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Placental Endocrine Disruption Induced by Cadmium: Effects on P450 Cholesterol Side-Chain Cleavage and 3ß-Hydroxysteroid Dehydrogenase Enzymes in Cultured Human Trophoblasts

^a Departments of Obstetrics and Gynecology, ^b Structural and Cellular Biology, ^c Physiology, and ^d Interdisciplinary Program in Molecular and Cellular Biology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112-2699 ^e Developmental Research Laboratories, Shionogi & Co., Ltd., Osaka 561-0825, Japan

We previously suggested that cadmium (Cd), an environmental toxicant and constituent of tobacco smoke, inhibits progesterone secretion in cultured human placental trophoblasts by inhibiting low-density lipoprotein receptor mRNA expression. In the current study, we investigated whether Cd also disrupts progesterone synthesis via P450 cholesterol side-chain cleavage (P450_scc) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD), enzymes that play important roles in placental steroidogenesis. Human cytotrophoblasts were purified by density gradient centrifugation and incubated in Dulbecco modified Eagle medium + 10% fetal bovine serum with 0, 5, 10, or 20 µM CdCl₂ for 96 h. Cells progressed to syncytiotrophoblastic maturity regardless of treatment. No differences (P > 0.05) in cell protein and lactate dehydrogenase activity were observed between untreated trophoblasts and those treated with CdCl₂. However, P450_scc and 3ß-HSD mRNA transcript levels declined in a dose-dependent manner (P <0.05) in trophoblasts cocultured with 5, 10, or 20 µM CdCl₂. P450_scc activity was similarly inhibited (P < 0.05) by CdCl₂ treatment, although 3ß-HSD activity was not significantly affected. Coculture with 8-bromo-cAMP enhanced progesterone secretion in untreated cultures but did not reverse the decline in progesterone secretion induced by CdCl₂ treatment. CdCl₂ failed to influence cAMP content in cultured cells. Collectively, results suggest that P450_scc enzyme is another site at which Cd interferes with placental progesterone production. However, it is unlikely that an inhibition of cAMP is involved with the inhibition of progesterone biosynthesis by Cd in human trophoblasts.

First decision: 11 November 2001.

¹ Correspondence: Michael C. Henson, Department of Obstetrics and Gynecology, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112-2699. FAX: 504 584 1846;michael.henson{at}tulane.edu

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