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THE CUMULATIVE EFFECTS OF THE FUNGICIDE PROCYMIDONE AND THE PLASTICIZER DI(N-BUTYL) PHTHALATE ON SEXUAL DIFFERENTIATION IN MALE SPRAGUE-DAWLEY RATS.
Ostby, Joseph1, Furr, Johnathan1, Gray, Earl1, 1
ABSTRACT- This study investigated the cumulative effects of two antiandrogens which do not share common mechanisms of toxicity, to determine if coadministration of these compounds produced additive, synergistic or antagonistic effects on androgen-dependent tissue development. The androgen-receptor (AR) antagonist, procymidone (P), competitively inhibits natural ligand-AR binding, and dibutyl phthalate (DBP) which possesses no detectable affinity for the AR is thought to inhibit fetal testosterone synthesis. Timed-pregnant Sprague-Dawley rats were gavaged daily from gestational day 14 - 18 with the vehicle (5 ml corn oil/kg-bw), 50 mg P/kg/5 ml vehicle, 500 mg DBP/kg/5 ml vehicle or 50 mg P/kg/2.5 ml vehicle + 500 mg DBP/kg/2.5 ml vehicle. These dosages were selected to produce a low incidence of gross malformations when each compound was administered alone. Individually, both P and DBP reduced male anogenital distance (AGD) at two days of age and increased the percent of areolas in 13 day old males. The combination of P + DBP was estimated to produce an additive effect on AGD and the percent of areolas/male. Separately, P and DBP reduced ventral prostate and levator ani/bulbocavernosus muscle weights and increased the number of permanent nipples/male. Together, P + DBP produced an estimated additive or slightly greater than additive effect on the ventral prostate, levator ani/bulbocavernosus muscle and number of permanent nipples/male. Independently, P produced a 1.5 % incidence of hypospadias, while DBP had no effect on glans penis development. However, the combined dose of P + DBP yielded a 49% incidence of hypospadias. Also, the combined dose of P + DBP reduced cauda epididymal weights by 17%, seminal vesicle weights by 19% and increased the incidence of vaginal pouches (27%) and bladder stones (11%), while neither P nor DBP altered the development of any of these tissues. In conclusion, coadministration of the antiandrogens P and DBP which alter androgen-dependent tissue development through different mechanisms of action, appeared to produce at least an additive effect on most of the androgen sensitive endpoints measured in this study. This abstract does not necessarily reflect USEPA policy.
KEY WORDS: antiandrogens, androgen-receptor antagonist, testosterone synthesis inhibitor, additivity