A critical role for estrogen signaling in penis development

Abstract

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

Atrazine induces penis abnormalities including hypospadias in mice

“…The ATR hypospadias phenotype was similar to that of mice exposed to the potent oestrogen diethylstilbestrol. 4,17 Collectively, the stunted growth and disrupted morphology of the MUMP, as well as hypospadias phenotype of ATR-exposed mice, are consistent with ATR eliciting an anti-androgenic and pro-oestrogenic response during penis development. Given the association between EDCs and the increasing incidence of hypospadias in humans, these data implicate ATR to be one of the many potential causative agents in the etiology of this common disease.…”

“…17 Furthermore, exposure of the developing penis to exogenous oestrogen is known to prevent urethral closure and demasculinise the developing genitalia leading to a smaller overall penis size and reduction of structures including the MUMP. 4,23,24 Therefore, the stunted growth and altered morphology of the MUMP, evident in all the ATR-exposed mice, are consistent with an endocrine disruption caused by the exposure. This is further validated by the incidence of hypospadias observed in one ATR-exposed mouse (14.3% incidence in the ATR cohort).…”

“…This is a well-established standard methodology for determining hypospadias in the mouse penis. 4,17 Statistical analyses All data were tested for normality using the Shapiro-Wilk test. Data subjected to repeated measures analysis were tested for sphericity using the Mauchly's sphericity test.…”

“…3 Correct urethral closure is dependent on androgens and blocked by exogenous oestrogens. 4 Environmental toxicants, namely, endocrine disrupting chemicals (EDCs), can interfere with both androgen and oestrogen signalling pathways. 5 EDCs are increasing exponentially in their abundance and are highly pervasive in our environment, due to their beneficial properties, such as being effective plasticisers, preservatives or pesticides, and their use in numerous industrial and manufacturing processes.…”

Hormonal and Molecular Regulation of Phallus Differentiation in a Marsupial Tammar Wallaby

“…The RNA-seq analysis identifies two sets of genes, including WNT5A, MAFB, RSPO4, lnc-RSPO4, FGF10, WIF1 and AP-1, FGF10, IGFBP3, IGFBP6, IGFBP5, EFNB2, that interact with SHH and IGF1, respectively, in the tammar phalluses at day 50 pp. Interestingly, due to the In mice, oestrogen signalling clearly has a regulatory role in phallus development [93,94], as we have found in the tammar [13,15,88]. In the tammar co-expression network, about 50% of estrogen receptor 1 (ESR1) co-expressed coding genes and lncRNAs are also associated with AR [88], suggesting an interaction between androgen receptor (AR) signalling and ESR1 signalling during tammar phallus development [88].…”