Synergistic protective effects of melatonin and ascorbic acid against benzene-induced genotoxicity, oxidative stress, and activin A/follistatin dysregulation in a rat model of pre-leukemia

抄録

Benzene exposure is a major risk factor for hematologic malignancies, including acute myeloid leukemia (AML), through mechanisms involving genotoxicity, oxidative stress, and dysregulation of hematopoietic signaling pathways. This study investigated the protective effects of melatonin, vitamin C, and their combination against benzene-induced pre-leukemic alterations in rats, with emphasis on bone marrow genotoxicity, oxidative stress, and activin A/follistatin expression. Forty male Wistar rats were allocated into five groups (n=8): control, benzene, benzene + melatonin, benzene + vitamin C, and benzene + combined treatment. Genotoxicity was assessed using bone marrow micronucleus assays, while oxidative stress biomarkers, serum activin A/follistatin levels, and bone marrow gene expression were evaluated using biochemical assays, ELISA, and qPCR, respectively. Benzene exposure significantly increased micronucleus frequency, reduced %PCE and PCE/NCE ratio, elevated %NCE, and suppressed activin A and follistatin expression. Melatonin or vitamin C alone partially attenuated these abnormalities, whereas combined treatment demonstrated the strongest protective effects, including marked improvement of genotoxicity indices, restoration of catalase activity, and significant upregulation of activin A and follistatin gene expression. Combined melatonin and vitamin C supplementation attenuated benzene-associated pre-leukemic alterations, particularly genotoxic and oxidative stress-related abnormalities. Combined melatonin and vitamin C supplementation attenuated benzene-associated pre-leukemic alterations in rats, particularly genotoxic and oxidative stress-related abnormalities. These protective effects were accompanied by modulation of activin A/follistatin expression patterns, suggesting a potential association between restoration of this signaling axis and improved bone marrow homeostasis. However, further mechanistic studies are required to determine whether activin A/follistatin signaling directly contributes to the observed protective effects.