Low-level exposure to trifluoroacetic acid may induce testicular damage in adolescent mice via ribotoxic stress response and NLRC5-PANoptosome-related signaling.

Trifluoroacetic acid (TFA) is considered a per- and polyfluoroalkyl substance (PFAS) by the European Chemicals Agency, yet its potential reproductive toxicity remains poorly understood. Here, we investigated the testicular effects and underlying mechanisms of TFA exposure in adolescent male mice. Based on environmental and potential dietary exposure levels, available toxicological and risk-assessment information, and the findings of our preliminary experiment, mice were orally administered TFA at 0.0042, 0.042, 0.42, or 4.2 mg/kg/day for 21 days, followed by a 7-day recovery period. Residual TFA remained detectable in the serum and testes after the recovery period, and doses ≥ 0.042 mg/kg/day induced Leydig cell and spermatogenic cell damage, accompanied by reduced testosterone levels. TFA exposure also increased testicular oxidative stress (OS) and activated the ribotoxic stress response (RSR) and NLRC5-PANoptosome-related signaling. These cellular stress responses were associated with activation of PANoptosis-related pathways, involving pyroptosis, apoptosis, and necroptosis, and ultimately contributed to testicular tissue injury and impaired testicular function. Collectively, our findings demonstrate that TFA exposure at environmentally and risk-assessment-relevant levels induces testicular injury in adolescent male mice and identify a potential mechanistic link between OS, RSR, NLRC5-PANoptosome-related signaling, and PANoptosis. These findings provide new insights into the reproductive toxicity of TFA and highlight the need for further evaluation of its potential health risks.