Severe iron deficiency during gestation affects the sexual differentiation of the embryo, sometimes leading to the development of ovaries in genetically male mice, demonstrates a study published in the journal Nature. “ It is the first time iron deficiency has been scientifically linked to sex determination", says to Science and Future Makoto Tachibana, who led this work at Osaka University (Japan).
For turtles and crocodiles, it is the temperature at which the embryos develop that determines whether they will develop into males or females. In mammals, however, it is the sex chromosomes that guide this process: XX for females, XY for males. In particular, it is the Sry gene, present on the Y (male) chromosome, that promotes the growth of testes instead of allowing the embryo to naturally develop towards female characteristics. Researchers in this field have therefore generally treated genetic sex determination as if it were largely independent of environmental signals", comment Shannon Dupont and Blanche Capel, cell biologists at Duke University Medical Center (USA), in a commentary on this work in the same journal.
The uterine environment is in fact controlled in terms of variations in temperature, pH or nutrients compared to what an egg undergoes. However, maternal environmental factors resulting from differences in nutrition, metabolism, or regulation of metal levels are potential sources of variability that could affect embryonic development.", point out the researchers.
Some XY embryos develop ovaries in the absence of iron
This is what this new Japanese study demonstrates. Our results are surprising, because no one had anticipated that iron levels could be involved in sex determination.", notes Makoto Tachibana. The link between the two is called KDM3, an enzyme that requires iron to function. Its role is to enable the expression (activation) of the Sry gene in male embryos by removing inhibitory molecules. " In other words, iron deficiency prevents KDM3 from functioning, leading to the inhibition of Sry. And without Sry, female sex development occurs by default.", summarizes Makoto Tachibana.
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By genetically manipulating the amount of iron delivered to the cells, the mice produced 39 XY embryos, 7 of which showed signs of female development, including ovaries instead of testes. Similarly, administering an iron-sequestering product to pregnant mice resulted in 72 XY individuals, 5 of which had female characteristics. Although the percentage of affected XY embryos was small, it is important to remember that these were embryos for which the outcome was obvious, i.e., there was full female sexual development", comment Shannon Dupont and Blanche Capel. Especially since it is not excluded that other mechanisms are at play in sexual differentiation and which attenuate the effect of iron deficiency.
Results that remain to be confirmed in humans
Could iron deficiency in a pregnant woman also affect the development of her unborn son? This is a very important question, but at this point, we don't yet have the answer. If Sry is essential for male sex determination in humans, it remains to be determined whether iron or KDM3 contributes to Sry activation in humans." , answers Makoto Tachibana. However, previous studies on human cohorts have demonstrated that the two severe forms of genetic anemia known as Diamond-Blackfan and Fanconi appear to be risk factors for the so-called "46,XY" disorder of sexual development, in which XY (genetically male) individuals show female sexual development.
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But the sensitivity of mammals to iron deficiency is probably not as strong as one might fear.By studying mouse gonad (sex organ) cells in the laboratory, researchers determined that iron deficiency must reach a threshold of 40% from the normal level for the Sry gene to be almost completely repressed. “ It is unlikely that such a level of iron deficiency would occur under normal environmental conditions. It is expected to have deleterious effects not only on sex determination, but also on various other physiological systems.", specifies Makoto Tachibana. In any case, and that human pregnancies turn out to be more or less sensitive to iron deficiency than those of mice, " there is no harm in preventing anemia", concludes the researcher.
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