\u201cTo our knowledge, this is the first demonstration that an environmental factor can influence sex determination in a mammal,\u201d lead author Makoto Tachibana, a developmental biologist, told El Pais<\/a>. \u201cThe most important implication of this finding is that environmental and metabolic conditions influence fundamental developmental decisions that until now were thought to be strictly determined by genetics.\u201d<\/p>\n A Matter of Iron<\/p>\n The results stem from a simple question: what happens when developing embryos are starved of iron?<\/p>\n Iron is not just for blood. Inside developing gonads, it plays a crucial role in activating enzymes that remove chemical tags from DNA\u2014tags that otherwise keep key genes like Sry silent. One enzyme in particular, called KDM3A, needs ferrous iron (Fe\u00b2\u207a) to function. Without it, Sry stays off. And if Sry doesn\u2019t speak, the embryo becomes female, regardless of its XY chromosome pair.<\/p>\n To test this, Tachibana\u2019s team tried three separate strategies. First, they knocked out an iron transport gene, Tfrc, in gonadal cells of mouse embryos. Seven out of 39 genetically male mice developed ovaries instead of testes.<\/p>\n Then, they gave pregnant mice an oral iron chelator\u2014a compound that binds iron and makes it unavailable. This chemical mimic of iron deficiency caused three out of 72 XY embryos to develop ovotestes, mixed-sex organs containing both ovarian and testicular tissue.<\/p>\n Finally, the team fed mice a long-term low-iron diet. That alone didn\u2019t trigger a sex change\u2014until they combined it with a mutation in Kdm3a. Then, some XY embryos again reversed sex.<\/p>\n Across all experiments, the mechanism was the same: reduced iron blocked the removal of methyl groups\u2014epigenetic tags\u2014that silence Sry. The gene never activated and the embryos became females.<\/p>\n \u201cThis study provides clear evidence that variations in metabolism in the controlled uterine environment interface with the genetic sex-determination cascade and affect testis development,\u201d wrote Shannon Dupont and Blanche Capel, developmental biologists at Duke University, in a commentary also published in Nature<\/a>.<\/p>\n An Environmental Lever in a Genetic Lock<\/p>\n The findings are provocative because mammals have long been considered immune to environmental influences on sex. In reptiles and fish, the story is different. Temperature, social rank, or even parasites can nudge embryos toward one sex or another. Mammals, though, were thought to be locked into their genetic fate. Until now.<\/p>\n \u201cDiscovering that something as mundane as iron concentration can cause a mammalian embryo to develop as a female is spectacular,\u201d said Francisco Javier Barrionuevo, a geneticist at the University of Granada, who was not involved in the study. He speculated that such sex reversals in humans could have gone unnoticed in the past\u2014especially in cases of extreme malnutrition.<\/p>\n For now, no such human cases have been identified. \u201cAt this point, we don\u2019t know if a similar process could occur in humans,\u201d Tachibana admitted. \u201cIt\u2019s a very important question that deserves to be investigated.\u201d<\/p>\n Iron deficiency is not rare. It is the most common nutritional deficiency worldwide, especially in pregnant women. Mild cases are typically corrected with diet or supplements. Severe iron deficiency, however, is a known risk factor for miscarriage and impaired fetal development.<\/p>\n This study raises a new possibility: could iron levels during pregnancy subtly alter not just sex determination, but other features of development typically seen as hardwired?<\/p>\n \u201cIt opens up the possibility that the mother\u2019s diet could affect not only the formation of testes but also other traits of \u2018masculinity,\u2019\u201d Dupont and Capel wrote.<\/p>\n![\"From](\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/06\/1749486611_185_SHVRYW23BFBQLGJSTPHAPOUJB4-1024x791.jpg\")
<\/a>From left to right, a healthy male mouse, an intersex mouse, and a female one, born to iron-deficient mothers. Credit: Makoto Tachibana<\/p>\n
![\"Male-ification](\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/06\/assets_task_01jx05znbeekerdtrjym90zzp1_1749131835_img_0-1024x683.webp.webp\")
<\/a>Male-ification commenced. Image generated using Sora\/ChatGPT<\/p>\n