Peri-implantation 6PPD-Q exposure impairs endometrial decidualization and induces pregnancy loss

Abnormal endometrial decidualization is a critical contributor to implantation failure and pregnancy loss, with exposure to environmental pollutants increasingly recognized as a potential risk factor. N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q), an ozonation byproduct of the tire antioxidant 6PPD, is widely detected in environmental matrices. Despite growing concern over its reproductive toxicity, the effects of peri-implantation exposure on endometrial decidualization remain unclear. In this study, peri-implantation 6PPD-Q exposure (4 mg/kg) in mice significantly reduced implantation site weight at embryonic day 7.5 (E7.5), increased embryo resorption rate at E13.5, decreased placental and fetal weights in viable embryos, and further reduced litter size and offspring birth weight. 6PPD-Q markedly reduced polyploid decidual cells at E7.5 in both pregnant and pseudopregnant mouse models. In pregnant mice, it also disrupted the expression of decidualization markers and steroid hormone receptors, accompanied by defective decidual angiogenesis. Transcriptomic analysis further revealed dysregulation of biological processes associated with decidualization, angiogenesis, immune regulation, cytoskeletal and matrix remodeling, and metabolism. In vitro, telomerase-immortalized human endometrial stromal cells (T-hESCs) exhibited dose-dependent (0.01-10 μM) reductions in viability and decidual markers IGFBP1, PRL, BMP2, and WNT4 upon 6PPD-Q exposure. This study provides new mechanistic insights into the reproductive toxicity of this emerging contaminant during early pregnancy.