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PRESENTED AT THE TRIANGLE CONSORTIUM FOR REPRODUCTIVE BIOLOGY MEETING ON 2/11/06: DI(N-BUTYL) PHTHALATE AND DIETHYLHEXYL PHTHALATE IN COMBINATION ALTER SEXUAL DIFFERENTIATION IN A CUMULATIVE MANNER AS A RESULT OF DEPRESSED FETAL TESTOSTERONE PRODUCTION AND INSL3 GENE EXPRESSION IN MALE RATS
HOWDESHELL, K., J. FURR, C. R. LAMBRIGHT, V. S. WILSON, AND L. E. GRAY. PRESENTED AT THE TRIANGLE CONSORTIUM FOR REPRODUCTIVE BIOLOGY MEETING ON 2/11/06: DI(N-BUTYL) PHTHALATE AND DIETHYLHEXYL PHTHALATE IN COMBINATION ALTER SEXUAL DIFFERENTIATION IN A CUMULATIVE MANNER AS A RESULT OF DEPRESSED FETAL TESTOSTERONE PRODUCTION AND INSL3 GENE EXPRESSION IN MALE RATS. Presented at Triangle Consortium for Reproductive Biology, Chapel Hill, NC, February 11, 2006.
Plasticizers di(n-butyl) phthalate (DBP) and diehtylhexyl phthalate (DEHP) have similar modes of action: in utero exposure reduces testosterone (T) production in fetal male rats, inhibits reproductive tract differentiation, and induces reproductive organ malformations. In utero exposure to DBP or DEHP also decreases expression of insulin-like factor 3 (insl3), a hormone responsible for gubernacular ligament development. We hypothesized that (1) co-administered DBP and DEHP would act in a cumulative fashion to induce reproductive malformations, and (2) cumulative changes in fetal steroid hormones and expression of genes responsible for insl3 and steroid production would enhance the incidence of reproductive malformations in adulthood. Pregnant rats were gavaged on gestation days (GD) 14-18 with vehicle control, 500 mg/kg DBP and/or DEHP. In experiment one, adult male offspring were necropsied, and reproductive malformations and androgen-dependent organ weights were recorded. In experiment two, GD18 fetal testes were incubated for T production, and processed for gene expression by qrtPCR. The DBP+DEHP dose increased the incidence of reproductive malformations in a cumulative fashion with the chemicals acting in an additive manner. Androgen-dependent organ weights also exhibited decreases in the DBP+DEHP combination dose. Fetal T, and the expression of insl3 and genes in the steroidogenic pathway (steroidogenic acute regulatory protein and cyp11a) were significantly reduced by DEHP and further decreased by the DBP+DEHP dose. These data indicate that individual anti-androgenic phthalates with a similar mode of action can elicit cumulative effects on fetal testis hormone production and reproductive tract differentiation when administered as a mixture. Disclaimer: This abstract does not necessarily reflect EPA policy.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
REPRODUCTIVE TOXICOLOGY DIVISION