The doses and duration of dosing in these previous studies were greater than those used in this study. Furthermore, the authors of the previous studies suggested that the effects of MXC on gonadotropins might be a secondary effect due to ovarian atrophy. In other studies of female CD-1 mice, the effects of MXC on female reproduction were speculated to be due to estrogen mimicry and/ or damage to the hypothalamic-pituitary-ovarian axis. These studies, however, did not include measurements of estradiol, FSH, or LH. It appears from the results of our study that the increase in atresia and the decline in healthy antral follicles observed after MXC treatment are not due to a decrease in estradiol, FSH, or LH.
Our study shows that MXC treatment does not significantly affect the levels of ERa, ERp, or FSHR in the ovary. This is the first in vivo study that we are aware of that has examined the effect of MXC on ERa, ERp, or FSHR. As stated previously, estrogen is necessary for FSHR induction, and our results suggest that MXC does not mimic estrogen to induce, nor does it block estrogen to reduce FSHR content. Furthermore, our study suggests that MXC does not act as an estrogen to induce levels of estrogen receptor.
In conclusion, our data suggest that MXC-induced atresia involves the Bax and Bcl-2 protein signaling pathways. Our data also suggest that MXC does not induce atresia by altering levels of estradiol or the gonadotropins, nor does it alter levels of ERa, ERp, or FSHR. There are many other members of the Bcl-2 family, and future studies should look at the expression of other Bcl-2 family members in treated follicles, such as Mcl-1 and Bok, as each is thought to be a major player in ovarian apoptosis. Such studies will lead to an increased understanding of how toxicants induce atresia, and possibly lead to treatments for toxicant-induced ovarian failure.