Impact of an antidiabetic drug on male fertility after foetal exposure in mice

Metformin is a drug used to regulate glucose levels in the blood and is prescribed as a treatment for type 2 diabetes. It can also be prescribed to patients during pregnancy who suffer from gestational diabetes or obesity. However, the consequences of foetal exposure to metformin on the fertility of offspring are poorly documented. That is why researchers have turned their attention to how the drug affects the fertility of offspring when administered to gestating mice.

A drop in fertility among male offspring

Researchers at INRAE had already shown that exposure to metformin in mice during the embryonic stages slows testicular growth and leads to a drop in the production of testosterone in male foetuses (cf references). In this new study, 12 female mice were given metaformin in drinking water for the duration of pregnancy in quantities equivalent to those given to humans for the treatment of diabetes. Another control group of 8 mice was given water with no added metformin. The study showed that metformin does not accumulate in foetal tissue but passes into the bloodstream and the amniotic fluid that surrounds the foetus during pregnancy. This exposure upsets the metabolism of the foetus and provokes a slowdown in testicular growth in males. The researchers also observed that male mice exposed to metformin during pregnancy weighed more than those of the control group and accumulated twice as much fat as males from the control group.

To study the consequences on fertility, male and female offspring from female mice exposed to metformin during gestation were mated with mice from the control group. Male mice who had been exposed to metformin were less fertile than those from the control group, siring litters 30% smaller (5.5 pups on average per litter for males exposed to metformin v. 8 pups per litter from males from the control group). To understand the cause of this decrease in fertility, the scientists studied the sperm produced by the male mice. They observed a lower sperm count in the males exposed to metformin. They also observed higher levels of malformations of sperm cell heads (25% in males exposed v. 15% in the control group), higher rates of sperm DNA damage (55% in exposed males v. 25% in males from the control group), and greater genomic DNA methylation associated with TET proteins, an epigenetic marker influencing gene expression.

Perturbations in metabolism during the foetal stage, here induced by metformin, could affect fertility in adulthood, but these results have yet to be confirmed in humans.  With this in mind, a cohort study carried out by the faculty of medicine of the Norwegian University of Science and Technology is currently underway to identify the effects on humans. Studies on animals will also continue, notably to see if the effects persist over several generations.