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Iron deficiency in pregnant mice may lead to the development of ovaries in a small proportion of offspring carrying XY chromosomes, which typically determine male sex. The findings, in Nature this week, reveal a link between iron metabolism and sex determination in mammals.

A key gene responsible for male sex determination in mammals is Sry, which controls the development of the testes and is found on the Y chromosome. An enzyme called KDM3A that is essential for regulating Sry gene expression is known to rely on Fe²⁺ for its activity. However, how iron levels may influence sex determination remains unclear.

To explore the potential connection between iron metabolism and sex determination in mammals, Makoto Tachibana and colleagues conducted a series of experiments using cultured cells and mice. They found that genes favoring accumulation of Fe²⁺ are upregulated in developing mouse embryonic gonads during the crucial period of sex determination.

When the authors reduced iron levels in cultured cells to approximately 40% of normal levels, expression of the Sry gene was largely suppressed, and the XY gonads began to show genetic markers associated with ovary development.

The researchers then tested the effects of both short-term and long-term iron deficiency in pregnant mice. Short-term iron deficiency was induced by administering an iron-removing drug to pregnant mice for about five days around the time of embryonic sex determination. Among 72 XY offspring born to these mothers, four developed two ovaries and one developed an ovary and a testis.

Long-term iron deficiency was induced through a low-iron diet starting four weeks before pregnancy and continuing for six weeks. This long-term low-iron diet showed no effect on sex determination until a loss-of-function mutation in the gene that encodes KDM3A was introduced in the mothers. This resulted in male-to-female sex reversal in two of 43 XY offspring. No abnormalities were observed in offspring born to mothers with normal iron levels in either of the experiments.

The findings demonstrate a key role of iron in mammalian sex determination, although the effects of iron deficiency on human pregnancies were not investigated.