Prenatal exposure to valproic acid (VPA) in rat offspring is capable of inducing experimental autism with neurobehavioral aberrations. This study investigated the effect of docosahexaenoic acid (DHA) on hippocampal cell death, learning and memory alteration in an experimental rat autism model. We found that DHA supplementation (75, 150 or 300 mg/kg/day, 21 days) rescued the VPA (600 mg/kg) induced DHA reduction in plasma and hippocampus in a dose-dependent manner, increased the levels of hippocampal p-CaMKII and p-CREB without affecting total protein level, and altered BDNF-AKT-Bcl-2 signaling pathway, as well as inhibited the activity of caspase-3. DHA also influenced the content of malondialdehyde (MDA) and the activities of antioxidant enzymes in the VPA-treated offspring. Consistent with the previous results, we also observed that 300 mg/kg DHA supplementation markedly increased the cell survival, decreased the cell apoptosis, and increased mature neuronal cell in the hippocampus in VPA-treated offspring. Utilizing the Morris water maze test, we found that DHA prevented cognitive impairment in offspring of VPA-treated rats. The data suggested that DHA may play a neuroprotective role in hippocampal neuronal cell and ameliorates dysfunctions in learning and memory in this rat autism model. Thus, DHA could be used as treatment intervention for mitigating behavioral dysfunctions in autism spectrum disorder (ASD).
Abstract:Objective: A study in a Caucasian population has identified two single-nucleotide polymorphisms (SNPs) in ZNF533, one in DOCK4, and two in IMMP2L, which were all significantly associated with autism. They are located in AUTS1 and AUTS5, which have been identified as autism susceptibility loci in several genome-wide screens. The present study aimed to investigate whether ZNF533, DOCK4, and IMMP2L genes are also associated with autism in a northeastern Chinese Han population. Methods: We performed a similar association study using families with three individuals (one autistic child and two unaffected parents). A family-based transmission disequilibrium test (TDT) was used to analyze the results. Results: There were significant associations between autism and the two SNPs of ZNF533 gene (rs11885327: χ 2 =4.5200, P=0.0335; rs1964081: χ 2 =4.2610, P=0.0390) and the SNP of DOCK4 gene (rs2217262: χ 2 =5.3430, P=0.0208). Conclusions: Our data suggest that ZNF533 and DOCK4 genes are linked to a predisposition to autism in the northeastern Chinese Han population.
BackgroundAutism is a common, severe and highly heritable neurodevelopmental disorder in children, affecting up to 100 children per 10,000. The MET gene has been regarded as a promising candidate gene for this disorder because it is located within a replicated linkage interval, is involved in pathways affecting the development of the cerebral cortex and cerebellum in ways relevant to autism patients, and has shown significant association signals in previous studies.Principal FindingsHere, we present new ASD patient and control samples from Heilongjiang, China and use them in a case-control and family-based replication study of two MET variants. One SNP, rs38845, was successfully replicated in a case-control association study, but failed to replicate in a family-based study, possibly due to small sample size. The other SNP, rs1858830, failed to replicate in both case-control and family-based studies.ConclusionsThis is the first attempt to replicate associations in Chinese autism samples, and our result provides evidence that MET variants may be relevant to autism susceptibility in the Chinese Han population.
