Effects of DES in a Third Generation

Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects

2013 Selected Abstracts

Walker and Haven predicted that “if the high intensity of DES multigenerational carcinogenicity seen in mice is applicable to the human population, this is a health problem of major proportions.” They go on to say that it “could take over 50 years” to detect the effects in future generations, due to the length of time required for diseases such as cancer to manifest. It is predicted that cross-generational responses to DES exposure are possible due to epigenetic changes in the DNA and that the “germ cell pool could have become massively contaminated”. For example, early exposure to EDCs, like DES, is thought to reprogram mouse female reproductive tract development and affect how the reproductive tract responds to endogenous estrogens later in life. They suggest that “environmental estrogens may be more potent than previously suspected, due to synergistic action from concurrent exposures.”

The studies on the cohort of men (grandsons) and women (granddaughters) whose mothers were exposed prenatally to DES (grandchildren had no direct exposure) are limited as they are just beginning to reach the age when relevant health problems can be studied. Studies that have been performed contain preliminary data, as the power is low. Therefore, the main sources of information for third generation effects are rodent studies. In general, multi-generational mouse studies have shown an increased susceptibility to tumor formation in the third generation which suggests that DES grandchildren are also at an increased risk for cancer.


Currently there are no human studies that definitively show any adverse effects of DES for the third generation of females. A small cohort study of 28 DES granddaughters found no abnormalities in the lower genital tract and no cases of CCA. These results led authors to conclude that third generation effects were unlikely even after they acknowledged that the number of participants was too small and the women were too young for the findings to have any real significance.

Multigenerational rodent studies, as a primary source for information on the effects of DES exposure, disagree with those preliminary findings in humans. Although severe effects of DES were apparent in the first round of CD-1 mouse offspring (second generation), the third generation did not exhibit the same subfertility, regardless of exposure timing or dose. However, these studies have found an increased susceptibility to tumor formation in the third generation. Aged third generation female mice had increased risks for uterine cancers, benign ovarian tumors, and lymphomas. One study found cervical adenocarcinomas, which are not generally seen in untreated mice, in third generation females similar to those induced by direct prenatal DES exposure. In the same study, third generation female mice had increases in ovarian, uterine, and mammary tumors with the total number of reproductive tumors being statistically significant from the control mice.


The early reports of DES grandsons show an increase in hypospadias in this population. Hypospadias occurred twenty times more frequently in the DES grandsons’ cohort, which suggests that their mothers (DES daughters) may have had a disturbed hormonal balance during their reproductive life that interfered with the genital development of the male fetus. The prevalence of hypospadias was found to be >3% in DES grandsons but the risk of the defect is still low. Mouse studies in the third generation DES-exposed male population have found an increased susceptibility for reproductive tumor formation, specifically in the testes, prostate, and seminal vesicles. No effect on reproductive capacity or other deformities was seen in DES grandsons.


  • Full study (free access) : Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects, Birth defects research. Part C, Embryo today : reviews, NCBI PubMed PMC3817964, 2013 Nov 5.
  • Featured image credit Oskars Sylwan.

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