A recent study published in the Nature journal, titled "Maternal iron deficiency causes male-to-female sex reversal in mouse embryos," has sparked widespread attention and confusion. Many have interpreted this as evidence that iron deficiency during pregnancy can change a male fetus into a female, seemingly contradicting basic biological knowledge that sex is determined at conception by XY or XX chromosomes. However, a closer look at the research reveals a more nuanced reality. This article delves deep into the study’s findings, clarifying the complex mechanisms at play in the context of epigenetic regulation. It further discusses the implications for human pregnancies, weighing the theoretical risks against real-world epidemiological data. Additionally, it emphasizes the importance of addressing iron deficiency during gestation—all while grounding the analysis in scientific context and real-world data. By comprehensively exploring these aspects, readers can gain a clear understanding of the study's significance and its relevance to maternal and fetal health.
A groundbreaking study in the prestigious journal Nature has recently made waves with a headline that seems to challenge long-held biological beliefs: "Maternal iron deficiency causes male-to-female sex reversal in mouse embryos."
The claim has left many people startled. Does this mean that if a pregnant woman doesn’t get enough iron, her unborn son could somehow become a daughter? Isn’t a baby’s sex determined the moment a sperm fertilizes an egg? Do the XY chromosomes suddenly lose their power? Is everything we learned in high school biology being overturned?
Before jumping to conclusions—or worse, trying to manipulate the sex of a child based on this headline—it’s crucial to dig into the actual research. As we’ll see, the title refers to a specific biological phenomenon, not a literal "sex change" as commonly understood.
What Did the Study Actually Discover?
Basic biology teaches us that genetic material plays a major role in shaping our physical traits. Yet, even identical twins—who share nearly identical DNA—can have differences that can’t be explained by their genetic code alone. This is because genes aren’t like machines that run perfectly once they’re "installed"; their activity is influenced by a variety of factors.
Some factors boost a gene’s activity, while others dampen it, leading to big differences in how genes are "expressed" and, consequently, in the traits they produce. This field of study is known as epigenetics, and the Nature paper explores how epigenetic factors interact with genes during early development.
In the earliest stages of embryonic growth, an undifferentiated structure called the primordial gonad forms—this has no distinct male or female characteristics. As development progresses, if the embryo carries a Y chromosome, a gene on that chromosome called Sry (the sex-determining region Y) triggers the primordial gonad to develop into testes. Without a Y chromosome, the gonad naturally develops into ovaries.
The researchers behind the Nature study noticed something intriguing: during the critical period when male mouse embryos’ primordial gonads start to develop into testes, the iron metabolism pathways in these gonads become highly active. Genes responsible for absorbing iron and producing ferrous ions (a form of iron) were much more active, while genes involved in excreting iron were less so. Additionally, ferrous ions accumulated in both the cytoplasm and nuclei of the gonad cells. Clearly, iron levels in the gonad cells of male embryos rise significantly during this key developmental window.
Figure 1: Activation of iron metabolism pathways in embryonic gonads
This led to a critical question: Could iron play a unique role in the development of testes?
To find out, the researchers conducted further experiments. They found that genes related to iron intake indeed influence the epigenetic regulation of the Sry gene. Maintaining a proper iron balance, they concluded, is essential for the primordial gonad cells to develop male characteristics.
Lab experiments on cells confirmed that iron deficiency prevents the Sry gene from functioning properly, causing the primordial gonad to develop into ovaries instead of testes. However, this effect could be reversed: either by replenishing iron in time or by genetically forcing the Sry gene to activate, the gonad would switch back to developing into testes.
Figure 2: Iron deficiency leads to inhibition of Sry activation in cultured gonads
In the animal experiments, when mother mice were made acutely iron-deficient using an iron-chelating agent (a substance that binds to iron and removes it) during the critical period of gonad development, 4 out of 72 male (XY) mouse pups were born with two ovaries, and 1 had one ovary and one testis. In contrast, when mother mice were fed an iron-poor diet before and early in pregnancy—leading to iron-deficiency anemia by the critical gonad development stage—all 58 XY offspring had normally developed gonads, despite the fetuses being iron-deficient.
The research team further delved into the molecular mechanisms. They found that iron deficiency affects an enzyme called Kdm3a, which is crucial for removing certain chemical marks (histone methylation) that keep the Sry gene "switched off" initially. With less iron available, Kdm3a can't do its job effectively, and the Sry gene remains less active. This reduced activity disrupts the normal cascade of events that should lead to testes development, resulting in the development of ovaries instead.
In summary, the study found that iron deficiency can disrupt the epigenetic regulation of the Y-chromosome gene Sry, interfering with the development of the male mouse embryo’s reproductive system. Put simply, iron deficiency may cause the gonads of a male mouse fetus to develop into ovaries rather than testes—which is what the paper’s title means by "male-to-female sex reversal."
Importantly, this is a disruption of gonad development in male embryos, not a literal "transformation" of a male fetus into a female. It's also important to note that this is a complex biological process that involves multiple steps in gene regulation and cell differentiation, all of which are delicately balanced and can be perturbed by factors like iron deficiency.
Should Pregnant Women Be Concerned?
In short: Not overly. Looking at the study’s results, while cell experiments clearly show that iron deficiency harms the gonad development of male mice, the animal experiments tell a more reassuring story. Even in the extreme scenario where mother mice were made severely iron-deficient with chelating agents, only 5 out of 72 XY mice (about 7%) showed abnormal gonad development. When iron deficiency was induced through a poor diet (resulting in anemia), none of the 58 XY mice had gonad issues.
