Fetal and early postnatal environmental exposures and reproductive health effects in the female

DES exposure induces changes in the expression of many genes such as Wnt7a, Hoxa9, Hoxa10, Hoxa11, lactoferrin and c-fos genes

2008 Study Abstracts

Current studies are investigating the possibility that neonatal estrogen exposure may alter activin signaling in the ovary, thereby leading to ovarian pathologies. We have examined the effect of neonatal DES and E2 exposure on the mRNA and protein levels of the key factors involved in activin signaling in the mouse ovary. Preliminary results demonstrate that neonatal estrogen exposure decreases activin subunit gene expression and impacts activin signaling, indicating that activin genes are targets of estrogen action in the mouse ovary. Future studies will further characterize the mechanisms underlying the effects of premature estrogen and activin exposure on adult ovarian and follicular function.

From the 1940s to 1970s, the xenoestogen DES was extensively prescribed to pregnant women at risk for miscarriage. 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. Since DES is readily metabolized and cleared within days after exposure, the persistent alterations resulting from developmental DES exposure cannot simply be explained by residual body burden of the compound. DES exposure also induces changes in the expression of several uterine genes involved in tissue patterning, such as Wnt7a, Hoxa9, Hoxa10 and Hoxa11, contributing to changes in tissue architecture and morphology. DES-induced developmental programming appears to require the estrogen receptor α (ERα), suggesting that signaling through this receptor is crucial for establishing developmental programming. These initial observations with DES firmly established the developmental period as a window of susceptibility during which an inappropriate xenoestrogen exposure can induce developmental programming and increase risk for diseases, including cancer, later in life.

We have recently demonstrated that developmental programming can increase the risk for developing uterine leiomyoma in adulthood the adult. Utilizing rats carrying a germline defect in the tuberous sclerosis complex 2 (Tsc-2) tumor suppressor gene that are predisposed to uterine leiomyomas, we found that an early life exposure to DES during development of the uterus increased risk for uterine leiomyoma from 65% to greater than 90% and increased tumor multiplicity and size in genetically predisposed animals, but failed to induce tumors in wild-type rats. Importantly, we found that DES exposure imparted a hormonal imprint on the developing uterine myometrium in both wild-type and carrier rats, causing an increase in expression of estrogen-responsive genes prior to the onset of tumors. Thus, when developmental programming of estrogen-responsive genes was combined with the presence of the Tsc-2 tumor suppressor gene defect, the result was an increased risk of developing hormone-dependent leiomyoma in adult animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor suppressor gene penetrance in genetically susceptible individuals. Developmental programming occurred as a result of the hormonal imprint imparted on the developing uterus by the brief early life exposure to DES.

Sources

  • Full study (free access) : Fetal and Early Postnatal Environmental Exposures and Reproductive Health Effects in the Female, Fertility and Sterility, NCBI PubMed PMC2527475, 2008 Feb.
  • Featured image Mel Elías.
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