Epoxiconazole (CAS-No. 133855-98-8) was recently shown to cause both a marked depletion of maternal
estradiol blood levels and a significantly increased incidence of late fetal mortality when administered to pregnant rats throughout gestation (
GD 7-18 or 21);
estradiol supplementation prevented this
epoxiconazole effect in rats (Stinchcombe et al., 2013), indicating that
epoxiconazole-mediated
estradiol depletion is a critical key event for induction of late
fetal resorptions in rats. For further elucidation of the mode of action, the placentas from these modified prenatal developmental toxicity experiments with 23 and 50 mg/kg bw/d
epoxiconazole were subjected to a detailed histopathological examination. This revealed dose-dependent placental degeneration characterized by cystic dilation of maternal sinuses in the labyrinth, leading to
rupture of the interhemal membrane. Concomitant degeneration occurred in the trophospongium. Both placentas supporting live fetuses and late
fetal resorptions were affected; the highest degree of severity was observed in placentas with late resorptions. Placental degeneration correlated with a severe decline in maternal serum
estradiol concentration. Supplementation with 0.5 and 1.0 μg of the
synthetic estrogen estradiol cyclopentylpropionate per day reduced the severity of the degeneration in placentas with live fetuses. The present study demonstrates that both the placental degeneration and the increased incidence of late
fetal resorptions are due to decreased levels of
estrogen, since
estrogen supplementation ameliorates the former and abolishes the latter.