Environmentally relevant doses of endocrine disrupting chemicals affect male fertility by interfering with sertoli cell glucose metabolism in mice

The growing global deterioration in several aspects of human health has been partly attributed to hazardous effects of endocrine-disrupting chemicals (EDCs) exposure. Therefore, experts and government regulatory agencies have consistently advocated for studies on the combined effects of EDCs that model human exposure to multiple environmental chemicals in real life. Here, we investigated how low concentrations of bisphenol A (BPA), and phthalates compounds affect the Sertoli cell glucose uptake/lactate production in the testis and male fertility. An EDC mixture containing a detected amount of each chemical compound in humans, called daily exposure (DE), and DE increased in magnitude by 25 (DE25), 250 (DE250), and 2500 (DE2500), and corn oil (control) were administered for six weeks to male mice. We found that DE activated estrogen receptor beta (Erβ) and glucose-regulated protein 78 (Grp 78) and disrupted the estradiol (E2) balance. In addition, DE25, DE250, and DE2500 doses of the EDC mixture via binding with Sertoli cells' estrogen receptors (ERs) inhibited the glucose uptake and lactate production processes by downregulating glucose transporters (GLUTs) and glycolytic enzymes. As a result, endoplasmic reticulum stress (ERS), marked by unfolded protein response (UPR) activation, was induced. The accompanying upregulation of activating transcription factor 4 (ATF4), inositol requiring enzyme-1 (IRE1), C/EBP homologous protein (CHOP), and mitogen-activated protein kinase (MAPK) signaling promoted antioxidant depletion, testicular cell apoptosis, abnormal regulation of the blood-testis barrier, and decreased sperm count. Therefore, these findings suggest that human and wildlife exposure to multiple environmental chemicals can produce a wide range of reproductive health complications in male mammals.