Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study

Titus, Linda; Hatch, Elizabeth E.; Drake, Keith M.; Parker, Samantha E.; Hyer, Marianne; Palmer, Julie R.; Strohsnitter, William C.; Adam, Ervín; Herbst, Arthur L.; Huo, Dezheng; Hoover, Robert N.; Troisi, Rebecca

doi:10.1016/j.reprotox.2018.12.008

Cited by 55 publications

(31 citation statements)

References 44 publications

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“…Only one study has attempted to ascertain F2 neurodevelopmental impairments (Kioumourtzoglou et al ), and it indeed detected a link. Although a recent study found no evidence of same‐sex orientation in female F2s borne of female DES exposed F1s (Titus et al ), no other study has probed sociosexual outcomes in F2s other either sex, whether through male or female F1s. We note that a recent animal study found these types of F2 effects when F0 dams were exposed to EDCs (Krishnan et al ).…”

Section: The Imperative To Intensify Research On Des F2smentioning

confidence: 98%

“…Ovarian cancer risk is higher in F2 daughters of F1 women prenatally exposed to DES (Titus‐Ernstoff et al ). A new paper reports that F2 women of F1 exposed females have increased risks of menstrual aberrations, preterm birth, and possibly ectopic pregnancy (Titus et al ). Also recently, the first study to investigate neurodevelopmental outcomes in the DES F2 generation found significantly elevated odds for attention deficit hyperactivity disorder (ADHD) in the F2 grandchildren of F0 women who took DES during pregnancy (Kioumourtzoglou et al ).…”

Section: A Growing Body Of Empirical Evidencementioning

confidence: 99%

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Pregnancy drugs, fetal germline epigenome, and risks for next‐generation pathology: A call to action

Escher

Robotti²

2019

Environ and Mol Mutagen

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Drugs taken during pregnancy can affect three generations at once: the gestating woman (F0), her exposed fetus (F1), and the fetal germ cells that confer heritable information for the grandchildren (F2). Unfortunately, despite growing evidence for connections between F0 drug exposures and F2 pathology, current approaches to risk assessment overlook this important dimension of risk. In this commentary, we argue that the unique molecular vulnerabilities of the fetal germline, particularly with regard to global epigenomic reprogramming, combined with empirical evidence for F2 effects of F1 in utero drug and other exposures, should change the way we consider potential long‐term consequences of pregnancy drugs and alter toxicology's standard somatic paradigm. Specifically, we (1) suggest that pregnancy drugs common in the postwar decades should be investigated as potential contributors to the “missing heritability” of many pathologies now surging in prevalence; (2) call for inclusion of fetal germline risks in pregnancy drug safety assessment; and (3) highlight the need for intensified research to ascertain generational impacts of diethylstilbestrol, a vanguard question of human germline toxicity. Only by fully addressing this important dimension of transplacental exposure can we responsibly evaluate safety of drug exposures during pregnancy and convey the full scope of risks, while also retrospectively comprehending the generational legacy of recent history's unprecedented glut of evolutionarily novel intrauterine exposures. Environ. Mol. Mutagen. 60:445–454, 2019. © 2019 Wiley Periodicals, Inc.

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Section: The Imperative To Intensify Research On Des F2smentioning

confidence: 98%

Section: A Growing Body Of Empirical Evidencementioning

confidence: 99%

Pregnancy drugs, fetal germline epigenome, and risks for next‐generation pathology: A call to action

Escher

Robotti²

2019

Environ and Mol Mutagen

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“…The adverse health effects include a rare form of vaginal cancer in girls, increased incidence of uterine fibroids, endometriosis, impaired fecundity and earlier age at menopause [11]. Startlingly, reproductive effects are still apparent in women whose mothers have been prenatally exposed to DES [12].…”

Section: Characterisation Of Susceptible Windowsmentioning

confidence: 99%

Safeguarding Female Reproductive Health Against Endocrine Disrupting Chemicals—The FREIA Project

Duursen

Boberg

Christiansen

et al. 2020

IJMS

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Currently available test methods are not well-suited for the identification of chemicals that disturb hormonal processes involved in female reproductive development and function. This renders women’s reproductive health at increasing risk globally, which, coupled with increasing incidence rates of reproductive disorders, is of great concern. A woman’s reproductive health is largely established during embryonic and fetal development and subsequently matures during puberty. The endocrine system influences development, maturation, and function of the female reproductive system, thereby making appropriate hormone levels imperative for correct functioning of reproductive processes. It is concerning that the effects of human-made chemicals on the endocrine system and female reproductive health are poorly addressed in regulatory chemical safety assessment, partly because adequate test methods are lacking. Our EU-funded project FREIA aims to address this need by increasing understanding of how endocrine disrupting chemicals (EDCs) can impact female reproductive health. We will use this information to provide better test methods that enable fit-for-purpose chemical regulation and then share our knowledge, promote a sustainable society, and improve the reproductive health of women globally.

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“…In humans, women prenatally exposed to the endocrine-disrupting chemical diethylstilbestrol (DES) have an increased risk of reproductive tract anomalies, menstrual irregularities, infertility, pregnancy loss, and vaginal adenocarcinoma [ 64 ]. F2 women (daughters born to prenatally DES-exposed mothers) have been found to attain menstrual regularization later; they also were more likely to report irregular menstrual periods [ 65 , 66 ]. Similarly, F2 males (sons born to prenatally DES-exposed mothers) had an increased risk of hypospadias and testicular germ cell tumors [ 67 – 69 ].…”

Section: Potential Examples Of Non-genetic Germline Inheritance In Humentioning

confidence: 99%

Evidence for germline non-genetic inheritance of human phenotypes and diseases

Senaldi

Smith-Raska

2020

Clin Epigenet

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It is becoming increasingly apparent that certain phenotypes are inherited across generations independent of the information contained in the DNA sequence, by factors in germ cells that remain largely uncharacterized. As evidence for germline non-genetic inheritance of phenotypes and diseases continues to grow in model organisms, there are fewer reports of this phenomenon in humans, due to a variety of complications in evaluating this mechanism of inheritance in humans. This review summarizes the evidence for germline-based non-genetic inheritance in humans, as well as the significant challenges and important caveats that must be considered when evaluating this process in human populations. Most reports of this process evaluate the association of a lifetime exposure in ancestors with changes in DNA methylation or small RNA expression in germ cells, as well as the association between ancestral experiences and the inheritance of a phenotype in descendants, down to great-grandchildren in some cases. Collectively, these studies provide evidence that phenotypes can be inherited in a DNA-independent manner; the extent to which this process contributes to disease development, as well as the cellular and molecular regulation of this process, remain largely undefined.

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Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study

Cited by 55 publications

References 44 publications

Pregnancy drugs, fetal germline epigenome, and risks for next‐generation pathology: A call to action

Pregnancy drugs, fetal germline epigenome, and risks for next‐generation pathology: A call to action

Safeguarding Female Reproductive Health Against Endocrine Disrupting Chemicals—The FREIA Project

Evidence for germline non-genetic inheritance of human phenotypes and diseases

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