Deletion of TLR-4 attenuates fetal alcohol exposure-induced gene expression and social interaction deficits.
Deletion of TLR-4 attenuates fetal alcohol exposure-induced gene expression and social interaction deficits.
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DOI：
10.1016/j.alcohol.2018.04.004
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Rao R
中科院分区：
文献类型：
--
作者：
Shukla PK;Meena AS;Rao R;Rao R
Fetal alcohol spectrum disorders (FASD) are associated with social interaction behavior and gastrointestinal (GI) abnormalities. These abnormal behaviors and GI abnormalities overlap with autism spectrum disorder (ASD). We investigated the effect of fetal alcohol exposure (FAE) on social interaction deficits (hallmark of autism). Evidence indicates that exogenous lipopolysaccharide (LPS) administration during gestation induces autism-like behavior in the litters. LPS regulates the expression of genes underlying differentiation, immune function, myelination and synaptogenesis in fetal brain by the LPS receptor, TLR-4-dependent mechanism. In this study, we evaluated the role of TLR-4 in FAE-induced social behavior deficit. WT and TLR4−/− pregnant mice were fed Lieber-DeCarli liquid diet with or without EtOH. Control group was pair-fed with isocaloric diet. Social behavior was tested in the adult litters at postnatal day 60. Frontal cortex mRNA expression of autistic candidate genes (Ube3a, Gabrb3, Mecp2) and inflammatory cytokine genes (IL-1β, IL-6, TNF-α) were measured by RT-qPCR. Adult male litters of EtOH-fed WT dams showed low birth weight compared to litters of pair-fed WT dams. However, their body weights at adulthood were greater compared to the body weights of litters of pair-fed WT dams. There were no body weight differences in litters of TLR4−/− dams. Social interaction deficit was observed only in male litters of EtOH-fed WT dams, but it was not observed in both male and female litters of EtOH-fed TLR4−/− dams. Expressions of autism candidate genes, Gabrb3 and Ube3a were elevated, while that of Mecp2 gene was suppressed in the frontal cortex of male, but not female litters of EtOH-fed WT mice. The expressions of inflammatory cytokine genes, IL-1β, IL-6 and TNF-α were also significantly increased in the frontal cortex of male, but not female, litters of EtOH-fed dams. The changes in the expression of autistic and cytokine genes were unaffected in the litters of EtOH-fed TLR4−/− dams. These data also indicate that TLR4 mediates FAE-induced changes in social interactions and gene expression in brain, suggesting that EtOH-induced LPS absorption from the maternal gut may be involved in gene expression changes in the fetal brain.
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DOI：
10.1002/hep.23009
发表时间：
2009-08
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Rao R
通讯作者：
Rao R
DOI：
10.1111/acer.12777
发表时间：
2015-08
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Chaudhry KK;Samak G;Shukla PK;Mir H;Gangwar R;Manda B;Isse T;Kawamoto T;Salaspuro M;Kaihovaara P;Dietrich P;Dragatsis I;Nagy LE;Rao RK
通讯作者：
Rao RK
影响因子：
5.3
作者：
Alfonso-Loeches, Silvia;Pascual-Lucas, Maya;Guerri, Consuelo
通讯作者：
Guerri, Consuelo
影响因子：
11.2
作者：
Vargas, DL;Nascimbene, C;Pardo, CA
通讯作者：
Pardo, CA
影响因子：
3.2
作者：
McHugh RK;Wigderson S;Greenfield SF
通讯作者：
Greenfield SF