Fetal alcohol spectrum disorders (FASD) are associated with significant cardiac pathologies. In a compromised uterine environment, maternal stressors drive fetal adaptations that prioritize brain development, potentially at the expense of the heart. This study examined the role of the TRPM2 channel and its interaction with autophagic and stress-signaling pathways in a prenatal alcohol exposure model. Using a rodent model of prenatal ethanol exposure, as described previously, cardiac tissues from male and female offspring were analyzed by H&E staining for histopathology and by immunohistochemistry for key proteins, including JNK, AKT, mTOR, ATG5, ATG7, BNIP3, S100, and TRPM2. Histopathological analysis confirmed myocardial damage in PHAC offspring, including inflammatory infiltration, cardiomyocyte degeneration, and hemorrhage. Cardiac TRPM2 expression was significantly up-regulated in a sex-dependent manner, whereas autophagy-related markers (ATG5, ATG7, and BNIP3) were dysregulated, particularly in females. Elevated levels of JNK, AKT, mTOR, and the injury marker S100 were also observed. In addition, PHAC offspring exhibited significant impairments in spatial learning and memory in the Morris water maze test. Overall, planned alcohol exposure caused significant cardiac stress and damage marked by TRPM2 channel overexpression, accompanied by sex-dependent activation of autophagic pathways and dysregulation of AKT/mTOR/JNK signaling. These findings suggest that TRPM2 upregulation may represent a central mediator of alcohol-induced fetal cardiac injury, potentially through modulation of autophagy.
