For the first time, scientists alter the biological sex of a mammal without touching its DNA

While it has been known that the sexual determination of other species can be affected but external factors like temperature, social hierarchy, body size, or parasites infecting the mother, mammals were thought to be different. Not anymore.

A new study by a team of researchers has found that mammalian male embryos can develop ovaries instead of testes if the mother lacks sufficient iron while pregnant. The findings show that even in the highly protected environment of the uterus, “environmental and metabolic conditions can influence fundamental developmental decisions that were previously thought to be strictly determined by genetics.”

Scientists alter the biological sex of a mammal without touching its DNA

All humans are neither male nor female at the moment of conception but both. It’s not until about a six weeks after the sperm has fertilized the egg that the genetic information begins the process of developing the sexual organs. That process will then begin to physically define a male or female.

Genetic females, who have two X chromosomes, begin developing ovaries, while genetic males, who have one X and one Y chromosome, start developing testes. However, Makoto Tachibana, a biologist at Osaka University in Japan who led a team of researchers, found that when iron was lacking during gestation, genetic males developed ovaries instead of testes.

“As far as we know, this is the first demonstration that an environmental factor can influence sex determination in a mammal,” explained Tachibana to El País, whose findings were published in Nature. “The most important implication of this finding is that environmental and metabolic conditions can influence fundamental developmental decisions that were previously thought to be strictly determined by genetics.”

Lack of iron turns off the testicular gene

Genetically male embryos developing ovaries is not new. Nearly forty years ago the Sry gene was discovered, which is the genetic fragment on the male Y chromosome that is the main driver of sexual differentiation in mammals. Without it, an embryo with both X and Y chromosomes, despite being genetically male, the gonads begin transforming into ovaries, a rare genetic condition.

However, when the team of researchers reduced iron concentration in male mice by 60% at the cellular level it turned off the testicular gene. They then reproduced the experiment in pregnant mice with male embryos which resulted in the complete sex reversal of 6 out of 39 XY offspring.

Could this happen in humans?

Iron deficiency is a known health risk for both the mother and the baby as it can cause anemia. Extremely low iron levels, the study explains, alters the chemical process in the enzyme KDM3A, which shuts down the Sry gene at the moment sex is determined.

The genetically male mice with two embryos appeared healthy after eight weeks but the researchers didn’t know if they could’ve reproduced. When the same process happens in humans it typically leads to infertility.

Could this happen in humans? “At this point, we don’t know if a similar process could occur in humans,” Tachibana admits. He explained that finding such low levels of iron naturally would be difficult.

However, he added that “it’s a very important question that deserves to be investigated.”

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