Melatoninergic Modulation of Benzene-Induced Pre-Leukemic Alterations in Rats: Effects of Melatonin, Agomelatine, and Luzindole : Short title: Melatoninergic Modulation in Benzene-Induced Pre-Leukemi.

BACKGROUND: Benzene is a well-established leukemogen associated with hematotoxicity, oxidative injury, inflammation, and genotoxic alterations, particularly in relation to acute myeloid leukemia (AML). Melatonin has antioxidant and anti-inflammatory properties that may exert protective effects against benzene-induced pre-leukemic alterations. MATERIALS AND METHODS: This study evaluated melatoninergic modulation in a benzene-induced pre-leukemic rat model. Rats were assigned to five groups (n=8): control, benzene-only, benzene + melatonin (10 mg/kg), benzene + agomelatine (10 mg/kg), and benzene + melatonin + luzindole (0.2 mg/kg). Benzene was administered intravenously as a benzene:2-propanol: distilled water mixture (1:5:5, v/v/v) every 48 h for 4 weeks. Melatonin and agomelatine were administered orally once daily, while luzindole was used to assess melatonin receptor blockade. Hematological indices, leukocyte ratios, platelet parameters, bone marrow micronucleus endpoints, Activin A, Follistatin, MDA, 8-OHdG, CAT, and SOD were assessed. RESULTS: Benzene exposure induced hematological disruption, altered leukocyte and platelet-related indices, increased micronucleus formation, and disturbed oxidative stress markers. Melatonin and agomelatine attenuated several benzene-induced alterations, including changes in erythropoietic indices, micronucleus frequency, leukocyte distribution, platelet-related parameters, MDA, and CAT activity. Luzindole partially reduced selected protective effects, suggesting that some responses may involve melatonin receptor-related pathways. However, inconsistent Activin A trends and unchanged Follistatin levels require cautious interpretation. CONCLUSION: Melatonin and agomelatine attenuated several hematological, genotoxic, and oxidative alterations in benzene-exposed rats. Luzindole partially modified these effects, suggesting possible melatonin receptor involvement alongside non-receptor antioxidant and anti-inflammatory actions.