Recent human and animal studies have suggested that the neuroendocrine axis is a specific target for low level lead (Pb) toxicity. Critical unanswered questions are when does the insult occur (prenatally or postnatally) and what is/are the specific mechanism(s) of action? It is known that the activation of hypothalamic N-methyl-D-aspartic acid (NMDA) receptors will stimulate luteinizing hormone releasing hormone (LHRH) luteinizing hormone (LH) secretion and advance the onset of puberty. There is now convincing evidence that insulin-like growth factor I (IGF-I) and leptin are also involved in LHRH/LH secretion and the acquisition of puberty. The present investigation will utilize in vivo and in vitro techniques as well as molecular biology to determine what effect(s) low level Pb exposure in utero only, during lactation only, or in utero plus during lactation may have on the above substances and their respective influence on the neuroendocrine events of puberty. We will use four specific aims to assess: 1) The effects of Pb on the expression of specific proteins shown to be involved in the pubertal process, i.e. IGF-I and its type 1 receptor, leptin and its receptor, and the NMDA receptor. These results will be correlated with assessments of hypothalamic, pituitary and ovarian hormones, as well as with specific indices of growth and puberty; 2) the potential of Pb to block the ability of these proteins to induce or influence the timing of puberty; 3) the effects of Pb on IGF-1, as well as NMDA-receptor activated and leptin induced secretion of LH in vivo; and 4) the effects of Pb on IGF-1, as well as on NMDA-receptor activated and leptin- induced LH secretion in vitro. These studies are designed to obtain information which will allow us to better understand the critical time point(s) for Pb induced insult to occur and the detrimental effects and mechanism(s) of action of exposure to Pb during in utero and early postnatal development on growth and neuroendocrine regulation in the young female.
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