Depleção de glutationa reduzida (gsh) por xenobióticos causa estresse oxidativo associado à infertilidade em peixes e mamíferos

Abstract

GSH plays a crucial role as an antioxidant in both male and female fertility. It acts as a natural defender against oxidative agents such as chemicals, reactive oxygen species (ROS), and lipid peroxides in gonadal cells. This action contributes to the improvement of sperm and egg quality. However, the reduction of GSH levels in reproductive tissues leads to damage to animal gametes. This occurs due to the decrease of this molecule in reproductive organs, causing the accumulation of reactive oxygen species. These species react with DNA, proteins, and membrane lipids of gametic cells during and after the maturation process. Thus, in accordance with the strategic vision of 21st-century toxicity testing (TTS21), this work aims to develop an adverse effect pathway as a predictive model for reproductive toxicity induced by GSH-depleting xenobiotics in fish and mammals. To achieve this, experimental toxicological data for ATZ were used to connect molecular changes to phenotypic alterations associated with reproductive dysfunction and support the proposed pathway. The results indicate that GSH conjugation with chemicals such as ATZ can plausibly lead to reproductive disorders in fish and mammals through oxidative stress. Furthermore, it was demonstrated that starting from 0.2 mg/L, ATZ can trigger the adverse outcome pathway (AOP) in fish. Additionally, network analysis reveals that ATZ-induced oxidative stress triggers reproductive toxicity through DNA damage and cellular apoptosis in reproductive tissues. These two processes can lead to all identified adverse effects. Furthermore, in silico searching for ATZ targets related to infertility via oxidative stress in humans identified nine proteins, among which Tp53, Bcl2, Esr1, and Nos3 stand out as the most relevant and may represent crucial markers of reproductive toxicity induced by ATZ via oxidative stress. Finally, gene enrichment analysis indicates that these proteins are involved in various biological processes and pathways directly associated with oxidative stress, DNA damage, and apoptosis, further reinforcing the developed network.