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CUMULATIVE EFFECTS OF DIBUTYL PHTHALATE AND DIETHYLHEXYL PHTHALATE ON MALE RAT REPRODUCTIVE TRACT DEVELOPMENT: ALTERED FETAL STEROID HORMONES AND GENES.
Citation:
HOWDESHELL, K., J. FURR, C. R. LAMBRIGHT, V. S. WILSON, AND L. EARL GRAY. CUMULATIVE EFFECTS OF DIBUTYL PHTHALATE AND DIETHYLHEXYL PHTHALATE ON MALE RAT REPRODUCTIVE TRACT DEVELOPMENT: ALTERED FETAL STEROID HORMONES AND GENES. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 99(1):190-202, (2007).
Impact/Purpose:
To show that individual phthalates with a similar mode of action, but with different active metabolites, can elicit cumulative effects when administered as a mixture.
Description:
Exposure to the plasticizers diethylhexyl phthalate (DEHP) and di(n-butyl) phthalate (DBP) during sexual differentiation causes male reproductive tract malformations in rats and rabbits. In the fetal male rat, these two phthalate esters decrease testosterone (T) production and insulin-like factor 3 (Insl3) gene expression, a hormone critical for gubernacular ligament development. We hypothesized that co-administered DEHP and DBP would act in a cumulative fashion to induce reproductive malformations, inhibit fetal steroid hormone production and suppress the expression of Insl3 and genes responsible for steroid production. Pregnant Spraque Dawley rats were gavaged on gestation days (GD) 14-18 with vehicle control, 500 mg/kg DBP, 500 mg/kg DEHP, or combination of DBP and DEHP (500 mg/kg each chemical). 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 qrt-PCR. The DBP+DEHP dose increased the incidence of reproductive malformations and reduced androgen-dependent organ weights in cumulative fashion acting in an apparent dose-additive manner. Fetal T and expression of Insl3 and genes in the steroidogenic pathway [steroidogenic acute regulatory protein (Star) and Cyp11a] were significantly reduced by DEHP and further decreased by the DBP+DEHP dose. These data indicate that individual phthalates with a similar mode of action, but with different active metabolites (monobutyl phthalate versus monoethylhexyl phthalate), can elicit cumulative effects when administered as a mixture.
