Elevated exposure to Benzophenone-type Ultraviolet filters Is associated with increased endometrial cancer Risk: Mediation by key metabolites.

Benzophenone-type UV filters (BP-UVFs) are estrogen-disrupting chemicals, which warrant the in-depth analysis between BP-UVFs exposure and the hormone-dependent diseases and related clinical outcomes. In this study, we performed screening and association analysis on exogenous BP-UVFs including their transformation products (TPs) and endogenous small-molecule metabolites in the plasma of 191 participants in Shandong, China, including 70 endometrial cancer (EC) patients and 121 healthy controls. Plasma levels of 4-OH-BP, BP, D2561, and Michler's ketone were significantly higher in the EC group. Through in vitro transformation experiments, 8 TPs of BP were identified, 5 of which were discovered for the first time, and BP-12-TP1 was detected in human plasma. Both the single and mixed exposure models suggested that BP, 4-OH-BP levels were associated with increased risks of EC. A total of 114 differential endogenous metabolites were identified by untargeted metabolomics. BP, 4-OH-BP, and D2561 were significantly associated with 105, 63, and 61 endogenous metabolites, respectively. Arginine biosynthesis, Alanine, aspartate and glutamate metabolism, and Glyoxylate and dicarboxylate metabolism were enriched as the metabolic pathways associated with mixed exposure to BP-UVFs. Mediation analysis indicated that all pathway-enriched metabolites mediated the associations of both BP and 4‑OH‑BP with EC risk. Our study comprehensively screened BP‑UVF exposure and its associated metabolic profiles, providing epidemiological evidence linking such exposure to EC risk.