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Makoto Tachibana, center back row, with the rest of his team from Osaka University in Japan.
All living people have been both male and female at the same time for six weeks. Although our sex is determined at the moment the sperm fertilizes the egg, it is not until a month and a half later that the biological programming to develop testes or ovaries is activated.Textbooks have always taught that this process is 100% dictated by genetics: males have one female and one male chromosome, XY, and females have two female chromosomes, XX. But on Wednesday, the results of a bold experiment with mice were published, showing that very low iron levels in the mother can transform males into females, regardless of their genetics.
"To our knowledge, this is the first demonstration that an environmental factor can influence sex determination in a mammal," Makoto Tachibana, a biologist at Osaka University in Japan and leader of the research, published in the journal Nature, tells EL PAÍS. "The most important implication of this finding," he adds, "is that environmental and metabolic conditions influence fundamental developmental decisions that until now were thought to be strictly determined by genetics."
Almost four decades ago, the study of people born with ovaries despite being genetically male (XY), and vice versa — a rare genetic disorder — led to the discovery of the SRY gene. This genetic fragment within the male Y chromosome is the main factor responsible for sexual differentiation in mammals. If the gene is present, the gonads begin to form testes at six weeks of development; if not, they inevitably become ovaries.
This process also initiates the production of sex hormones and the activation of other genes that produce more physical traits characteristic of each sex. All this happens in the highly protected environment of the uterus, safe from environmental interference. Mammals are unusual in this respect, since many animals determine their sex based on temperature, social hierarchy, size, or parasites infecting the mother, as occurs in some reptiles, fish, and insects.
The researchers discovered that if iron concentration is reduced by 60% at the cellular level, the testicular gene is switched off. When they reproduced this iron deficiency in pregnant female mice carrying males, they observed that six out of 39 XY offspring were born with two ovaries, a complete sex reversal. Another mouse was born intersex, with one ovary and one testicle.
The same happened in another set of experiments, where they studied the morphology of embryos from mothers treated with a drug that sequesters iron from the body: five out of 72 males developed female sexual organs. Although these numbers of sex reversal might seem small, it is an undeniable effect on a fundamental developmental mechanism previously thought to be shielded from the outside.
The study details how an external factor ends up influencing the fetus's genetics. It is through epigenetics, a collection of chemical marks sensitive to environmental factors located on the genome that modify its functioning.
Extremely low iron affects the enzyme KDM3A, which modifies a chemical change that turns off the testis-producing gene SRY right at the moment of sex determination. The result is genetically male mice with two ovaries that lived apparently healthy up to eight weeks, although it has not been studied whether they could reproduce — in humans, sex reversal usually leads to infertility.
Iron deficiency in the body, which can cause anemia, is a health risk for both the mother and the baby. This deficiency is usually not severe and can be corrected on its own or by eating iron-rich foods such as cockles. However, in more severe cases, it must be treated, as it can increase the risk of miscarriage, perinatal mortality, and susceptibility to infections in the baby.
"At this point, we don't know if a similar process could occur in humans," says Tachibana. While he believes it would be difficult to find such low iron levels in nature, he argues "it's a very important question that deserves to be investigated."
Francisco Javier Barrionuevo, professor of genetics at the University of Granada in Spain, who did not participate in the study, highlights its importance. "Discovering that something as mundane as iron concentration can cause a mammalian embryo to develop as a female is spectacular," he explains.
His team is investigating several biological components that can interfere in this process, including one they discovered very recently: tiny RNA sequences with no apparent function that are nevertheless capable of causing a complete sex reversal. In this case, the biologist warns, it is even more surprising because it is an external element not linked to the genetic code. Barrionuevo returns to the question raised by his Japanese colleague.
"Something like this has never been described in humans, as the study itself explains, but I think it could have happened in cases of extreme malnutrition and simply gone undetected," he adds.
In an op-ed published alongside the study, cellular biologists Shannon Dupont and Blanche Capel, from Duke University in the United States, celebrate the "impressive series of experiments." This study "provides clear evidence that variations in metabolism in the controlled uterine environment interface with the genetic sex-determination cascade and affect testis development," state the researchers.
Chapel and Dupont note that iron deficiency is a known factor that can affect the health of both the mother and the baby, potentially impacting their neurological development. Following this line of thought, they wonder what other more subtle effects this deficiency might have, which opens up the possibility that the mother's diet could affect not only the formation of testes but also other traits of "masculinity."
For the first time, an external factor turns a male mammal into a female
An experiment in mice has discovered that a mother’s iron deficiency alters sex determination. Until now, it was believed that only genetics defined this biological trait
