EDCs: Reproductive Effects of Early Life Exposures: The DES Example

2009 Study Abstract

Ovarian Follicular Development and the Environment

The ovarian follicle is the functional unit of the ovary and is comprised of an oocyte surrounded and supported by the somatic granulosa and theca cells (28). The health of the follicle can impact the health of the woman as well as the health of her offspring. For example, decreased numbers of follicles, multiple eggs per follicle and incomplete follicular development can all result in decreased fertility. The precise mechanisms involved in early ovarian follicle formation are not known, but are essential in organizing the fetal ovary and establishing the postnatal follicle number that will provide the female with sufficient oocytes for a lifetime of fertility.

Estrogen and activin are two known factors that play an important role in regulating oocyte and follicle development and function and aberrant development and ovarian pathologies are observed in mice exposed to neonatal estrogen or activin. Neonatal exposure of rats to estradiol benzoate has been show to delay follicle and interstitial development. Neonatal exposure to diethylstilbestrol (DES) or the natural estrogen estradiol (E2) results in lack of corpora lutea in adult mice, suggesting that these effects persist beyond reproductive tract development and impact fertility in the adult. Neonatal exposure to DES, E2, or the phytoestrogen genistein also induces formation of multi-oocytic follicles in mice – an effect that is also reported in alligators exposed to environmental estrogenic contaminants. Additionally, activin administered during the critical, postnatal period of primordial follicle formation changes the number of postnatal follicles. Current mechanistic studies are exploring whether neonatal estrogen exposure alters activin signaling in the ovary; preliminary findings of decreased activin subunit gene expression and impacted activin signaling in the mouse ovary support this hypothesis.

Uterus Development and the Environment

Women exposed to DES in utero during critical periods of reproductive tract development developed several types of reproductive tract abnormalities, as well as an increased incidence of cervical-vaginal cancer later in life. Animal studies that simulate the human DES experience have since shown that exposure of the developing reproductive tract of CD-1 mice to DES imparts a permanent estrogen imprint that alters reproductive tract morphology, induces persistent expression of the lactoferrin and c-fos genes and induces a high incidence of uterine adenocarcinoma. Experiments in rats have shown exposure to DES during the critical window of uterine development leaves a hormonal imprint on the developing uterine myometrium in rats that were genetically predisposed to uterine leiomyoma, increasing the risk for adult uterine leiomyoma from 65% to greater than 90% and increasing tumor multiplicity and size. DES-induced developmental programming appears to require the estrogen receptor α , suggesting that signaling through this receptor is crucial for establishing developmental programming.

Studies have now been extended beyond DES to demonstrate that other environmental estrogens reprogram gene expression in the uterus : exposure to genistein and BPA during the period of maximum sensitivity to developmental programming induces the expression of the estrogen-responsive genes calbindin and progesterone receptor. Neonatal BPA exposure attenuated estrogen-responsive genes whereas genistein exposure induced an even higher level of estrogen responsiveness than DES exposure. In contrast to DES, exposure to these environmental estrogens does not disrupt ovarian function in adult females, which continue to cycle normally.

Sources

• PMC, Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: executive summary, PMC2440710, Feb 1, 2009.

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