A novel group of ovarian toxicants: the psoralens

The psoralens are naturally occurring metabolites found in many crop plants; synthetic forms of 5-methoxypsoralen (bergapten) and 8-methoxypsoralen (xanthotoxin) are widely used in skin photochemotherapy. Our previous research documented that dietary bergapten and xanthotoxin reduced birthrates in female rats when males and females were exposed to these chemicals. The present study was designed to determine the cause of this reduced birthrate and whether this resulted from direct impact on the females. The study demonstrates that bergapten and xanthotoxin administered, either alone or in combination to female rats (mated to undosed males), significantly reduced the number of implantation sites, pups, and corpora lutea in dosed females compared with control animals. Additionally, full uterine weight and empty uterine weight were significantly reduced. These compounds also significantly reduced circulating estrogen levels in a dose-dependent manner. Interestingly, the psoralens significantly induced mRNAs of liver enzymes typically induced by polycyclic aromatic hydrocarbons, CYP1A1 and UGT1A6; the higher the dose, the greater the induction. UGT 2B1 mRNA, typically induced by phenobarbital-like compounds, was not significantly affected. Thus, enhanced oxidative metabolism and conjugation of estrogens in psoralen-treated animals may provide a partial explanation for the effects observed. These findings are also consistent with psoralen-induced reduction in ovarian follicular function and ovulation.