Epoxiconazole‐Induced Degeneration in Rat Placenta and the Effects of Estradiol Supplementation

Abstract

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.

Effects of Estrogen Coadministration on Epoxiconazole Toxicity in Rats

“…In addition, hematologic parameters, clinical chemistry parameters, sex hormones, and the weights of previously identified target organs were determined in the dams at necropsy. The placentas were subjected to detailed histopathologic analysis (Rey Moreno et al, ). Finally, in an intervention experiment, groups of pregnant rats administered EPX from GD 7 to 21 were co‐treated with estrogen (i.e., ECP).…”

“…Also, the incidence of vaginal hemorrhage was reduced with increasing ECP dose. It is possible that the vaginal hemorrhage was indicative of placental damage (Rey Moreno et al, ) and may have contributed to the observed anemia.…”

“…The clarification of the human relevance of the estrogen‐related mechanism behind EPX‐mediated late fetal resorptions in rats warrants further studies. In particular, this involves histopathological investigation of the placenta (Rey Moreno et al, ), since it is the materno‐fetal interface and crucial for fetal maintenance. The human relevance is best addressed in a species which is closer to humans with reference to placentation and hormonal regulation of pregnancy, such as the guinea pig (Schneider et al, ).…”

Species Differences in Developmental Toxicity of Epoxiconazole and Its Relevance to Humans

“…However, the dose of 50 mg/kg body weight per day also elicited distinct maternal toxicity, as shown by reduced corrected body weight, reduced food consumption, clear anemia, and almost complete suppression of maternal serum estradiol. Placentas of fetuses undergoing late resorption showed degenerative changes of the labyrinth and trophospongium (Rey Moreno et al., ). These results indicate that intrauterine resorptions are not caused by a specific embryo‐fetotoxic effect of epoxiconazole, but rather due to a maternally mediated effect at toxic dose levels on the placentas, which are no longer able to adequately nourish the fetuses.…”

“…These results indicate that intrauterine resorptions are not caused by a specific embryo‐fetotoxic effect of epoxiconazole, but rather due to a maternally mediated effect at toxic dose levels on the placentas, which are no longer able to adequately nourish the fetuses. Both the increased incidence of late resorptions and degeneration of the placentas could be prevented by maternal supplementation with estrogen (Rey Moreno et al., ; Stinchcombe et al., ). However, this supplementation did not prevent the other maternally toxic effects of epoxiconazole, that is, reduced body weight gain and anemia.…”