Comparative Dose‐Dependent Effects of Bisphenol A, F, and S on Testicular Oxidative Stress, DNA Damage, and Reproductive Hormones in Rats

Bisphenol A (BPA) is a well-known endocrine-disrupting compound whose use has increasingly been limited by regulatory agencies in recent years. Structurally related analogs such as bisphenol S (BPS) and bisphenol F (BPF) have been introduced as replacement compounds. However, in vivo studies directly and comparatively evaluating the biological effects of these analogs under the same experimental conditions remain limited. Accordingly, this study investigated the comparative effects of BPA, BPS, and BPF administered at doses of 25, 50, and 100 mg/kg/day over a 28-day exposure period on oxidative stress, DNA damage, and reproductive hormones in adult male Wistar rats. DNA damage was determined in lymphocytes and testicular tissue using the comet assay. Glutathione, superoxide dismutase, catalase, and malondialdehyde levels were measured in blood and testicular tissue, whereas serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were analyzed using the enzyme-linked immunosorbent assay. The strongest genotoxic effect occurred in the 50 mg/kg BPA group, suggesting a nonlinear (nonmonotonic) dose-response relationship. No consistent linear change in oxidative stress parameters was observed with increasing dose, and compound- and dose-specific heterogeneous responses were detected. Decreased testosterone levels in most exposure groups, together with variable responses in LH and FSH levels, suggest the potential disruption of the hypothalamic-pituitary-gonadal axis. The observation that BPS and BPF exhibited biological effects comparable to those of BPA for certain parameters does not support the assumption that structural analogs of BPA are consistently safer. The results emphasize the need for comparative risk evaluation of bisphenol analogs used as substitutes for BPA and underscore the presence of nonlinear genotoxic response patterns.