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Redox-mitochondrial-epigenetic network disruption and its intergenerational impact in zebrafish: Protective effects
Sandeep R Reddy1, Prabhakar Kamarthy2, Manjunatha Bangeppagari1
1Zebrafish Drug Screening Center, Department of Cell Biology and Molecular Genetics, Sri Devaraj Urs Academy of Higher Education and Research (A Deemed to Be University), Tamaka, Kolar, Karnataka 563103, India.
Background:
Oxidative stress is a central mechanism of chronic toxicity, disrupting metabolic, inflammatory, apoptotic, mitochondrial, and epigenetic processes. Potassium bromate (KBrO₃) induces oxidative stress, but its systemic effects following chronic exposure and modulation by metformin remain insufficiently characterized. This study evaluated chronic KBrO₃ toxicity in zebrafish, the effects of concurrent metformin exposure, and molecular responses in F1 offspring following parental exposure.
Methods:
Adult zebrafish were exposed to KBrO₃ for 28 days with or without metformin co-treatment. Histopathological analyses of liver, ovary, intestine, and testis were performed. IL-1β, insulin, and vitellogenin were analyzed by ELISA, wheras oxidative stress, metabolic, inflammatory, apoptotic, and epigenetic markers by qPCR. Global DNA methylation, mitochondrial DNA copy number, and relative telomere length were evaluated in F0 and F1 cohorts. Data were analyzed using conventional statistics, principal component analysis, and Spearman correlation.
Results:
KBrO₃ exposure was associated with alterations in antioxidant defence, metabolism, inflammation, apoptosis, mitochondrial and epigenetic endpoints, and tissue pathology. Metformin co-treatment attenuated multiple KBrO₃-associated molecular and histopathological alterations. In F1 offspring, selected gene-expression and DNA methylation alterations were observed, whereas mtDNA copy number and relative telomere length did not differ significantly among groups, indicating endpoint-specific intergenerational responses. Multivariate analyses identified coordinated biomarker patterns associated with treatment.
Conclusion:
Chronic KBrO₃ exposure produced coordinated molecular and tissue alterations, while metformin co-treatment attenuated several associated responses. Selected F1 molecular and epigenetic alterations indicate intergenerational responses following parental exposure, although F2/F3 generations were not assessed. These findings support further investigation of metformin as a pharmacological modulator of oxidative stress-associated toxicity.