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MALFORMATIONS IN GUBERNACULAR LIGAMENT DEVELOPMENT INDUCED BY DEHP, DBP, AND BBP ARE ASSOCIATED WITH DECREASES IN INSL3 GENE EXPRESSION IN THE FETAL RAT TESTIS
Citation:
Wilson, V S., C R. Lambright, J. R. Furr, C R. Wood, G A. Held, AND L E. Gray Jr. MALFORMATIONS IN GUBERNACULAR LIGAMENT DEVELOPMENT INDUCED BY DEHP, DBP, AND BBP ARE ASSOCIATED WITH DECREASES IN INSL3 GENE EXPRESSION IN THE FETAL RAT TESTIS. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
Malformations in gubernacular ligament development induced by DEHP, DBP, and BBP are associated with decreases in insl3 gene expression in the fetal rat testis.
Vickie S.Wilson, Christy Lambright, Johnathan Furr, Carmen Wood, Gary Held, L. Earl Gray Jr. U.S. EPA, ORD, NHEERL, Reproductive Toxicology Division, RTP, NC
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 about 3 males per 100 at birth, but only a small percentage has been linked directly to genetic defects. Recently, concern has arisen over the apparent increase in male reproductive health problems and the potential role of endocrine disrupting chemicals in the etiology of these conditions. The phthalate esters (PE) are high production volume, ubiquitous environmental chemicals, some of which alter sexual differentiation, inducing gubernacular agenesis and other male rat reproductive tract malformations. We hypothesized that phthalate-induced gubernacular lesions likely result from an inhibition of Leydig cell insl3 gene expression. Three phthalates, di-n-ethylhexyl phthalate (DEHP), dibutyl phthalate (DBP) and benzyl butyl phthalate (BBP) were administered orally to the dam (750 mg/kg/day) on gestation day (GD) 14 through 18 and the fetal testes examined on GD18 for effects on steroid hormone production and insl3 gene expression. Compared to chemicals like vinclozolin, linuron, and prochloraz that act as AR antagonists and/or inhibit fetal Leydig cell testosterone production, only the three phthalates significantly reduced both ex vivo testosterone production and insl3 gene expression when quantified by real-time rtPCR. Dose response studies with DEHP (0, 100, 300, 600 or 900 mg/kg/day) also showed a dose dependent decrease in both testicular testosterone production and insl3 message levels in the GD18 rat fetus. These results provide the first demonstration of dose dependent PE-induced alteration of insl3 mRNA in the fetal male rat testis. Disclaimer: Abstract of a proposed presentation and does not necessarily reflect EPA policy.