Maternal Iron Deficiency Alters Genetic Sex Determination in Mice

Recent research conducted by a team at Osaka University has uncovered groundbreaking insights into how maternal iron levels can override genetic sex determination in mammals. The study, published in the prestigious journal *Nature* on June 9, 2025, reveals that iron deficiency during pregnancy may lead to genetically male embryos developing as females, challenging long-held beliefs about the rigidity of genetic sex determination.

During the early stages of embryonic development, all mammalian embryos exist in a state of ambiguity regarding their sex. This limbo lasts for approximately six weeks, during which the presence of the Sry gene on the Y chromosome is critical for the development of male characteristics. Once activated, Sry prompts the formation of testes, leading to the production of male hormones and the establishment of male sexual characteristics. However, the study led by Dr. Makoto Tachibana, a developmental biologist at Osaka University, has demonstrated that the availability of iron plays a crucial role in this process.

Dr. Tachibana stated, "To our knowledge, this is the first demonstration that an environmental factor can influence sex determination in a mammal." The implications of this finding extend beyond mere academic curiosity; they raise significant questions about the impact of maternal nutrition on fetal development and sexual differentiation.

The research was prompted by a fundamental question: What happens to developing embryos when they are deprived of iron? Iron is essential not only for blood oxygenation but also for the activation of enzymes that remove chemical tags from DNA. These tags, particularly methyl groups, serve to silence key genes, including Sry. One enzyme, KDM3A, requires ferrous iron (Fe²⁺) to function effectively. Without adequate iron, this enzyme cannot act, resulting in the silencing of Sry and the default development of female characteristics in XY embryos.

In a series of experiments, the researchers employed three distinct approaches to assess the effects of iron deficiency on sex determination. Firstly, they genetically modified mouse embryos by knocking out the iron transport gene Tfrc, leading to the development of ovaries in seven out of 39 genetically male mice. Secondly, they administered an oral iron chelator to pregnant mice, which resulted in three out of 72 XY embryos developing mixed-sex organs, known as ovotestes. Finally, a long-term low-iron diet combined with a mutation in the Kdm3a gene triggered sex reversal in some XY embryos. Across all experiments, the consistent mechanism was the inability to remove methyl groups that silence Sry, resulting in female development despite the presence of XY chromosomes.

This research is particularly notable because mammals have traditionally been viewed as impervious to environmental influences on sex determination. Contrastingly, in other species such as reptiles and fish, environmental factors like temperature and social conditions can affect sex differentiation. Dr. Francisco Javier Barrionuevo, a geneticist at the University of Granada, remarked, "Discovering that something as mundane as iron concentration can cause a mammalian embryo to develop as a female is spectacular."

While no direct evidence exists yet to suggest that similar mechanisms occur in humans, the study raises important considerations regarding maternal health and nutrition. Iron deficiency is a prevalent issue globally, particularly among pregnant women, and is known to contribute to adverse pregnancy outcomes such as miscarriage and impaired fetal development. The potential for maternal diet to influence not just sex determination but other developmental traits traditionally seen as genetically fixed is a groundbreaking consideration in the field.

As the researchers continue to explore the implications of their findings, they emphasize the necessity for further investigations into how maternal health can impact fetal development. This study lays the groundwork for a reevaluation of the interplay between environmental factors and genetic programming in mammals, potentially reshaping our understanding of developmental biology. The future of research in this area holds promise for uncovering more about the complex interaction between genetics and the environment, particularly in the context of human health and development.