Transgenerational neuroendocrine disruption of reproduction

2011 summary of epigenetic and transgenerational effects of DES

Key points

  • The hypothalamic neuroendocrine systems develop in a sexually dimorphic manner, largely because of differences in levels of gonadal steroids
  • Environmental endocrine disrupting chemicals (EDCs) impair the function of the neuroendocrine systems that control reproduction
  • Developmental exposure to EDCs, particularly during embryonic and early postnatal periods, permanently impairs functions and predisposes individuals to disease later in life owing to altered epigenetic programming
  • The mechanisms of EDC action include effects on the epigenetic molecular machinery that controls gene expression in hypothalamic and reproductive tissues
  • Effects of EDCs may be transmitted transgenerationally through molecular changes to the germline or through context-dependent modifications to somatic cells by continued exposures to EDCs or the individual’s social or environmental context

DES and epigenetic transmission

Transgenerational epigenetic effects of the estrogenic EDC diethylstilbesterol (DES) began with observations of rare vaginal clear-cell carcinomas and reproductive tract abnormalities in young women whose mothers had been prescribed DES in a misguided effort to avert miscarriage. These observations provided the first evidence for developmental programming or the fetal basis of adult disease caused by exogenous estrogens in humans. A potent estrogenic pharmaceutical, DES not only failed to reduce miscarriage risk, but it also exposed the developing daughters and sons to high levels of prenatal estrogens and predisposed them to adult diseases. Animal studies have replicated many of these effects of prenatal DES treatment and have begun to reveal the molecular mechanisms by which DES programs developing tissues. The case of DES is important because it is one of the first to link fetal exposure to a hormonally active compound with the latent development of disease years or even decades after the insult. This example in humans has laid the groundwork for much of the work on the effect of other EDC exposures to the fetus.

Epidemiological studies have also found that DES is associated with a small but significant increase in birth defects in grandchildren of women given DES during pregnancy. The granddaughters reported an increase in heart conditions,  slight but significant differences in their menstrual cycles and a reduction in live births when compared with women whose grandmothers were not exposed to DES.  Another study found an increase in the risk of hypospadias in the sons of women who were exposed to DES in utero,  and there was the single clinical observation that the 15-year-old granddaughter of a woman who took DES while she was pregnant developed a small-cell carcinoma of the ovary  Although the sample sizes in the last two studies were exceedingly small (28 and 1, respectively), they provide preliminary evidence for the potential of transgenerational effects of EDCs in the human population.

Rodent studies have revealed transgenerational epigenetic effects of DES. DES exposure of the F1 generation during embryonic and early postnatal development at a range of dosages had adverse consequences in the F2 generations. In F2 males, the incidence of proliferative lesions of the testes was increased, and serum estradiol concentration was reduced. In F2 females, the incidence of uterine adenocarcinomas and other tumors of the reproductive tract was increased in a subset of the dosage groups. Exposure of newborn (postnatal day 1–5) F1 female mice to 2 μg of DES led to demethylation of the estrogen-sensitive gene lactotransferrin promoter at two CpG dinucleotides (−464 and −454) in the uterus, and to upregulation of uterine expression of lactotransferrin in both F1 female mice and their F2 female offspring.  Female F1 animals exposed to the same dosing paradigm had decreased methylation of exon 4 of the Fos gene on postnatal day 5 and increased Fos mRNA expression in the uterus in adulthood.  Additionally, mice exposed gestationally to 10 μg/kg of DES from embryonic days 9–16 resulted in increased methylation of the homeobox A10 promoter and intron and increased Hox-A10 protein expression in the postnatal uterus (day 14).

Treatment of newborn, female and male mice on post-natal days 1–5 with 3 μg per pup per day of DES changed total DNA methylation in reproductive tissues. DES also altered expression of the enzymes that regulate DNA methylation. For example, expression of DNA methyltransferases 1, 3a and 3b was increased in the epididymis, and DNA methyltransferases 1 and 3b were increased in the uterus of mice exposed to DES compared with animals exposed to the vehicle control. Finally, in rats treated with 1 mg/kg DES on postnatal days 10–12, the exposure decreased global histone trimethylation at lysine 27 in the uterus on postnatal day 12 and altered the expression of several estrogen-sensitive genes in the uterus of the neonatal and adult exposed animals. Although most of these studies have only been conducted in tissues from F1 individuals, they provide insight into the potential targets for molecular epigenetic modifications that merit further study in subsequent generations in rodents.


  • Transgenerational neuroendocrine disruption of reproduction, Endocrinology, NCBI PubMed PMC3976559, 2011 Jan 25.
  • Summary of epigenetic and transgenerational effects of DES featured image PMC3976559/table/T1.

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