Exposure to high doses of tyre antioxidant 6PPD causes senescence to induce unexplained miscarriage by suppressing BAZ1B-mediated ubiquitination degradation of P21.

backgroundUnexplained miscarriage (UM) highly occurs and largely limits human reproduction. Cellular senescence is a ubiquitous process that is associated with many human diseases. Increasing global usage and wear of tyres result in worldwide pollution of 6PPD (an antioxidant in tyres) in various environments and even in pregnant women's bodies. Importantly, whether 6PPD exposure might cause senescence to induce unexplained miscarriage is largely unknown and should be urgently explored.

methodsWe combined case-control study using a UM case-control group and in vitro functional assays using mouse model and human trophoblast HTR-8/SVneo cells. The associations between environmental exposure to 6PPD and cell senescence were explored. Trophoblast cell senescence and the BAZ1B-mediated ubiquitination degradation of P21 were also investigated.

findingsHigher urinary 6PPD levels are closely associated with villous tissue senescence and miscarriage (n = 50). 6PPD-exposed mouse model further confirms that exposure to high doses of 6PPD causes placental senescence (≥12 mg/kg/d) to induce mouse miscarriage (≥36 mg/kg/d). In cellular mechanisms, 6PPD exposure down-regulates BAZ1B expression levels, suppresses BAZ1B-mediated ubiquitination degradation of P21, and thus up-regulates P21 protein levels. Subsequently, the up-regulated P21 results in cell senescence, which further induces miscarriage. The mechanisms in 6PPD-exposed trophoblast cells are consistent with those in 6PPD-exposed mouse placental tissues and in UM vs HC women villous tissues. Therapeutic down-regulation of p21, supplement with murine Baz1b, or direct suppression of senescence could effectively reduce placental senescence and suppress mouse miscarriage in the 6PPD-exposed mouse models.

interpretationThis study not only discovers new health risks of 6PPD exposure on miscarriage, explores potential pathogenesis and biological mechanisms in 6PPD-induced miscarriage, but also provides potential biological targets for treatment against miscarriage, providing a new example about the crosstalk among environmental 6PPD exposure, cellular senescence, and female reproductive health.

fundingThis work was supported by Natural Science Foundation of China (NSFC No. 82373602), Shenzhen Medical Research Fund (No. B2303002), the National Key R&D Program of China (No. 2025YFC2708402), Guangdong Basic and Applied Basic Research Foundation (2023B1515120054 and 2023A1515110497), Shenzhen Science and Technology Program (No. JCYJ20241202152800001, JCYJ20250604142511015, JCYJ20230807111401002, JCYJ20230807111401002, JCYJ20250604142519025), China Postdoctoral Science Foundation (No. 2025M780729), Shanxi Province Higher Education "BillionProject" Science and Technology Guidance Project; MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Futian Healthcare Research Project (No. FTWS011).