Environmental ciprofloxacin triggers pregnancy loss: senescence-driven miscarriage via TRIM21-mediated MFF degradation.

Abstract

BACKGROUND: Antibiotic abuse has become a top public health problem worldwide. Ciprofloxacin (CIP) has the highest detection rate in human but its association with unexplained miscarriage (UM) is completely unknown. Senescence is a ubiquitous cellular process but its association with UM is still unclear. METHODS: We 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 CIP and cell senescence were explored. Trophoblast cell senescence, the mitochondrial dysfunctions, and the TRIM21-mediated ubiquitination degradation of MFF were investigated. FINDINGS: Higher urinary CIP levels are associated with villous tissue senescence and woman miscarriage. CIP-exposed mouse model further confirms that CIP exposure causes placental senescence to induce mouse miscarriage. Mechanistically, CIP up-regulates tripartite motif containing 21 (TRIM21) levels, promotes TRIM21-mediated ubiquitination degradation of mitochondrial fission factor (MFF), and thus reduces MFF levels. Subsequently, the reduced MFF causes mitochondrial dysfunctions and cell senescence, further inducing miscarriage. INTERPRETATION: Collectively, this study discovers new risk of CIP exposure on miscarriage, explores pathogenesis and biological mechanisms of CIP-induced miscarriage, provides targets for treatment against miscarriage, and describes the crosstalk among environmental antibiotics, biological mechanisms, and reproductive health. FUNDING: This work was supported by the NSFC (NSFC No. 82373602 and No. 82571347), SMRF (No. B2303002), GBABRF (2023B1515120054 and 2023A1515110497), NSFC Joint Fund Key Support Project (grant no. U24A20748), the JITCBR (202407), HCGP (A2024281), SSTP (No. JCYJ20220530144403008, JCYJ20220818103607015, JCYJ20230807111401002, JCYJ20240813180400002, and JCYJ20241202152800001), CRSFFWJMF 320.6750.2022-06-47, FHRP (No. FTWS011 and FTWS2022002).