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CHANGES IN FETAL TESTIS GENE EXPRESSION AND STEROID HORMONE SYNTHESIS INDUCED IN MALE OFFSPRING AFTER MATERNAL TREATMENT WITH PHTHALATE ESTERS
Citation:
WILSON, V. S., C. R. LAMBRIGHT, J. FURR, K. L. BOBSEINE, C. R. WOOD, G. A. HELD, AND L. E. GRAY. CHANGES IN FETAL TESTIS GENE EXPRESSION AND STEROID HORMONE SYNTHESIS INDUCED IN MALE OFFSPRING AFTER MATERNAL TREATMENT WITH PHTHALATE ESTERS. Presented at Triangle Consortium for Reproductive Biology, UNC-Chapel Hill, NC, February 12, 2005.
Description:
Targeted inactivation of the insulin-like hormone 3 (insl3) gene in male mice results in altered gubernacular development, disrupted testis decent, and cryptorchidism. Cryptorchidism is a fairly common human malformation, being displayed in 1-3% of males at birth. Since only a small percentage of these lesions can be linked to known genetic defects of insl3 or its receptor LGR8, developmental exposure to man-made chemicals has been implicated in the increase in this reproductive malformation. Phthalate esters (PE) are high production volume, ubiquitous environmental chemicals some of which induce reproductive malformations in rats when administered during sexual differentiation. Recently we have shown that malformations in gubernacular ligament development induced by high doses of DEHP are associated with decreased insl3 gene expression, a gene critical for proper gubernacular ligaments formation. To date in studies with antiandrogenic chemicals, PE are the only class that produces agenesis of the gubernacular ligaments. Compared to chemicals like vinclozolin, linuron, and prochloraz that act as AR antagonists and/or inhibit fetal Leydig cell testosterone production, only the phthalates tested significantly reduced both ex vivo testosterone production and insl3 gene expression when quantified by real-time rtPCR. Dose response studies with DEHP demonstrated a dose dependent decrease in testosterone production that was statistically significant at 300, 600 and 900 mg/kg/day. Insl3 gene expression was also decreased in a dose dependent manner. Effects on the expression of other testicular genes and on production of other steroid hormones are currently being examined. Thus far, the changes demonstrated are consistent with the malformations previously observed in male offspring after in utero exposure to similar doses of DEHP. It appears that in utero DEHP-treatment may alter the paracrine environment of the testis, via an as yet undetermined mechanism of action, such that the fetal Leydig cells proliferate rather than differentiate and hence fail to develop the capacity to synthesize both steroid and peptide hormones. As both insl3 and androgens are necessary for normal gubernacular development, interactions of phthalates with one-another or with other anti-androgenic toxicants, could act in concert to induce cumulative effects on the development of this unique reproductive structure. Disclaimer: Abstract of a proposed presentation and does not necessarily reflect EPA policy.