In utero exposure to both high- and low-dose diethylstilbestrol disrupts mouse genital tubercle development†

Stewart, Melanie K; Mattiske, Deidre M.; Pask, Andrew J

doi:10.1093/biolre/ioy142

Cited by 21 publications

(10 citation statements)

References 41 publications

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“…Exogenous testosterone given during early to mid‐gestation increases female AGD in diverse animal models including rodents, monkeys, and sheep (Abbott et al, 2012 ; DeHaan et al, 1987 ; Hotchkiss et al, 2007 ; Rhees et al, 1997 ). High doses of prenatal estrogenic chemicals decrease AGD in rodents, apparently through their ability to suppress testosterone production (Stewart et al, 2018 ). Thus, although AGD is generally used as a proxy for prenatal testosterone exposure, AGD—and reproductive development more broadly—involves complex interactions between testosterone and estrogen (Barrett et al, 2014 ; Williams et al, 2001 ).…”

Section: Resultsmentioning

confidence: 99%

Endometriosis and polycystic ovary syndrome are diametric disorders

Dinsdale

Crespi

2021

Evolutionary Applications

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Evolutionary and comparative approaches can yield novel insights into human adaptation and disease. Endometriosis and polycystic ovary syndrome (PCOS) each affect up to 10% of women and significantly reduce the health, fertility, and quality of life of those affected. PCOS and endometriosis have yet to be considered as related to one another, although both conditions involve alterations to prenatal testosterone levels and atypical functioning of the hypothalamic-pituitary-gonadal (HPG) axis. Here, we propose and evaluate the novel hypothesis that endometriosis and PCOS represent

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Section: Resultsmentioning

confidence: 99%

Endometriosis and polycystic ovary syndrome are diametric disorders

Dinsdale

Crespi

2021

Evolutionary Applications

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“…Another explanation could be lent from observations that estrogenic compounds can reduce the ability of Leydig cells to synthesize testosterone, as reviewed elsewhere (Svechnikov et al 2010). A recent study where mice were exposed to diethylstilbestrol (DES) also resulted in a short AGD in male offspring, again hypothesized to be caused by reduced testosterone production (Stewart et al 2018). This is in agreement with what has been observed in rats following exposure to high doses of estrogens, where AR expression is lost in all tissues that show 'anti-androgenic' effects, as well as a reduction in Leydig cell numbers (Williams et al 2001).…”

Section: Agd In Animal Toxicity Studies: Miscellaneous Compoundsmentioning

confidence: 99%

Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders

et al. 2018

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Male reproductive development is intricately dependent on fetal androgen action. Consequently, disrupted androgen action during fetal life can interfere with the development of the reproductive system resulting in adverse effects on reproductive function later in life. One biomarker used to evaluate fetal androgen action is the anogenital distance (AGD), the distance between the anus and the external genitalia. A short male AGD is strongly associated with genital malformations at birth and reproductive disorders in adulthood. AGD is therefore used as an effect readout in rodent toxicity studies aimed at testing compounds for endocrine activity and anti-androgenic properties, and in human epidemiological studies to correlate fetal exposure to endocrine disrupting chemicals to feminization of newborn boys. In this review, we have synthesized current data related to intrauterine exposure to xenobiotics and AGD measurements. We discuss the utility of AGD as a retrospective marker of in utero anti-androgenicity and as a predictive marker for male reproductive disorders, both with respect to human health and rodent toxicity studies. Finally, we highlight four areas that need addressing to fully evaluate AGD as a biomarker in both a regulatory and clinical setting.

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“…It is well established that chemicals that block androgens can cause hypospadias (8)(9)(10). Interestingly, estrogen and estrogen-mimicking chemicals also impact penis growth and urethral closure, causing hypospadias in mice and humans alike (14)(15)(16). We are exposed to many chemicals in everyday life that impact our endocrine-signaling pathways.…”

mentioning

confidence: 99%

A critical role for estrogen signaling in penis development

et al. 2019

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Hypospadias, a developmental defect of the penis, is one of the most common congenital malformations in humans. Its incidence has rapidly increased over recent decades, and this has been largely attributed to our increased exposure to endocrine‐disrupting chemicals. Penis development is primarily an androgen‐driven process; however, estrogen and xenoestrogens are known to affect penis development in both humans and mice. Here, we investigated the role of estrogen in the developing penis. Using a novel penis culture system, we showed that exogenous estrogen directly targets the developing penis in utero to cause hypospadias. In addition, we also uncovered an unexpected endogenous role for estrogen in normal postnatal penis development and showed that a loss of estrogen signaling results in a mild hypospadias phenotype, the most common manifestation of this disease in humans. Our findings demonstrated that both androgen and estrogen signaling are intrinsically required for normal urethral closure. These findings confirmed that penis development is not an entirely androgen‐driven process but one in which endogenous estrogen signaling also plays a critical role.—Govers, L. C., Phillips, T. R., Mattiske, D. M., Rashoo, N., Black, J. R., Sinclair, A., Baskin, L. S., Risbridger, G. P., Pask, A. J. A critical role for estrogen signaling in penis development. FASEB J. 33, 10383†10392 (2019). http://www.fasebj.org

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In utero exposure to both high- and low-dose diethylstilbestrol disrupts mouse genital tubercle development†

Cited by 21 publications

References 41 publications

Endometriosis and polycystic ovary syndrome are diametric disorders

Endometriosis and polycystic ovary syndrome are diametric disorders

Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders

A critical role for estrogen signaling in penis development

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