@article{howdeshell_wilson_furr_lambright_rider_blystone_hotchkiss_gray_2008, title={A mixture of five phthalate esters inhibits fetal testicular testosterone production in the sprague-dawley rat in a cumulative, dose-additive manner}, volume={105}, ISSN={["1096-6080"]}, DOI={10.1093/toxsci/kfn077}, abstractNote={Phthalate diesters are chemicals to which humans are ubiquitously exposed. Exposure to certain phthalates during sexual differentiation causes reproductive tract malformations in male rats. In the fetal rat, exposure to the phthalates benzylbutyl phthalate (BBP), di(n)butyl phthalate (DBP), and diethylhexyl phthalate (DEHP) decreases testicular testosterone production and insulin-like 3 hormone mRNA levels. We characterized the dose-response effects of six individual phthalates (BBP, DBP, DEHP, diethyl phthalate [DEP], diisobutyl phthalate [DiBP], and dipentyl phthalate [DPP]) on gestation day (GD) 18 testicular testosterone production following exposure of Sprague-Dawley rats on GD 8-18. BBP, DBP, DEHP, and DiBP were equipotent (ED50 of 440 +/- 16 mg/kg/day), DPP was about threefold more potent (ED50 = 130 mg/kg/day) and DEP had no effect on fetal testosterone production. We hypothesized that coadministration of these five antiandrogenic phthalates would reduce testosterone production in a dose-additive fashion because they act via a common mode of toxicity. In a second study, dams were dosed at 100, 80, 60, 40, 20, 10, 5, or 0% of the mixture. The top dose contained 1300 mg of total phthalates/kg/day including BBP, DBP, DEHP, DiBP (300 mg/kg/day per chemical), and DPP (100 mg DPP/kg/day). This mixture ratio was selected such that each phthalate would contribute equally to the reduction in testosterone. As hypothesized, testosterone production was reduced in a dose-additive manner. Several of the individual phthalates and the mixture also induced fetal mortality, due to pregnancy loss. These data demonstrate that individual phthalates with a similar mechanism of action can elicit cumulative, dose additive effects on fetal testosterone production and pregnancy when administered as a mixture.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Howdeshell, Kembra L. and Wilson, Vickie S. and Furr, Johnathan and Lambright, Christy R. and Rider, Cynthia V. and Blystone, Chad R. and Hotchkiss, Andrew K. and Gray, Leon Earl, Jr.}, year={2008}, month={Sep}, pages={153–165} }
 @article{howdeshell_furr_lambright_wilson_ryan_gray_2008, title={Gestational and lactational exposure to ethinyl estradiol, but not bisphenol a, decreases androgen-dependent reproductive organ weights and epididymal sperm abundance in the male long evans hooded rat}, volume={102}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfm306}, abstractNote={Many chemicals released into the environment are capable of disrupting normal sex steroid balance, including the oral contraceptive ethinyl estradiol (EE) and the plastic monomer bisphenol A (BPA). EE and BPA are reported to impair reproductive organ development in laboratory animals; however, effects of lower doses of these chemicals have been debated. The goal of the current study was to determine whether relatively low oral doses of EE or BPA would alter male reproductive morphology and associated hormone levels of Long Evans hooded rat. Dams were gavaged with corn oil vehicle, EE (0.05-50 mug/kg/day) or BPA (2, 20, and 200 mug/kg/day) during pregnancy through lactation from gestational day 7 to postnatal day (PND) 18. Anogenital distance was measured at PND2 and nipple retention was measured at PND14 in male pups. Male offspring were euthanized beginning at PND150, and sera and organs were collected for analyses. Adult body weight was significantly decreased in males exposed to 50 mug EE/kg/day. Developmental EE exposure reduced androgen-dependent tissue weights in a dose-dependent fashion; for example, seminal vesicle and paired testes weights were reduced with >/= 5 mug EE/kg/day. Epididymal sperm counts were also significantly decreased with 50 mug EE/kg/day. In contrast, treatment with 2, 20, or 200 mug BPA/kg/day or EE at 0.05-1.5 mug/kg/day did not significantly affect any male endpoint in the current study. These results demonstrate that developmental exposure to oral micromolar doses of EE can permanently disrupt the reproductive tract of the male rat.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, author={Howdeshell, Kembra L. and Furr, Johnathan and Lambright, Christy R. and Wilson, Vickie S. and Ryan, Bryce C. and Gray, L. Earl, Jr.}, year={2008}, month={Apr}, pages={371–382} }
 @inproceedings{howdeshell_rider_wilson_gray_2008, title={Mechanisms of action of phthalate esters, individually and in combination, to induce abnormal reproductive development in male laboratory rats}, volume={108}, number={2}, booktitle={Environmental Research (New York, N.Y.)}, author={Howdeshell, K. L. and Rider, C. V. and Wilson, V. S. and Gray, L. E.}, year={2008}, pages={168–176} }
 @article{howdeshell_furr_lambright_rider_wilson_gray_2007, title={Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: Altered fetal steroid hormones and genes}, volume={99}, ISSN={["1096-6080"]}, DOI={10.1093/toxsci/kfm069}, abstractNote={Exposure to plasticizers di(n-butyl) phthalate (DBP) and diethylhexyl phthalate (DEHP) 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 peptide 3 (insl3) gene expression, a hormone critical for gubernacular ligament development. We hypothesized that coadministered DBP and DEHP would act in a cumulative dose-additive fashion to induce reproductive malformations, inhibit fetal steroid hormone production, and suppress the expression of insl3 and genes responsible for steroid production. Pregnant Sprague Dawley rats were gavaged on gestation days (GD) 14-18 with vehicle control, 500 mg/kg DBP, 500 mg/kg DEHP, or a combination of DBP and DEHP (500 mg/kg each chemical; DBP+DEHP); the dose of each individual phthalate was one-half of the effective dose predicted to cause a 50% incidence of epididymal agenesis. In experiment one, adult male offspring were necropsied, and reproductive malformations and androgen-dependent organ weights were recorded. In experiment two, GD18 testes were incubated for T production and processed for gene expression by quantitative real-time PCR. The DBP+DEHP dose increased the incidence of many reproductive malformations by >or=50%, including epididymal agenesis, and reduced androgen-dependent organ weights in cumulative, dose-additive manner. Fetal T and expression of insl3 and cyp11a were cumulatively decreased by the DBP+DEHP dose. These data indicate that individual phthalates with a similar mechanism of action, but with different active metabolites (monobutyl phthalate versus monoethylhexyl phthalate), can elicit dose-additive effects when administered as a mixture.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Howdeshell, Kembra L. and Furr, Johnathan and Lambright, Christy R. and Rider, Cynthia V. and Wilson, Vickie S. and Gray, L. Earl, Jr.}, year={2007}, month={Sep}, pages={190–202} }