Chronic Exposure to 6PPD-Q Induces HPO Axis Dysfunction and Metabolic Disturbances in Female Offspring Mice

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q) is an emerging environmental pollutant with limited research on its reproductive toxicity. In this study, female offspring mice were exposed to 6PPD-Q during gestation and lactation. The results revealed that 6PPD-Q exposure disrupted the hypothalamus-pituitary-ovary (HPO) axis in postnatal day (PND) 22 female offspring mice, leading to precocious puberty and estrous cycle irregularities, accompanied by substantial metabolic alterations. At PND 71, disturbances in the HPO axis and metabolic functions were observed. In both in vivo and in vitro experiments, 6PPD-Q was found to suppress hypothalamic gonadotropin releasing hormone (GnRH) secretion via the Kisspeptin/GPR54 pathway, inhibit pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion through the PKC/c-Raf/ERK1/2/IEGs pathway, and induce oxidative stress in human granulosa-like tumor cell line (KGN), resulting in a reduction in estradiol (E₂) secretion. Collectively, this study provides novel theoretical insights into the potential reproductive toxicity and metabolic impact of 6PPD-Q.