A single exposure to alcohol during brain development induces microencephaly and neuronal losses in genetically susceptible mice, but not in wild type mice.
Maternal alcohol abuse during pregnancy can damage the fetal brain and lead to fetal alcohol syndrome (FAS). Despite public warnings discouraging alcohol use during pregnancy, many pregnant women continue to drink intermittently because they do not believe that occasional exposures to alcohol can be harmful to a fetus. However, because of genetic differences, some fetuses are much more susceptible than others to alcohol-induced brain injury. Thus, a relatively low quantity of alcohol that may be innocuous to most fetuses could damage a genetically susceptible fetus. Neuronal nitric oxide synthase (nNOS) can protect developing mouse neurons against alcohol toxicity by synthesizing neuroprotective nitric oxide. This study examined whether a single exposure to alcohol, which causes no evident injury in wild type mice, can damage the brains of mice genetically deficient for nNOS (nNOS-/- mice). Wild type and nNOS-/- mice received intraperitoneal injections of alcohol (0.0, 2.2, or 4.4mg/g body weight) either as a single dose on postnatal day (PD) 4 or as repeated daily doses over PD4-9. Brain volumes and neuronal numbers within the hippocampus and cerebral cortex were determined on PD10. Alcohol exposure on PD4-9 restricted brain growth and caused neuronal death in both strains of mice, but the severity of microencephaly and neuronal loss were more severe in the nNOS-/- mice than in wild type. The 4.4 mg/g alcohol dose administered on PD4 alone caused significant neuronal loss and microencephaly in the nNOS-/- mice, while this same dose caused no evident injury in the wild type mice. Thus, during development, a single exposure to alcohol can injure a genetically vulnerable brain, while it leaves a wild type brain unaffected. Since the genes that confer alcohol resistance and vulnerability in developing humans are unknown, any particular human fetus is potentially vulnerable. Thus, women should be counseled to consume no alcohol during pregnancy.
de Licona
Hannah Klein
HK
Neuroscience Graduate Program, University of Iowa College of Medicine, Iowa City, IA, United States.
Karacay
Bahri
B
Mahoney
Jo
J
McDonald
Elizabeth
E
Luang
Thirath
T
Bonthius
Daniel J
DJ
D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D002452:Cell Count; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000187:drug effects* / Q000254:growth & development; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D005260:Female; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects* / Q000254:growth & development; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008831:Microcephaly / Q000139:chemically induced* / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000235:genetics*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D011897:Random Allocation; D013997:Time Factors
D000431:Ethanol; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse