Nothing masculine, female organs: Iron deficiency can reverse the sex of mice

BarcelonaWhat determines whether a mammal is male or female? Until now, science has only had one answer: genetics. For example, metabolic factors. Specifically, iron deficiency in the mother during pregnancy can profoundly affect some mouse offspring and eventually cause sex reversal. programmed A mouse that has no testicles may end up developing ovaries for a seemingly trivial reason. Researchers reproduced a deficient iron concentration—around 60% below normal levels—in female mice that were, a priori, pregnant with males, and observed that 6 of the 39 offspring were born with ovaries. Led by Makoto Tachibana of Osaka University, the research It was published this Wednesday in the magazine Nature and represents a first step in investigating the effects of iron deficiency on human pregnancies.

Females have two female chromosomes, XX, and males have one female and one male chromosome, XY. The Y chromosome is responsible for differentiation between the sexes: when the Sry gene is activated in the gonads, the testes are formed, and when it is absent, the ovaries develop. To unlock this mechanism and make the embryo male, the enzyme KDM3A plays a relevant role. And, in turn, this depends greatly on iron. From there, the team of scientists wondered whether, in mammals, maternal environmental factors derived from differences in nutrition, metabolism, or the regulation of metal levels could be potential sources of variability that could affect embryonic development.

A key enzyme

According to the research, extremely low maternal iron at the cellular level in the uterus affects the enzyme KDM3A, which modifies a chemical switch that turns off the testes-producing gene Sry right at the time of sex determination, around six weeks into gestation. Given this association, Tachibana set out to decipher what relationship there might be between an embryo's sex determination and an external factor, namely the way this essential mineral is metabolized. That is, the impact on epigenetics, the chemical marks added to DNA and the proteins that package it to regulate its activity.

When the authors reduced iron levels in the cultured cells, Sry expression was largely suppressed, and the XY gonads began to show genetic markers associated with ovarian development. The group then tested the effects of short-term iron deficiency on pregnant female mice, giving them a drug that depletes this mineral for about five days around the time of embryonic sex determination. The result was that of the 72 offspring born with XY chromosomes, four developed two ovaries, and one developed one ovary and one testis.