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* Departments of Obstetrics and Gynecology, Physiology, Structural and Cellular Biology, and the Interdisciplinary Program in Molecular and Cellular Biology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and Department of Obstetrics, Gynecology and Reproductive Sciences, University of Saskatchewan, Saskatoon, Saskatchewan S7N OW8, Canada
To whom requests for reprints should be addressed at 1 the Department of Obstetrics and Gynecology (SL-11), Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112-2699. E-mail: henson{at}tulane.edu
Cadmium (Cd2+) is a common environmental pollutant and a major constituent of tobacco smoke. Exposure to this heavy metal, which has no known beneficial physiological role, has been linked to a wide range of detrimental effects on mammalian reproduction. Intriguingly, depending on the identity of the steroidogenic tissue involved and the dosage used, it has been reported to either enhance or inhibit the biosynthesis of progesterone, a hormone that is inexorably linked to both normal ovarian cyclicity and the maintenance of pregnancy. Thus, Cd2+ has been shown to exert significant effects on ovarian and reproductive tract morphology, with extremely low dosages reported to stimulate ovarian luteal progesterone biosynthesis and high dosages inhibiting it. In addition, Cd2+ exposure during human pregnancy has been linked to decreased birth weights and premature birth, with the enhanced levels of placental Cd2+ resulting from maternal exposure to industrial wastes or tobacco smoke being associated with decreased progesterone biosynthesis by the placental trophoblast. The stimulatory effects of Cd2+ on ovarian progesterone synthesis, as revealed by the results of studies using stable porcine granulosa cells, appear centered on the enhanced conversion of cholesterol to pregnenolone by the cytochrome P450 side chain cleavage (P450scc). However, in the placenta, the Cd2+-induced decline in progesterone synthesis is commensurate with a decrease in P450scc. Additionally, placental low-density lipoprotein receptor (LDL-R) mRNA declines in response to Cd2+ exposure, suggesting an inhibition in the pathway that provides cholesterol precursor from the maternal peripheral circulation. Potential mechanisms by which Cd2+ may affect steroidogenesis include interference with the DNA binding zinc (Zn2+)-finger motif through the substitution of Cd2+ for Zn2+ or by taking on the role of an endocrine disrupting chemical (EDC) that could mimic or inhibit the actions of endogenous estrogens. Divergent, tissue-specific (ovary vs. placenta) effects of Cd2+ also cannot be ruled out. Therefore, in consideration of the data currently available and in light of the potentially serious consequences of environmental Cd2+ exposure to human reproduction, we propose that priority should be given to studies dedicated to further elucidating the mechanisms involved.
Key Words: cadmium • placenta • stable granulosa cells • steroidogenesis • toxicology
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