Transgenerational Inheritance of DES Exposure

Mechanisms of the Maternal Exposome and Implications for Health Outcomes

2016 Study Abstract

It is well established that the environment contributes to health. However, few studies have evaluated environmental exposures in women that may influence future health of their offspring. Knowledge gained may inform nursing how to better advocate for patients and families; and provide individualized interventions and education. Therefore, a more comprehensive investigation of the maternal exposome to uncover mechanistic insight into complex disease in offspring is warranted. To advance understanding of biological mechanisms that contribute to high-risk birth outcomes and offspring predisposition to disease, it will be necessary to measure a range of exposures and biomarkers before and during pregnancy.

Evidence for Trans-generational Inheritance of Exposures

Exposures of the gametes, including those that occur during the prenatal period and early development, have been found to play a large role in risk of disease over the lifespan. Studies in animal models have documented epigenetic changes that persist from generation to generation. For example, in murine models, the methylation changes associated with DES exposure persist into the third generation suggesting in utero exposures may have a lasting impact on the health of future generations. The same chemical clearly demonstrates a link between environment and germ-line mutations in humans as a trans-generational alteration in DNA methylation patterns of the fetus caused by exposure to DES in utero. DES is a synthetic estrogen that was administered to pregnant women to prevent spontaneous abortions prior to the mid 1970’s. DES causes hypermethylation of the homeobox protein Hox-A10 (HOXA10), a gene that controls uterine organ development, resulting in reproductive tract anomalies that persist into adulthood. Hypermethylation of HOXA10 was specific to the fetus and did not occur in laboratory experiments using cell lines or the somatic cells of pregnant women who received DES, suggesting that this molecular alteration is unique to in utero exposure.

Investigations are ongoing in grandchildren of women given DES. Current clinical evidence suggests DES granddaughters have more menstrual irregularities, infertility, and stillbirths; and both granddaughters and grandsons exhibit more birth defects. This accumulating evidence supports that epimutations occur from exposure during gonadal sex determination, a highly vulnerable period when the germ line DNA is demethylated and remethylated in a sex specific manner. The chemically-induced modifications in epigenetic programming of the germ line results in differentially altered epigenomes and transcriptomes in all tissues propagated from the affected sperm or ovum, which can influence development of disease in later life. Although data is sparse related to trans-generational effects of environmental exposures in human studies, there is a need to better inform clinicians and patients about this critically vulnerable period during, and prior to, pregnancy. Confirmation of animal models of trans-generational effects will require the enrollment at least 3 generations of participants (grandparent, parent, and child).

Sources

  • Full study (free access) : Mechanisms of the Maternal Exposome and Implications for Health Outcomes, ANS Adv Nurs Sci, NCBI PubMed, PMC4860277, 2016 Apr-Jun.
  • Exposome Penetrance featured image PMC4860277/figure/F2.
DES DIETHYLSTILBESTROL RESOURCES

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