Organ-Specific Toxicity of Lynestrenol in Mandarin Fish: Hepatic Metabolic Collapse versus Ovarian Resilience through Efflux Transporter Activation

Abstract Lynestrenol (LYN), a fourth-generation synthetic progestin whose active metabolite norethisterone is frequently detected in aquatic environments, poses potential risks to fish. Using integrated multi-omics, enzymology, and histopathology, we investigated the organ-specific toxicity of chronic LYN exposure (0.01, 1 μg/L for 60 days) in female mandarin fish (Siniperca chuatsi). LYN induced severe, dose-dependent hepatic necrosis, driven by concurrent blockade of the 2-oxocarboxylic acid metabolism pathway (via idh1 suppression) and ammonia detoxification failure. Additionally, LYN triggered a multi-node blockade of the ubiquinoid antioxidant system through coordinated downregulation of hpda, nqo1, and ggcx, resulting in oxidative collapse (increased ROS, MDA, ALT; decreased T-AOC, NQO1, IDH1). In contrast, ovaries remained histologically intact with no masculinization. Ovarian resilience involved dual adaptation: recalibration of steroidogenesis (downregulation of cyp19a, hsd11b2, and cpeb2 coupled with esr1 upregulation) and, for the first time in teleost gonads under progestin exposure, upregulation of ABCC efflux transporters (abcc2/3), via l-arginine/Nrf2 signaling. These findings reveal that LYN causes catastrophic hepatic metabolic collapse while ovarian tissue maintains homeostasis through active detoxification and steroidogenic reprogramming, providing a mechanistic basis for multi-organ risk assessment of progestins.