Endocrine Biomarkers of Early Fetal Loss in Cynomolgus Macaques (Macaca fascicularis) Following Exposure to Dioxin1

Abstract

This study examines the endocrine alterations associated with early fetal loss (EFL) induced by an environmental toxin, TCDD (2,3,7, 8-tetrachlorodibenzo-p-dioxin), in the cynomolgus macaque, a well-documented reproductive/developmental model for humans. Females were administered single doses of 1, 2, and 4 microgram/kg TCDD (n = 4 per dose group) on gestational day (GD) 12. Urinary estrogen metabolites (estrone conjugates) were monitored to establish the day of ovulation, and serum hormones (estradiol, progesterone, chorionic gonadotropin, relaxin) were measured to assess ovarian and placental endocrine status before and after treatment. EFL occurred between GDs 22 and 32 in 10 of the 12 animals treated with TCDD. The primary endocrine alterations associated with TCDD treatment were significant decreases in serum estradiol and bioactive chorionic gonadotropin concentrations (p < 0.02). Less pronounced decreases in serum progesterone (p = 0.10) and relaxin (p < 0.08) also followed TCDD treatment. In contrast, immunoreactive chorionic gonadotropin concentrations were not reduced by TCDD exposure at any level, indicating that TCDD targets specific components of the chorionic gonadotropin synthesis 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 occurred after exposure to TCDD might reflect a toxic response initially mediated via endocrine imbalance, leading to placental insufficiency, compromised embryonic circulation, and subsequent EFL.

Comparison of chorionic gonadotropin expression in human and macaque (Macaca fascicularis) trophoblasts

“…And like hCG during very early pregnancy, cmCG matures from a "low" bioactive form (with limited capacity to stimulate progesterone at ovarian receptors to maintain pregnancy) to a "high" bioactive form (more capable of sustaining pregnancy) in a similar time course [Guo et al, 1999]. Taken together, these data imply that the roles of CG in early pregnancy in Old World monkeys and humans are indeed parallel, at least in the very early stages of pregnancy.…”

“…RT-PCR amplification of the mRNAs expressed from both primary and secondary trophoblasts yielded bands for cmGPH-α and cmCG-β (data not shown). We were able to detect the expression of bioactive cmCG [Guo et al, 1999] derived from trophoblasts at gestational day (GD) = 26 (± 2d) but were unable to detect cmCG expression at GD = 35-40. Additionally, we discovered that, as with human and baboon, more than one cmCG-β gene was expressed in the cynomolgous trophoblasts we examined.…”

Three-generation experiment showed female C57BL/6J mice drink drainage canal water containing low level of TCDD-like activity causing high pup mortality

“…These contaminants decrease fertility, increase prenatal mortality, cause birth defects, and increase the risk for endometriosis (Couture et al, 1990;Fenton et al, 2002;Guo et al, 1999;Heimler et al, 1998;Huisman et al, 1995;Rier et al, 1993). Reproductive organs seem to be more sensitive to TCDD toxicity.…”

Characterization of chlorpyrifos-induced apoptosis in placental cells

“…For example, endosulfan inhibits aromatase activity; whereas, methomyl, pirimicarb, propamocarb, iprodion, lindane and bisphenol-A enhance placental aromatase activity (Nativelle-Serpentini et al 2003). TCDD exposure is associated with fetus loss and the alteration of the secretion of chorionic gonadotropin hormone in primates (Guo et al 1999;Chen et al 2003;Myllynen et al 2005). With regards to chlorpyrifos, CPF and/or its metabolites have been detected in the fetuses of dams administered CPF perinatally (Mattsson et al 2000;Abdel-Rahman et al 2002).…”