Endocrine biomarkers of early fetal loss in cynomolgus macaques (Macaca fascicularis) following exposure to dioxin

This study examines the endocrine alterations associated with early fetal l oss (EFL) induced by an environmental toxin, TCDD (2,3,7,8-tetrachlorodiben zo-p-dioxin), in the cynomolgus macaque, a well-documented reproductive/dev elopmental model for humans. Females were administered single doses of 1, 2 , and 4 mu g/kg TCDD (n = 4 per dose group) on gestational day (CD) 12. Uri nary estrogen metabolites (estrone conjugates) were monitored to establish the day of ovulation, and serum hormones (estradiol, progesterone, chorioni c gonadotropin, relaxin) were measured to assess ovarian and placental endo crine status before and after treatment. EFL occurred between GDs 22 and 32 in 10 of the 12 animals treated with TCDD. The primary endocrine alteratio ns associated with TCDD treatment were significant decreases in serum estra diol and bioactive chorionic gonadotropin concentrations (p < 0.02). Less p ronounced decreases in serum progesterone (p = 0.10) and relaxin (p < 0.08) also followed TCDD treatment. In contrast, immunoreactive chorionic gonado tropin concentrations were not reduced by TCDD exposure at any level, indic ating that TCDD targets specific components of the chorionic gonadotropin s ynthesis machinery within the trophoblast to alter the functional capacity of the hormone. These data demonstrate the value of endocrine biomarkers in identifying a toxic exposure to primate pregnancy many days before direct signs of reproductive toxicity were apparent. The increased EFL that occurr ed after exposure to TCDD might reflect a toxic response initially mediated via endocrine imbalance, leading to placental insufficiency, compromised e mbryonic circulation, and subsequent EFL.