l'Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), UMR85 Physiologie de la Reproduction et des Comportements/Centre national de la Recherche Scientifique (CNRS), UMR7247/Université François Rabelais de Tours/Institut français du Cheval et de l'Équitation (IFCE), Nouzilly, France.
Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France.
Front Endocrinol (Lausanne). 2021 Oct 18;12:750145. doi: 10.3389/fendo.2021.750145. eCollection 2021.
Metformin is a drug used for the treatment of type 2 diabetes and disorders associated with insulin resistance. Metformin is also used in the treatment of pregnancy disorders such as gestational diabetes. However, the consequences of foetal exposure to metformin on the fertility of exposed offspring remain poorly documented. In this study, we investigated the effect of metformin exposure on the fertility of female and male offspring. We observed that metformin is detectable in the blood of the mother and in amniotic fluid and blood of the umbilical cord. Metformin was not measurable in any tissues of the embryo, including the gonads. The effect of metformin exposure on offspring was sex specific. The adult females that had been exposed to metformin presented no clear reduction in fertility. However, the adult males that had been exposed to metformin during foetal life exhibited a 30% reduction in litter size compared with controls. The lower fertility was not due to a change in sperm production or the motility of sperm. Rather, the phenotype was due to lower sperm head quality - significantly increased spermatozoa head abnormality with greater DNA damage - and hypermethylation of the genomic DNA in the spermatozoa associated with lower expression of the ten-eleven translocation methylcytosine dioxygenase 1 (TET1) protein. In conclusion, while foetal metformin exposure did not dramatically alter gonad development, these results suggest that metabolic modification by metformin during the foetal period could change the expression of epigenetic regulators such as Tet1 and perturb the genomic DNA in germ cells, changes that might contribute to a reduced fertility.
二甲双胍是一种用于治疗 2 型糖尿病和与胰岛素抵抗相关疾病的药物。二甲双胍也用于治疗妊娠疾病，如妊娠期糖尿病。然而，胎儿暴露于二甲双胍对暴露后代生育能力的影响仍记录甚少。在这项研究中，我们研究了二甲双胍暴露对雌性和雄性后代生育能力的影响。我们观察到，二甲双胍可在母亲的血液、羊水和脐带血中检测到。二甲双胍在胚胎的任何组织中都无法检测到，包括性腺。二甲双胍暴露对后代的影响具有性别特异性。暴露于二甲双胍的成年雌性动物的生育能力没有明显下降。然而，在胎儿期暴露于二甲双胍的成年雄性动物的产仔数与对照组相比减少了 30%。较低的生育能力不是由于精子产生或精子活力的变化。相反，表型是由于精子头部质量下降所致——显著增加的精子头部异常和 DNA 损伤，以及与 TET1 蛋白表达降低相关的精子基因组 DNA 超甲基化。总之，虽然胎儿二甲双胍暴露并没有显著改变性腺发育，但这些结果表明，胎儿期二甲双胍的代谢修饰可能会改变表观遗传调节剂如 Tet1 的表达，并扰乱生殖细胞中的基因组 DNA，这些变化可能导致生育能力降低。
