Pathways and Predictions
AOP Report: Glutathione Conjugation Leading to Reproductive Dysfunction via Oxidative Stress
Leonardo R. Vieira,
Terezinha Souza,
Davi F. Farias,
Leonardo R. Vieira
Post-Graduation Program in Biochemistry, Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza, Brazil
Department of Molecular Biology, Federal University of Paraíba, João Pessoa, Brazil
Search for more papers by this authorTerezinha Souza
Department of Molecular Biology, Federal University of Paraíba, João Pessoa, Brazil
Search for more papers by this authorCorresponding Author
Davi F. Farias
Post-Graduation Program in Biochemistry, Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza, Brazil
Department of Molecular Biology, Federal University of Paraíba, João Pessoa, Brazil
Address correspondence to [email protected]
Search for more papers by this authorLeonardo R. Vieira,
Terezinha Souza,
Davi F. Farias,
Leonardo R. Vieira
Post-Graduation Program in Biochemistry, Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza, Brazil
Department of Molecular Biology, Federal University of Paraíba, João Pessoa, Brazil
Search for more papers by this authorTerezinha Souza
Department of Molecular Biology, Federal University of Paraíba, João Pessoa, Brazil
Search for more papers by this authorCorresponding Author
Davi F. Farias
Post-Graduation Program in Biochemistry, Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza, Brazil
Department of Molecular Biology, Federal University of Paraíba, João Pessoa, Brazil
Address correspondence to [email protected]
Search for more papers by this authorFirst published: 17 October 2023
Abstract
We propose an adverse outcome pathway (AOP) for reproductive dysfunction via oxidative stress (OS). The AOP was developed based on Organisation for Economic Co-operation and Development (OECD) Guidance Document 184 and on the specific considerations of the OECD users' handbook supplement to the guidance document for developing and assessing AOPs (no. 233). According to the qualitative and quantitative experimental data evaluation, glutathione (GSH) conjugation is the first upstream key event (KE) of this AOP to reproductive dysfunction triggering OS. This event causes depletion of GSH basal levels (KE2). Consequently, this drop of free GSH induces an increase of reactive oxygen species (KE3) generated by the natural cellular metabolic processes (cellular respiration) of the organism. Increased levels of these reactive species, in turn, induce an increase of lipid peroxidation (KE4). This KE consequently leads to a rise in the amount of toxic substances, such as malondialdehyde and hydroxynonenal, which are associated with decreased quality and competence of gamete cell division, consequently impairing fertility (KE5 and adverse outcome). The overall assessment of the general biological plausibility, the empirical support, and the essentiality of KE relationships was considered as high for this AOP. We conclude that GSH conjugation is able to lead to reproductive disorder in fishes and mammals, via OS, but that the amount of stressor needed to trigger the AOP differs between stressors. Environ Toxicol Chem 2023;42:2519–2528. © 2023 SETAC
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