The goals of this project are: (1) to apply the biomarkers which have been developed for human reproductive epidemiology in a non-human primate model and to carry out experiments with this model which test the same hypotheses that are being addressed in the epidemiologic studies of Project I; and (2) to carry out experiments in vivo which are relevant to the mechanisms of dioxin toxicity that are being studied in Projects IV and V. Female macaques will be exposed to indole-3-carbanol (I3C) or Azaline B in the follicular or luteal phase of the cycle in order to disrupt hypothalamic- pituitary-ovarian axis, and the response in the treatment cycle and in the following cycle will be monitored with measurements of urinary metabolite of ovarian steroids and FSH. Urinary markers of bone metabolism will be measured in animals with ovarian cycle disruption to determine if prolongation of the follicular phase of the cycle is associated with bone loss. Exogenous estrogen will be given to animals with prolonged follicular phase and bone loss to determine if bone loss results from low estrogen levels. Pregnant macaques will be treated with I3C or TCDD during the pre- implantation, peri-implantation or post-implantation period. The pregnancies will be monitored with serum assays for bioactive and immunoreactive mCG to determine if the ratio of bioactive to immunoreactive mCG provides information on the time in gestation when the pregnancy was affected by the toxicant. The implantation sites of female macaques exposed to TCDD will be studied using morphological techniques to assess abnormalities to of trophoblast-endometrial interaction. Tissues from TCDD-treated animals will be provided to Projects IV and V.
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