Friday, December 4, 2015

Researchers Identify Genes Connecting Endocrine Disruption to Micropenis and Other Genital Malformations

Martin J Cohn
Researchers at the University of Florida Health recently announced that they have identified genes that are disrupted by abnormal hormone signalling at crucial points during development. These findings may lead to a better understanding of how some of the most common male genital birth defects, like micropenis, arise in humans.

The study was published in the Proceedings of the National Academy of Sciences journal. The research team was led by principal investigator Martin J. Cohn, Ph.D., a professor of molecular genetics and microbiology in the UF College of Medicine and a member of the UF Genetics Institute.

The discovery that environmental signals can interfere with the activity of genes that orchestrate genital development in mouse embryos has potential implications for increasingly common genital birth defects that affect one out of every 125 boys in developed countries.

Cohn and his team, Zhengui Zheng, Ph.D., and Brooke Armfield, Ph.D., both postdoctoral associates in the department of molecular genetics and microbiology, found that androgen and estrogen -hormones produced by the endocrine system - control a series of genes in the embryonic genitalia of mice.

In the team's experiments, when the balance between these two hormones was disrupted, the activity of those genes changed and the genitalia developed abnormally. That provided a new genetic link between endocrine disruption and genital defects, said Cohn.

However, it was not yet clear that disrupting the genes’ activity was the direct cause of these malformations. To answer that question, the researchers manipulated the target genes and discovered that inactivating even one of them was enough to cause feminization of the male genitals.

The hormonal disruptions led to several birth defects, including hypospadias, abnormal genital curving (known as chordee), micropenis; and ambiguous genitals.

photo showing a man's penis with chordee
Human penis with chordee.
The researchers note that the timing of the endocrine disruption was also very crucial. The researchers found a series of short periods of development when different genital deformities can arise in mice with otherwise normal, healthy genes. The type of genital malformation that develops is affected by the timing of the endocrine disruption.

For example, blocking the androgen signal during early development caused complete feminization of the genitalia, whereas slightly later disruptions led to hypospadias and chordee. After birth, either disrupting the androgen signal or increasing the estrogen signal resulted in micropenis, meaning that sexual differentiation of the genitalia begins before birth and continues through puberty.

“We identified very narrow windows of development that explain this broad spectrum of genital malformations.” Cohn said.

The researchers also pinpointed 22 genes expressed in embryonic genitalia that can be positively and negatively regulated by signals from the environment.

“I suspect that this could be the tip of the iceberg.” Cohn said.

Knowing which genes are responsible for genital birth defects and when the embryo is most vulnerable to endocrine disrupting signals is an important step forward, Cohn said. Over the past 40 years, the incidence of hypospadias has increased dramatically for unknown reasons. Mutations have been found in very few of the affected individuals.

photo of a man who has hypospadias
Example of penis with hypospadias

While there isn’t a scientific consensus about what causes genital birth defects, there is increasing evidence that environmental factors play a significant role.

“Our results suggest that if environmental factors disrupt the expression of genes during one of these critical developmental periods, then this can lead to the same kinds of malformations that result from mutations.” Cohn said.

Some chemicals that disrupt endocrine signaling occur in pesticides and herbicides, personal care products such as antibacterial soap and manufacturing of plastics.

“They’re pretty hard to avoid. We are exposed to endocrine disruptors every day.” Cohn said.

With this in mind, the researchers hope to better understand the mechanisms of endocrine disrupting chemicals that cause genital malformation.

“If we can determine how the embryo responds to the precise levels and combinations of endocrine disrupting chemicals in the environment, then there is an opportunity to improve prenatal care.” he said.

The team's ultimate goal is to find ways to protect embryos from the chemicals that cause genital birth defects.

The abstract of the study reads as following:

"Congenital penile anomalies (CPAs) are among the most common human birth defects. Reports of CPAs, which include hypospadias, chordee, micropenis, and ambiguous genitalia, have risen sharply in recent decades, but the causes of these malformations are rarely identified. Both genetic anomalies and environmental factors, such as antiandrogenic and estrogenic endocrine disrupting chemicals (EDCs), are suspected to cause CPAs; however, little is known about the temporal window(s) of sensitivity to EDCs, or the tissue-specific roles and downstream targets of the androgen receptor (AR) in external genitalia. Here, we show that the full spectrum of CPAs can be produced by disrupting AR at different developmental stages and in specific cell types in the mouse genital tubercle. Inactivation of AR during a narrow window of prenatal development results in hypospadias and chordee, whereas earlier disruptions cause ambiguous genitalia and later disruptions cause micropenis. The neonatal phase of penile development is controlled by the balance of AR to estrogen receptor α (ERα) activity; either inhibition of androgen or augmentation of estrogen signaling can induce micropenis. AR and ERα have opposite effects on cell division, apoptosis, and regulation of Hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling in the genital tubercle. We identify Indian hedgehog (Ihh) as a novel downstream target of AR in external genitalia and show that conditional deletion of Ihh inhibits penile masculinization. These studies reveal previously unidentified cellular and molecular mechanisms by which antiandrogenic and estrogenic signals induce penile malformations and demonstrate that the timing of endocrine disruption can determine the type of CPA."

    man showing his erect micropenis, ruler for proof
    Erect Micropenis
    more micropenis photos

    - Zhengui Zheng, Brooke A. Armfield, Martin J. Cohn. Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies. Proceedings of the National Academy of Sciences, 2015; 201515981 DOI: 10.1073/pnas.1515981112

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