Hotdogs and Beer: Dietary Nitrosamine Exposure Exacerbates Neurodevelopmental Effects of Ethanol in Fetal Alcohol Spectrum Disorder

In the immature brain, ethanol impairs insulin, insulin-like growth factor (IGF) and other trophic factor signaling, increases cellular stress, and impairs neuronal and glial functions. However, given the phenotypic heterogeneity of fetal alcohol spectrum disorder (FASD), which is not always ethanol dose-dependent, we hypothesized that cofactors modulate spectrum and severity of disease. Herein, we determined if N-nitrosodiethylamine (NDEA) exposures could mimic or exacerbate ethanol’s effects on cerebellar development; NDEA is present in processed foods, inhibits insulin signaling, and promotes oxidative injury. Rat pups were binge ethanol (2 g/kg) or vehicle exposed on postnatal day 3 (P3), P5, P7, and P9; and treated with vehicle or NDEA (2 mg/kg) on P7. Ethanol and NDEA disrupted cerebellar foliation and white matter integrity, inhibited expression of oligodendrocyte and astrocyte proteins, and increased expression of ER stress genes. Combined exposures had qualitatively additive effects. Therefore, cofactor exposures can either mimic or influence the phenotypic features of FASD.