A human’s sex is genetically determined. One of our 23 pairs of chromosomes carries genes that determine the embryo’s sex; males have two different sex chromosomes (XY) while females have two X chromosomes (XX). However, for six weeks, every mammalian embryo is in limbo—neither male nor female, but somewhere in between while the body develops. Then, a switch flips. A gene called Sry, nestled on the Y chromosome, turns on. Testes begin to form. Hormones follow. A genetic boy becomes a biological one.
That’s what the textbooks say. But a new study published in Nature turns this assumption on its head. Scientists at Osaka University in Japan have discovered that something as mundane as a mother’s iron levels can override this process entirely—turning genetically male mouse embryos into females.
“To our knowledge, this is the first demonstration that an environmental factor can influence sex determination in a mammal,” lead author Makoto Tachibana, a developmental biologist, told El Pais. “The 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.”
A Matter of Iron
The results stem from a simple question: what happens when developing embryos are starved of iron?
Iron is not just for blood. Inside developing gonads, it plays a crucial role in activating enzymes that remove chemical tags from DNA—tags that otherwise keep key genes like Sry silent. One enzyme in particular, called KDM3A, needs ferrous iron (Fe²⁺) to function. Without it, Sry stays off. And if Sry doesn’t speak, the embryo becomes female, regardless of its XY chromosome pair.
To test this, Tachibana’s 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.
Then, they gave pregnant mice an oral iron chelator—a 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.
Finally, the team fed mice a long-term low-iron diet. That alone didn’t trigger a sex change—until they combined it with a mutation in Kdm3a. Then, some XY embryos again reversed sex.
Across all experiments, the mechanism was the same: reduced iron blocked the removal of methyl groups—epigenetic tags—that silence Sry. The gene never activated and the embryos became females.
“This study provides clear evidence that variations in metabolism in the controlled uterine environment interface with the genetic sex-determination cascade and affect testis development,” wrote Shannon Dupont and Blanche Capel, developmental biologists at Duke University, in a commentary also published in Nature.
An Environmental Lever in a Genetic Lock
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.
“Discovering that something as mundane as iron concentration can cause a mammalian embryo to develop as a female is spectacular,” 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—especially in cases of extreme malnutrition.
For now, no such human cases have been identified. “At this point, we don’t know if a similar process could occur in humans,” Tachibana admitted. “It’s a very important question that deserves to be investigated.”
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.
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?
“It opens up the possibility that the mother’s diet could affect not only the formation of testes but also other traits of ‘masculinity,’” Dupont and Capel wrote.
Rewriting the Script of Sex
Nearly 40 years ago, the discovery of the Sry gene revolutionized biology’s understanding of sex. The gene was seen as the master key, unlocking a cascade of male development. It was elegant in its simplicity—and, scientists thought, untouchable by external noise.
But now, that view is being challenged by what appears to be one of biology’s softest touches: a micronutrient.
The genetically male mice with ovaries appeared otherwise healthy up to eight weeks of age, but researchers have not yet tested whether they can reproduce.
Still, this research lays a new foundation. It suggests a broader principle: that even the most fundamental biological decisions—like whether to become male or female—are not wholly encoded in the genome. They can be tuned, or even rewritten, by the environment in which development unfolds.
