Morin Augmented Myocardial eNOS/cGMP/PKG Signaling Pathway and Abated Oxidative and Inflammo-apoptotic Responses in Diethyl Phthalate and Bisphenol-S Co-Exposed Male Albino Rats

Cardiac failure accounts for many deaths worldwide. Increasing experimental evidence suggests that exposure to chemicals such as bisphenol-S (BPS) and diethyl phthalate (DEP) exacerbate cardiac injuries. Morin is a flavonoid with reported cardioprotective activity. This study evaluated the modulation of pathways relevant to cardiac endothelial function in rats exposed to BPS and DEP mixture (Mix). Thirty male albino rats were distributed across five groups (n = 6): control received dimethyl sulfoxide (DMSO) as vehicle, Mix dissolved in DMSO, Mix + morin (25 mg/kg), Mix + morin (50 mg/kg), and morin (50 mg/kg). After 21 days of oral exposure at 1 ml/kg bodyweight of the Mix and treatment with morin, the animals were sacrificed, and their hearts were excised for biochemical, histological, immunohistochemical, and gene expression analyses. Exposure to the Mix caused a significant increase in oxidative stress indices (H₂O₂, malondialdehyde, DNA fragmentation, and advanced oxidation protein products). Also, arginase, phosphodiesterase 5′, and the relative expression of TNF-α, interleukin-1β, Bax, androgen receptor, and vascular endothelial growth factor were markedly increased. In contrast, nitric oxide, reduced glutathione, interleukin-10 levels, superoxide dismutase, catalase, and glutathione peroxidase activities decreased significantly. Furthermore, p-NF-kB-p65 expression increased markedly in the Mix-exposed group. Morin treatment significantly reversed these perturbations in a dose-dependent manner in most instances. This study concludes that morin might offer a cardioprotective effect by enhancing the cardiac endothelial system and attenuating oxidative stress, inflammation, and apoptosis elicited by BPS and DEP co-exposure in male Wistar rats.