On Dec. 17, 2025, new research has mapped the cell types that specialise to form reproductive organs in both sexes, identifying key genes and signals that drive this process. The findings offer important insights into conditions affecting the reproductive organs, and how environmental chemicals may affect reproductive health.

Researchers at the Wellcome Sanger Institute and EMBL’s European Bioinformatics Institute (EMBL-EBI) used a combination of single-cell and spatial genomics technologies to analyse over half a million individual human cells from the developing reproductive system.  Published in Nature, the study provides the most detailed picture to date of how reproductive organs form in the womb, uncovering crucial biological pathways that shape their development.

Although chromosomal sex (XX or XY) is determined at conception, visible differences in the developing reproductive system do not appear until about six weeks later. At this stage, all embryos have undifferentiated gonads as well as the same paired structures — the Müllerian ducts and the Wolffian ducts — which have the potential to form the female or male internal reproductive organs. A gene on the Y chromosome called SRY triggers the undifferentiated gonads to develop into the testes; the testes then produce hormones that guide the Wolffian ducts to form male reproductive structures and cause the Müllerian ducts to regress. In the absence of SRY, the gonads become ovaries and the Müllerian ducts develop into female reproductive organs. 

While development of the testes and ovaries in humans has been mapped at the cellular and molecular level in detail due to their importance in fertility, the development of the rest of the reproductive system has been far less understood, until now. 

In the study, researchers at the Sanger Institute and EMBL-EBI analysed over half a million individual cells from 89 donated embryonic and fetal tissue samples, in order to look at what genes and signals underpin the differentiation of the male and female reproductive tract. The study is part of the Human Cell Atlas initiative which is mapping all cell types in the body to understand health and disease. 

Firstly, the scientists uncovered the genes that help the Müllerian duct mature in females, and other genes that are likely to trigger its breakdown in males. In the developing external genitals, they traced how the formation of the urethra differs between males and females, offering new clues about the causes of hypospadias, a condition where the urethra opens partway along the penis instead of at the tip.

Next, the researchers mapped changes in gene activity in the Müllerian and Wolffian ducts. To do this, they built a computational model that allowed the tracking of genes that are switched on or off along the length of these ducts as they grow. This revealed gradual, region-by-region shifts in gene activity and identified specific signalling pathways that help divide the ducts into distinct organs. As a result, the study proposes an updated model of how the HOX code shapes reproductive organs, revealing previously unreported HOX genes that pattern the upper fallopian tube and epididymis.

Finally, the team looked into how vulnerable developing reproductive tissues are to environmental disruption using tiny 3D models (known as organoids) of the developing uterine lining. When exposed to compounds such as bisphenol A (BPA) and butyl benzyl phthalate — which are both linked to health concerns — the organoids switched on oestrogen-responsive genes. This confirms that the fetal uterine lining can initiate a genetic response to environmental oestrogens.  However, the researchers note that it remains unclear what levels of these compounds the reproductive system is exposed to in real-world maternal conditions.

By creating this high-resolution atlas of the developing reproductive system, the researchers have provided a strong foundational reference map for how reproductive organs develop — offering new clues into how reproductive disorders arise.