Iron deficiency in pregnant mice may cause a small fraction of offspring carrying XY chromosomes, which normally determine male sex, to develop ovaries, according to a study published in Nature on June 4. The finding reveals a link between iron metabolism and sex determination in mammals.
An important gene that determines the sex of mammals is Sry, which controls testicular development and is located on chromosome Y. An enzyme called KDM3A is key to regulating the expression of the Sry gene, and its activity is known to depend on ferrous ions (Fe2+), but how iron levels affect sex determination remains unclear.
To study the relationship between iron metabolism and sex determination in mammals, Makoto Tachibana and colleagues at Osaka University in Japan conducted a series of experiments using cultured cells and mice. They found that during the critical period of sex determination, genes that favor Fe2+ accumulation are upregulated in the gonads of developing mouse embryos. When the authors reduced iron levels in cultured cells to about 40% of normal levels, Sry gene expression was significantly suppressed, and XY gonads began to show genetic markers related to ovarian development.
The authors then tested this effect in mice with short-term and long-term iron deficiency during pregnancy. Short-term iron deficiency was induced by injecting pregnant dams with an iron-depleting drug five days before and after the embryonic sex determination stage. These dams gave birth to approximately 72 XY offspring, of which four developed bilateral ovaries and one developed one ovary and one testis. Long-term iron deficiency was induced by a low-iron diet during the first four weeks of pregnancy and by introducing a loss-of-function mutation in the gene encoding KDM3A into the mother. This resulted in a sex change from male to female in two of the 43 XY offspring. In both experiments, no abnormalities were found in the offspring of dams with normal iron levels.
The scientists believe that although the effects of iron deficiency in human pregnancy have not been studied, the findings suggest an important role for iron in sex determination in mammals.
Related paper information: https://doi.org/10.1038/s41586-025-09063-2
(Original title: "A mother's iron deficiency may turn her son into a "daughter")