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

The Vz-exposed males showed a selective reduction of low-intensity (E1) erections. In this regard, the exposed offspring resemble males castrated as adults, which also show an early reduction of E1 erections (Leipheimer and Sachs 1993). The behavior of the exposed offspring is also reminiscent of male rats that have been administered serotonin receptor agonists (Mas et al. 1985) or agents that block the synthesis of nitric oxide (Hull et al. 1994). Both of these treatments reduce erections and increase seminal emissions. Perhaps the most parsimonious explanation of the differential regulation of penile erections versus seminal emissions has been offered by Hull and others. In a series of drug microinjection studies, this group has demonstrated that pharmacologic stimulation of dopamine D2 receptors in the medial preoptic area decreases the frequency of erections while increasing seminal emissions (Bazzett et al. 1991). Stimulation of D2 receptors in the paraventricular nucleus also facilitates seminal emission (Eaton et al. 1991; Pehek et al. 1989). On the other hand, stimulation of D1 receptors in the medial preoptic area has the opposite effect and occurs at much lower doses (Hull et al. 1992). Because the functional integrity of dopamine systems in this part of the brain is maintained by circulating testosterone (Du and Hull 1999), an environmental antiandrogen such as Vz might disrupt the development of these complex interactions.

As mentioned above, animal studies indicate that fetal males are far more sensitive to environmental antiandrogens than adults. Results from maternal stress studies shed some light on the likely developmental mechanisms affected by environmental antiandrogens. Maternal stress during the last week of pregnancy lowers the surge of plasma testosterone that is normally present in male rat fetuses during GD18 and GD19 (Ward and Weisz 1984). Attenuation of the GD18-19 surge is associated with impaired sexual behavior in adulthood (Dunlap et al. 1978; Ward and Reed 1985). This testosterone surge also exerts an organizational effect on the muscle and spinal cord mechanisms that control penile erections in adulthood (Grisham et al. 1991). Perinatal androgens serve to rescue SNB motor neurons from programmed death (Sengelaub et al. 1989), a process that could be blocked by an antiandrogen like Vz. In the present study, animals were exposed to Vz from GD14 through PND3 in order to compare our results with previous perinatal Vz investigations. However, because differentiation of spinal cord motor neurons continues until PND10 (Mills and Sengelaub 1993) and the weight of the adult BC muscle is the most sensitive to Vz exposure during the GD16-17 period (Wolf et al. 2000), it is likely that the toxic window for Vz on erectile function spans the GD16-PND10 period. Thus, it appears that the critical periods for masculinization of erectile function and play behavior in the male rat are the same. As of yet, no one has examined the effects of environmental antiandrogen exposure during this entire perinatal sensitive period. It may be the case that social play and erectile functions are responsive to even lower doses of Vz, if an exposure were to span the GD 16-PND 10 period.