LEAD TOXICITY--BIOCHEMICAL AND NEUROENDOCRINE MECHANISMS

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In the last few years the toxic effects of lead in children has become a major environmental issue in the U.S. However, while much research has centered on behavioral and neurotoxic effects of lead poisoning, few studies have systematically examined the effects of chronic lead exposure on the endocrine systems of reproduction and growth during development. It has been known for nearly 2000 years that lead exposure disrupts adult reproductive function with reports of sterility and miscarriages dating back to classical times. In clinical studies of lead-exposed male workers, decreases in spermatogenesis and variable effects on circulating levels of pituitary gonadotropins have been reported. The few animal studies in the literature suggest that lead exposure decreases plasma levels of testosterone in male rats into the castrate range with little or no effect on serum luteinizing hormone (LH) concentrations. This suggests multiple sites of lead action; 1) at the level of the gonads involving a direct effect of lead on gonadal steroidogenesis; and 2) at the level of the hypothalamus and or pituitary involving changes in responsiveness to steroid feedback. This latter site is hypothesized because castration results in elevation of serum LH in untreated rats due to reduced feedback of testosterone. Our preliminary data support such a dual site of lead action. The current application proposes to examine in detail the molecular mechanisms underlying the lead-induced impairment of the endocrine systems of reproduction and growth in a developmental animal model. This proposal focuses on disruption of hypothalamic-pituitary function (especially secretion of LH and GH), gonadal steroid biosynthesis and peripheral steroid metabolism. Specifically, the endocrine effects of lead exposure initiated in utero will be examined on developing male and female rats. Challenge and replacement experiments will be conducted in vivo to define hypothalamic-pituitary and gonadal sites of lead action and the molecular mechanisms underlying lead-induced alterations in gonadal and peripheral sex steroid metabolism, reproductive physiology and the male pubertal growth spurt.