Dose Response of Developmental Effects

Oral administration of vinclozolin at 100 or 200 mg/kg/day to pregnant rats during sexual differentiation (gestational day 14 to postnatal day 3) demas-culinizes and feminizes the male offspring. Vinclozolin-treated male offspring display female-like anogenital distance (AGD) at birth, retained nipples, cleft phallus with hypospadias, suprainguinal ectopic testes, a blind vaginal pouch, epididymal granulomas, and small to absent sex accessory glands. In contrast, the testis is a relatively insensitive target for antiandrogens as compared to the external genitalia and sex accessory glands, and female offspring do not display malformations or permanent functional alterations. A comparison of the in vitro dosimetry data with the biological effects of vinclozolin suggest that when M1 and M2 concentrations in maternal serum approach their respective K values for AR, male offspring would display hypospadias [109].

When we administered vinclozolin by gavage to the dam at 0,3.125,6.25,12.5, 25,50, or 100 mg/kg/day from gestational day (GD) 14 to postnatal day 3 [110], doses of 3.125 mg/kg/day and above reduced AGD in newborn male offspring and increased the incidence of nipples/areolas in infant male rats. These effects were associated with permanent alterations in other androgen-dependent tissues. Ventral prostate weight in one year old male offspring was reduced in all treatment groups (significant at 6.25,25,50, and 100 mg/kg/day) and permanent nipples were detected in males at 3.125 (1.4%), 6.25 (3.6%), 12.5 (3.9%), 25 (8.5%), 50 (91%), and 100 (100%) mg/kg/day. To date, permanent nipples in adult male offspring (not to be confused with areolas or what some authors incorrectly described as "retained nipples" in infant male rats) have never been observed in a control male from any study in our laboratory.Vinclozolin-treatment at 50 and 100 mg/kg/day induced reproductive tract malformations, reduced ejaculated sperm numbers, and fertility. Even though all of the effects of vinclozolin likely result from the same initial event (AR binding), the different endpoints displayed a wide variety of dose-response curves and ED50s and some of these dose response curves failed to display an obvious threshold.

These data demonstrate that vinclozolin produces subtle alterations in sex differentiation of the external genitalia, ventral prostate, and nipple tissue in male rat offspring at dosage levels below the previously described no-observed-effect-level (NOEL). Some of the functional and morphological alterations were evident at dosage levels one order of magnitude below that required to induce malformations and reduce fertility. Hence, multigenerational reproduction studies of antiandrogenic chemicals conducted under the "old" multigenerational test guidelines that did not include endpoints sensitive to antiandrogens at low dosage level could yield a NOEL that is at least an order of magnitude too high.

Another study was designed to determine the most sensitive period of fetal development to the antiandrogenic effects of vinclozolin [111]. Pregnant rats were dosed orally with vinclozolin at 400 mg /kg/day on either GD 12 -13, GD 14-15, GD 16-17, GD 18-19, or GD 20-21, with corn oil vehicle (2.5 ml/kg). Malformations and other effects were seen in male rat offspring dosed with vin-clozolin on GD 14-15, GD 16-17 and GD 18-19, with the most pronounced effects resulting from exposure on GD 16-17. These effects include reduced AGD, increased number areolas and nipples, malformations of the phallus, and reduced levator ani/bulbocavernosus weight. The fetal male rat is most sensitive to antiandrogenic effects of vinclozolin on GD 16 and 17, although effects are more severe and 100% of male offspring are affected with administration of vinclozolin from GD 14 through GD 19.

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