Alcohol Metabolism into Acetaldehyde in Developing Cerebral Arteries

Alcohol exposure during pregnancy leads to fetal alcohol spectrum disorders (FASD), yet the mechanisms through which alcohol disrupts the developing cerebrovasculature remain poorly defined. Acetaldehyde, the first oxidative metabolite of alcohol, can alter vascular function, but whether developing cerebral arteries possess intrinsic capacity to generate acetaldehyde is unknown. Alcohol is primarily oxidized by alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and catalase (CAT), and their local metabolic activity may contribute to cerebrovascular vulnerability. In this study, cerebral arteries were isolated from postnatal day (PND) 10 C57BL/6J mouse offspring (third trimester-equivalent to human pregnancy), and incubated ex vivo with physiologically relevant alcohol concentrations (13 or 50 mM). Acetaldehyde generation, transcript expression, protein abundance, and catalase-dependent metabolism were evaluated. Alcohol exposure produced a concentration-dependent increase in acetaldehyde generation within developing cerebral arteries, with comparable responses between males and females. Transcript analysis revealed that Adh1, Cyp2e1, and Cat were expressed across developing tissues; however, Western blotting showed that catalase was the only alcohol-metabolizing enzyme detectable at the protein level within developing cerebral arteries. Accordingly, catalase inhibition by sodium azide altered acetaldehyde production, revealing a significant blocker-sex interaction at the higher inhibitor concentration (0.06 mM). In summary, our ex vivo findings demonstrate that developing cerebral arteries possess intrinsic metabolic capacity to oxidize alcohol to acetaldehyde and that catalase plays an essential role in supporting this process at this developmental stage. These results point to a previously unrecognized metabolic pathway within the developing cerebrovasculature that may potentially contribute to early-life vulnerability to alcohol exposure.