Importance of genetics in fetal alcohol effects: Null mutation of the nNOS gene worsens alcohol-induced cerebellar neuronal losses and behavioral deficits

Abstract

The cerebellum is a major target of alcohol-induced damage in the developing brain. However, the cerebella of some children are much more seriously affected than others by prenatal alcohol exposure. As a consequence of in utero alcohol exposure, some children have substantial reductions in cerebellar volume and corresponding neurodevelopmental problems, including microencephaly, ataxia, and balance deficits, while other children who were exposed to similar alcohol quantities are spared. One factor that likely plays a key role in determining the impact of alcohol on the fetal cerebellum is genetics. However, no specific gene variant has yet been identified that worsens cerebellar function as a consequence of developmental alcohol exposure. Previous studies have revealed that mice carrying a homozygous mutation of the gene for neuronal nitric oxide synthase (nNOS−/− mice) have more severe acute alcohol-induced neuronal losses from the cerebellum than wild type mice. Therefore, the goals of this study were to determine whether alcohol induces more severe cerebellum-based behavioral deficits in nNOS−/− mice than in wild type mice and to determine whether these worsened behavior deficits are associated with worsened cerebellar neuronal losses. nNOS−/− mice and their wild type controls received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days 4–9. In adulthood, the mice underwent behavioral testing, followed by neuronal quantification. Alcohol caused dose-related deficits in rotarod and balance beam performance in both nNOS−/− and wild type mice. However, the alcohol-induced behavioral deficits were substantially worse in the nNOS−/− mice than in wild type. Likewise, alcohol exposure led to losses of Purkinje cells and cerebellar granule cells in mice of both genotypes, but the cell losses were more severe in the nNOS−/− mice than in wild type. Behavioral performances were correlated with neuronal number in the nNOS−/− mice, but not in wild type. Thus, homozygous mutation of the nNOS gene increases vulnerability to alcohol-induced cerebellar dysfunction and neuronal loss. nNOS is the first gene identified whose mutation worsens alcohol-induced cerebellar behavioral deficits.

Preventive effect of flavonoids from Wushan Shencha (Malus doumeri leaves) on CCl4‐induced liver injury

“…Studies have shown that carbon tetrachloride induces oxidative stress in organisms and produce a large number of free radicals. Mn‐SOD and Cu/Zn‐SOD inhibit free radicals and prevent liver injury (Sipes, Sisi, Sim, Mobley, & Earnest, ; Bonthius, Winters, Karacay, Bousquet, & Bonthius, ). CAT is an antioxidant enzyme that inhibits oxidative stress by clearing the body of hydrogen peroxide, slowing the oxidation caused by carbon tetrachloride, and thus inhibiting liver injury (Lee, Hyun, Jenner, & Halliwell, ).…”

Preventive effect of Lactobacillus plantarum KSFY02 isolated from naturally fermented yogurt from Xinjiang, China, on d-galactose–induced oxidative aging in mice

“…A decline in spleen weight indicates the occurrence of atrophy in the organ, which can reduce the immune function of the animal. Therefore, the organ indices of a mouse can directly reflect structural changes and functions of the organs and are important reference values for evaluating whether construction of a mouse model of aging is successful (Bonthius et al, 2015). The results of this study also show that oxidative aging causes a decrease in the organ indices in mice and that LP-KSFY02 could effectively alleviate the decreases in the organ indices caused by d-galactose and allow the organ indices of oxidative aging mice to remain close to those of normal mice.…”

Lactobacillus plantarum KSFY06 on d‐galactose‐induced oxidation and aging in Kunming mice

“…To further elucidate the antioxidant mechanism, this study has examined the changes in mRNA expression levels of eNOS, nNOS, nNOS and eNOS are basal-expressing tissue-constituting enzymes that participate in the entire process of learning and memory impairment (Bonthius et al, 2015). The content of nNOS and eNOS decreases after oxidative damage in the body, while increasing the levels of nNOS and eNOS in the body will also effectively control aging (Bonthius et al, 2015). In this study, L. plantarum KSFY06 can also effectively control the expression of iNOS in mouse liver tissue and spleen tissue, while increasing the expression of nNOS and eNOS to slow down the aging.…”