This suggests that in mice, it’s difficult for the fetal environment to reach the extreme iron-depleted state seen in cell experiments. So while there’s a theoretical risk, the actual occurrence of iron-related gonad abnormalities in male embryos is low. What’s more, the study only describes phenomena observed in cell and mouse experiments. Whether the same effects occur in humans remains unproven and requires further research.
Epidemiological data on humans supports this caution. The World Health Organization (WHO) reported in 2023 that 35.5% of pregnant women worldwide suffer from anemia, with iron deficiency being one of the most common causes. Many more pregnant women may be iron-deficient without meeting the criteria for anemia. Despite this high prevalence of iron deficiency in pregnancy, cases where a newborn with XY chromosomes has female physical traits are extremely rare.
A German epidemiological study found that only 2 out of every 10,000 newborns have ambiguous genitalia—and XY chromosomes with female-like traits are just one subset of these rare cases. This stark contrast between widespread iron deficiency and rare genital abnormalities strongly suggests that the risk of iron deficiency causing gonad development issues in human male fetuses is very low. Based on this Nature study alone, most people have little to worry about.
That said, while iron deficiency is unlikely to affect fetal gonad development in humans, it’s still a serious issue that demands attention for the health of both the mother and the baby—regardless of the baby’s sex.
Beyond the potential impact on gonad development, iron deficiency during pregnancy in humans has been associated with a host of other concerns. For the mother, it can lead to increased fatigue, making it difficult to carry out daily activities and take care of herself during pregnancy. It also heightens the risk of complications during childbirth, such as an increased likelihood of excessive bleeding (postpartum hemorrhage) due to the weakened state of the mother's body. For the fetus, iron deficiency can impede normal growth and development. It may lead to low birth weight, which in turn can be associated with various health problems in the newborn, including a higher susceptibility to infections and developmental delays in the long run.
Iron Deficiency Anemia: A Problem That Needs Attention
Beyond the iron in hemoglobin (the protein that carries oxygen in blood), the body stores extra iron for emergencies. A diagnosis of "iron deficiency anemia" means not only that hemoglobin levels are low but also that these iron stores are depleted. Even without anemia, low iron stores indicate a state of iron deficiency.
A 2025 review in the Journal of the American Medical Association (JAMA) refers to both low iron stores and iron deficiency anemia as "absolute iron deficiency" (distinguished from "functional iron deficiency," where iron is available but can’t be used due to issues like inflammation).
The review notes that absolute iron deficiency affects approximately 2 billion people worldwide. Whether or not it leads to anemia, it can cause symptoms such as fatigue, irritability, depression, poor concentration, restless legs syndrome (affecting 32–40% of cases), pica (a craving for non-food substances, seen in 40–50% of cases), shortness of breath, dizziness, exercise intolerance, and worsening heart failure. The likelihood and severity of these symptoms vary based on age, pre-existing conditions, and how severe or rapid the iron deficiency is.
During pregnancy, the risk of iron deficiency anemia is higher due to physiological changes like increased blood volume (which dilutes hemoglobin) and the growing fetus’s demand for iron. Iron deficiency in pregnancy not only brings the same risks as in non-pregnant adults but also raises the chances of complications such as placental abruption, postpartum hemorrhage, and poor fetal growth—threatening the health of both mother and child. For these reasons, proper prenatal care, including monitoring iron levels and supplementing when needed, remains crucial.
In the United States, for example, prenatal care guidelines often include routine blood tests to check iron levels early in pregnancy. If a woman is found to be iron-deficient, healthcare providers typically recommend iron supplements, along with dietary advice. Foods rich in iron, such as red meat, poultry, fish, beans, lentils, and fortified cereals, are encouraged in the diet. In some cases, if the anemia is severe, more intensive treatment options may be considered, such as intravenous iron therapy under medical supervision. Similarly, in European countries, there is a strong emphasis on early detection and management of iron deficiency during pregnancy to ensure the best possible outcomes for both mother and baby.
References
- Okashita N, Maeda R, Kuroki S, et al. Maternal iron deficiency causes male-to-female sex reversal in mouse embryos. Nature. Published online June 4, 2025. doi:10.1038/s41586-025-09063-2
- World Health Organization. Anaemia in women and children. 2023. Available at: https://www.who.int/data/gho/data/themes/topics/anaemia_in_women_and_children
- Thyen U, Lanz K, Holterhus PM, Hiort O. Epidemiology and initial management of ambiguous genitalia at birth in Germany. Hormone Research. 2006;66(4):195-203. doi:10.1159/000094782
- Auerbach M, DeLoughery TG, Tirnauer JS. Iron Deficiency in Adults: A Review. JAMA. 2025;333(20):1813-1823. doi:10.1001/jama.2025.0452
- American College of Obstetricians and Gynecologists. Anemia in Pregnancy: ACOG Practice Bulletin, Number 233. Obstetrics & Gynecology. 2021;138(2):e55-e64. doi:10.1097/AOG.0000000000004477
- Shi H, Chen L, Wang Y, et al. Severity of Anemia During Pregnancy and Adverse Maternal and Fetal Outcomes. JAMA Network Open. 2022;5(2):e2147046. Published 2022 Feb 1. doi:10.1001/jamanetworkopen.2021.47046