Omega 3 Fatty Acids Mitigate Monosodium Glutamate (MSG)-Induced Developmental Toxicity via Hepcidin/NF-κB Pathway Modulation and Iron Homeostasis Restoration in Male Rats.

Monosodium glutamate (MSG), a widely used flavor enhancer, acts as an excitatory neurotransmitter agonist. Excessive exposure during development can lead to excitotoxicity, characterized by overstimulation of glutamate receptors, neuronal injury, and systemic oxidative stress. This study investigated the effects of perinatal MSG exposure on male offspring and the protective role of omega 3 fatty acids supplementation. Forty-eight pregnant Wistar rats were divided into four groups: Control, MSG (10 mg/g, gestational day 1 to postnatal day 0), omega 3 fatty acids + MSG (185 mg/kg omega 3 fatty acids plus MSG), and omega 3 fatty acids alone. We assessed forty-eight male offspring (n=12/group) at postnatal day 21 using biochemical, hematological, molecular, and histopathological analyses. MSG exposure caused substantial maternal mortality (16.67%) and significantly reduced offspring survival (54.54%). In surviving offspring, it induced liver injury, iron overload, inflammation, anemia, and organ dysfunction. Omega 3 fatty acids supplementation was highly effective, preventing maternal mortality (100% vs 83.33% survival in the MSG group) and substantially restoring iron homeostasis and tissue architecture. It also reduced key inflammatory markers (IL-1β, IL-6, TNF-α) by over 80%. Our novel findings include non-transferrin-bound iron (NTBI) and tissue-specific microRNAs (miR-122, miR-192, miR-223), which have not previously been reported as MSG toxicity indicators, reveal a 1,150% increase in NTBI, hepatic iron accumulation, and disrupted gene expression of iron-related proteins (hepcidin antimicrobial peptide 1, ferritin light chain, transferrin receptor 1, aminolevulinate synthase 1). We also observed significant upregulation (p < 0.001) of microRNAs miR-122, miR-192, and miR-223 by 700%, 400%, and 500%, respectively. Histopathological examination confirmed severe liver damage in the MSG group. Mechanistically, Omega 3 fatty acids restored hepatic architecture and reduced renal and splenic inflammatory infiltration, as confirmed by histopathology, enhanced antioxidant defenses, downregulated hepcidin, suppressed the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, and modulated these key epigenetic mechanisms. These results identify novel biomarkers for MSG toxicity and support Omega 3 fatty acids as a promising developmental protective intervention.