Perinatal exposure to low levels of the environmental antiandrogen vinclozolin alters sex-differentiated social play and sexual behaviors in the rat

Environmental Health Perspectives, June, 2005 by Nathan K.W. Colbert, Nicole C. Pelletier, Joyce M. Cote, John B. Concannon, Nicole A. Jurdak, Sara B. Minott, Vincent P. Markowski

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Benchmark dose modeling. We performed benchmark dose calculations on the total erections per session and the total play behavior in the male offspring on PND34. These two variables were selected because they are the best overall measures of erectile function and play, and consequently, they generalize more readily to humans. A polynomial model provided the best description of the erection data. The corresponding E[D.sub.10] benchmark for erections was 1.23 mg/kg with a 95% lower bound of 0.84 mg/kg (Figure 7). The E[D.sub.01] benchmark was 0.11 mg/kg with a lower bound of 0.08 mg/kg. The linear model provided the best description of the play data. The E[D.sub.10] associated with total play in the male offspring on PND34 was 1.33 mg/kg with a lower bound of 0.77 mg/kg (Figure 8). The E[D.sub.01] for total play was 0.13 mg/kg with a lower bound of 0.08 mg/kg.

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Discussion

The results of this study clearly demonstrate that social and reproductive behaviors in the rat are disrupted by exposure to low doses of Vz during the perinatal period. Maternal doses of 12 mg/kg, administered from GD14 through PND3, were associated with a significant increase in social play behavior in PND34 offspring. We observed no Vz-mediated differences on PND22, indicating that the effect emerged as offspring matured. The increased play on PND34 was more pronounced in males than in females. In adulthood, male offspring produced significantly fewer penile erections, an effect that was even more sensitive than play behavior because a decrease was noted after maternal doses as low as 1.5 mg/kg.

Although other researchers have reported that high doses of Vz (200 mg/kg) administered to rat pups on PND2 and PND3 reduced play behavior (Hotchkiss et al. 2003), this study is the first to describe play behavior effects near the LOAEL of 11.5 mg/kg/day (U.S. EPA 2000a). Although we did not observe nipple and areola retention in immature male offspring, visual inspection of the data suggests that there was a dose-related trend.

The play behavior procedure used in the present study was more sensitive to low-dose effects than those used in previous investigations, possibly because of methodologic differences. In the present study we examined nape contact, pounce, pin, and wrestle, as well as mount behaviors, whereas previous studies examined only pin (Flynn et al. 2001) or pin and chase behaviors (Hotchkiss et al. 2003). Nape contact, a behavior that often initiates a play bout, was greatly affected by perinatal Vz, and this component was not examined in previous studies. Although we hypothesized that perinatal Vz would demasculinize male offspring and lead to a reduction of play behavior, we actually observed a dose-related increase in play. Exposure to other developmental toxicants such as prenatal morphine (Hol et al. 1996; Niesink et al. 1999), mycotoxins (Ferguson et al. 1997), or phytoestrogens (Flynn et al. 2000) has been associated with increased play, and, as mentioned above, social hyperactivity in juvenile rats is linked to aberrant sexual behavior in adults (Gerall et al. 1967).