NEUROPHYSIOLOGIC DYSFUNCTION, LEAD MOBILIZATION, AND MENOPAUSE

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The primary objectives of this proposal are to determine in a prospective longitudinal epidemiologic study in urban women with repeated measures. 1) whether lead is mobilized from bone into blood during menopause and whether 2) a dose-response relationship exists between the amount of lead released and indices of neuropsychological dysfunction. To test the hypotheses that lead is mobilized from bone during menopause and that this release is associated with subclinical neuropsychological dysfunction, we plan to assess blood and plasma lead levels, bone lead concentration, bone density, serum ferritin and hormone levels, standardized questionnaire data, menopausal symptoms, mood, and neuropsychological function in 200 women residing in New York City who are scheduled to undergo a surgically induced menopause (bilateral oophorectomy). The effect of hormone replacement therapy on lead levels and neuropsychologic functioning will also be assessed. Blood and bone levels will be obtained preoperatively and again at 6 months and 18 months after surgery. Bone mineral density will be evaluated at baseline preoperatively and the 18 month visit. Evaluation of neuropsychological function will be performed preoperatively and 18 months after surgery. Indicators of lead exposure will include whole blood and plasma lead levels, bone lead concentration determined non-invasively by means of 109CdK X-ray fluorescence (XRF) analysis. Bone mass will be measured by dual energy X-ray absorptiometry (DXA). Total bone lead content will be calculated as the product of bone lead concentration and bone mineral content. The difference between the pre and postoophorectomy total bone lead will provide an estimate of total postmenopausal lead exposure from skeletal sources. Measures of subclinical neuropsychological effects will include both computer-administered and manually-administered neuropsychological tests that assess a range of functions including memory, cognition, psychomotor abilities, attention, executive functioning, and mood. Menopausal symptoms will be evaluated by the menopausal index. Changes in neuropsychological function over the interval of observation will be compared with changes in blood and bone lead levels. In particular, changes in neuropsychological function will be correlated with the total quantity of lead release from bone. Potential confounders and effect modifiers will be assessed in all analysis. This study is expected to provide important insights into the effects of bone demineralization during menopause on blood and bone lead levels, on the relationship between bone mass and lead levels, and on the possible contribution of endogenous lead to the development of subclinical neuropsychological impairment in adult women. Its strength lies in its longitudinal study design, its use of state-of-the-art indicators of body lead burden, and its employment of well validated, broad based, and objective measures of neuropsychological function.