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IN UTERO EXPOSURE TO THE FUNGICIDE PROCYMIDONE AND DIBUTYL PHTHALATE PRODUCE DOSE ADDITIVE DISRUPTIONS OF MALE RAT SEXUAL DIFFERENTIATION
Citation:
HOTCHKISS, A. K., J. R. FURR, C. BLYSTONE, C. V. RIDER, L. E. GRAY, AND K. HOWDESHELL. IN UTERO EXPOSURE TO THE FUNGICIDE PROCYMIDONE AND DIBUTYL PHTHALATE PRODUCE DOSE ADDITIVE DISRUPTIONS OF MALE RAT SEXUAL DIFFERENTIATION. Presented at 2009 SOT Annual Meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
Postr presentation for the 2009 Society of Toxicology meeting
Description:
Procymidone (PRO) and dibutyl phthalate (DBP) alter male rat sexual differentiation by disrupting the androgen-signaling pathway via distinctly different cellular mechanisms of toxicity. DBP inhibits fetal Leydig cell androgen production whereas PRO binds AR and blocks androgen action in the target tissues. Here, we report on two studies in which pregnant rats were treated with a mixture of PRO and DBP. We hypothesized that these chemicals would induce adverse effects on reproductive development in a dose-additive fashion. In the 1st study, SD rats were gavaged on gestational day 14-18 with either corn oil, 50 mg/kg/d PRO, 750 mg/kg/d DBP, or 50 mg/kg/d PRO + 750 mg/kg/d DBP. The 2nd study was a fixed ratio study with a control group, a top dose group mixture (PRO at 150 mg/kg/d and DBP at 1125 mg/kg/d) or seven dilutions of the top dose (83, 67, 50, 33, 17, 8, or 4%). In F1 male rats, the mixtures resulted in dose-related reductions in AGD, increased nipple retention and malformations, and reduced reproductive tissue weights. Further, these changes were accurately predicted by dose- but not by response-addition models indicating that these chemicals did not interact independently. We also found a dose related increase in testicular interstitial cell adenomas and hyperplasia in the 67% and above groups and seminiferous tubular degeneration in the 50% and above groups; effects that could not be modeled given the absence or low incidence of similar lesions in the individual PRO and DBP studies. Despite different mechanisms, coadministration of DBP and PRO produced dose additive effects on androgen-dependent tissues. The data suggest that having a common mechanism should not be a requirement for conducting a cumulative risk assessment; rather it should be based on producing similar adverse effects. This abstract does not necessarily reflect US EPA policy.