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Polycystic ovarian syndrome (PCOS), frequently associated to obesity, is the main reproductive disorder in women in age to procreate. Some evidence suggests that pesticides can result in alterations of the female reproductive system, including polycystic ovary syndrome (PCOS). Here, we detected two fungicides, Tebuconazole (Tb) and Epoxiconazole (Epox) in the soils and waters of French area. Our hypothesis is that these two triazoles could be associated to the etiology of PCOS. We used the human KGN cell line and primary human granulosa cells (hGCs) from different group of patients: normal weight non PCOS (NW), normal weight PCOS (PCOS NW), obese (obese) and obese PCOS (PCOS obese). We exposed in vitro these cells to Tb and Epox from 0 up to 10 mM for 24 and 48 h and analysed cell viability and steroidogenesis. In hGCs NW, cell viability was reduced from 12.5 µM for Tb and 75 µM for Epox. In hGCs NW, Epox decreased progesterone (Pg) and estradiol (E2) secretions and inhibited STAR , HSD3B and CYP19A1 mRNA expressions from 25 µM and increased AHR mRNA expression from 75 µM. Tb exposure also reduced steroid secretion and STAR and CYP19A1 mRNA expressions and increased AHR mRNA expression but at cytotoxic concentrations. Silencing of AHR in KGN cells reduced inhibitory effects of Tb and Epox on steroid secretion. Tb and Epox exposure decreased more steroid secretion in hGCs from obese, PCOS NW and PCOS obese groups than in NW group. Moreover, we found a higher gene expression of AHR within these three groups. Taken together, both Epox and Tb reduced steroidogenesis in hGCs through partly AHR and Tb was more cytotoxic than Epox. These triazoles alter more strongly PCOS and/or obese hGCs suggesting that human with reproductive disorders are more sensitive to triazoles exposure., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

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 in utero 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 in utero 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Faure, Khoueiry, Quanico, Acloque, Guerquin, Bertoldo, Chevaleyre, Ramé, Fournier, Salzet, Dupont and Froment.)

Chemerin is a pro-inflammatory adipokine secreted and expressed predominantly by adipocytes. Chemerin is initially involved in the regulation of the immune system, the adipogenesis and the energy metabolism. However, several recent studies show that this adipokine and its receptors are present in the gonads. In vitro, chemerin reduces steroidogenesis in ovarian and testicular cells in rodents and humans. Chemerin and its receptors are also present in the placenta. Chemerin plays an important role in the regulation of fetal and maternal metabolism, fetal growth and metabolic homeostasis during pregnancy. This review describes the role of chemerin in metabolism and reproduction., (© 2015 médecine/sciences – Inserm.)

Adipokines are hormones mainly produced by the white adipose tissue, an endocrine organ involved in energy homeostasis. They play an important role in the regulation of lipid and glucose metabolisms, in inflammation and immune disorders. New roles for adipokines have recently emerged in the field of fertility and reproduction. Indeed, adipokines such as adiponectin and resistin are able to regulate the functions of male and female gonads and of the hypothalamic-pituitary axis. For example, they modulate steroidogenesis of gonadic somatic cells, germ cell maturation and secretion of gonadotrope hormones in various species. The reproductive system is tightly coupled with energy balance, and thereby metabolic abnormalities can lead to the development of physiopathological situations such as the polycystic ovary syndrome (PCOS). Obesity and overweight are significantly involved in the declining natural fertility and decrease the effectiveness of treatments. Women with obesity and/or PCOS have abnormal plasma adiponectin and resistin profiles. Thus, these adipokines could be a link between reproduction and energy metabolism and could partly explain some infertility related to obesity or PCOS., (© 2013 médecine/sciences – Inserm / SRMS.)