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.
StatusFinished
Effective start/end date12/8/8912/27/94

Funding

  • National Institutes of Health: $150,815.00
  • National Institutes of Health
  • National Institutes of Health

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Brain
Parturition
Haplorhini
Rodentia
Lithium
Primates
Drinking Behavior
Globus Pallidus
Macaca
Amygdala
Autoradiography
Mitogens
Cognition
Cholinergic Agents
Nervous System
Radioimmunoassay
Lead
Research Personnel
Hormones
Phenotype