BackgroudAutism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders with a genetic basis. The role of long-chain polyunsaturated fatty acids (LC-PUFAs) and the occurrence of autism has been the focus of many recent studies. The present study investigates whether genetic variants of the fatty acid desaturase (FADS) 1/2 and elongation of very long-chain fatty acids protein (ELOVL) 2 genes, which are involved in LC-PUFA metabolism, are associated with ASD risk.MethodsA cohort of 243 ASD patients and 243 unrelated healthy controls were enrolled in this case control study. Sixteen tag single nucleotide polymorphisms from the FADS1–2 and ELOVL2 genes were genotyped using the Sequenom Mass Array.ResultsThere were significant differences in allelic distribution of FADS2 rs526126 (OR = 0.55, 95% CI = 0.42–0.72, pFDR < 0.05) between autistic children and controls. FADS2 rs526126 and ELOVL2 rs10498676 were associated with decreased ASD risk in recessive model (OR = 0.07, 95% CI = 0.02–0.22, pFDR < 0.01; OR = 0.56, 95% CI = 0.35–0.89, pFDR = 0.042), while ELOVL2 rs17606561, rs3756963, and rs9468304 were associated with increased ASD risk in overdominant model (OR = 1.63, 95% CI = 1.12–2.36, pFDR = 0.036; OR = 1.64, 95% CI = 1.14–2.37, pFDR = 0.039; OR = 1.75, 95% CI = 1.22–2.50, pFDR = 0.017). The A/A genotype of rs10498676 was correlated with a decline in the Autism Diagnostic Interview-Revised communication (verbal and nonverbal) domain.ConclusionsThese findings provide evidence of an association between FADS2 and ELOVL2 polymorphisms and ASD susceptibility in Chinese children.Electronic supplementary materialThe online version of this article (10.1186/s12888-018-1868-7) contains supplementary material, which is available to authorized users.
To investigate whether the decreased level of serum polyunsaturated fatty acids (PUFAs) in patients with autism is associated with the expression of related liver metabolic enzymes, we selected rats that were exposed to valproic acid (VPA) on embryonic day 12.5 (E12.5) as a model of autism. We observed the serum levels of PUFAs and the expression of related liver metabolic enzymes, including Δ5-desaturase, Δ6-desaturase and elongase (Elovl2), in VPA-exposed and control rats on postnatal day 35 (PND35) and conducted sex dimorphic analysis. We found that the levels of serum PUFAs and related liver metabolic enzymes in the VPA rats were significantly reduced, in association with autism-like behavioral changes, the abnormal expression of apoptosis-related proteins and hippocampal neuronal injury, compared to the control rats and showed sex difference in VPA group. This finding indicated that rats exposed to VPA at the embryonic stage may exhibit reduced synthesis of serum PUFAs due to the down-regulation of liver metabolic enzymes, thereby inducing nervous system injury and behavioral changes, which is affected by sex in the meantime.
Based on the background of the Line F2-3 interval tunnel section of Jiujiawan in Urumqi Subway Line 1, this paper carries out the model test research on the antibreaking technology of the reducing dislocation layer in the tunnel section of the stick-slip fracture. The antibreaking effect of different locations and number of reducing dislocation layers in tunnel engineering is analyzed in this paper. The results show that when the double reducing dislocation layer, respectively, set between the surrounding rock and the primary support, and the primary support and the secondary lining, the antibreaking effect is the best. It is recommended to use this scheme for antibreaking design. The research results can provide reference for antibreaking design of traffic tunnels in active fault zones.
Autism spectrum disorder (ASD) is a neurodevelopment disorder with abnormalities of social interaction, communication and repetitive behaviors. The higher prevalence of ASD in men implies a potential relationship between sex hormones and ASD etiology. The ESR2 gene encodes estrogen receptor beta (ESR2) and plays an important role during brain development. A relationship between ESR2 and ASD has been suggested by studies on single nucleotide polymorphisms and mRNA and protein expression levels in ASD patients. Here, we explored the possible epigenetic regulation of the ESR2 gene in autism. We collected genomic DNA from the peripheral blood of Chinese Han males with autism and age-matched normal males and measured DNA methylation of CpG islands in the ESR2 gene, which consisted of 41 CpG sites among the proximal promoter region and an untranslated exon, by bisulfite sequencing. We also investigated a relationship between DNA methylation and phenotypic features of autism, as assessed by the Children Autism Rating Scale. We found little overall difference in the DNA methylation of the ESR2 5'-flanking region in individuals with autism compared with normal individuals. However, detailed analyses revealed that eight specific CpG sites were hypermethylated in autistic individuals and that four specific CpG sites were positively associated with the severity of autistic symptoms. Our study indicates that the epigenetic dysregulation of ESR2 may govern the development of autism.
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