Vitamin A deficiency from maternal gestation may contribute to autistic-like behaviors and gastrointestinal dysfunction in rats through the disrupted purine and tryptophan metabolism.

Vitamin A deficiency (VAD) has been linked to autism spectrum disorder (ASD) in multiple studies, and autistic children with gastrointestinal (GI) symptoms have been found to have lower VA levels than those without GI symptoms. However, the exact mechanism by which VAD causes both core symptoms and GI symptoms in ASD is ill defined. We constructed VAD and vitamin A normal (VAN) rat models from maternal gestation onwards. Autism-related behaviors were tested using the open-field test and the three-chamber test, and GI function was assessed with the GI transit time, the colonic transit time and fecal water content. Untargeted metabolomic analysis on the prefrontal cortex (PFC) and fecal samples was performed. VAD rats displayed autistic-like behaviors and impaired GI function compared to VAN rats. Metabolic profiles of both PFC and feces from VAD and VAN rats were significantly different. The differential metabolites in both PFC and feces between the VAN and VAD rats were mostly enriched in the purine metabolic pathway. Moreover, the most significantly affected metabolic pathway in PFC of VAD rats was the phenylalanine, tyrosine and tryptophan biosynthesis pathway, and the most remarkably altered metabolic pathway in the feces of VAD rats was the tryptophan metabolism pathway. These results indicate that VAD starting from maternal gestation might be linked to core symptoms of ASD and its GI co-occurring disorders through the purine and tryptophan-related metabolism disorders.

Valproic Acid Induces Autism-Like Synaptic and Behavioral Deficits by Disrupting Histone Acetylation of Prefrontal Cortex ALDH1A1 in Rats.

OBJECTIVES: This study aimed to investigate the impact of valproic acid (VPA) on the histone acetylation of acetaldehyde dehydrogenase 1A1 (ALDH1A1) and the mechanism underlying VPA-induced autism-like behavior. METHODS: Female Sprague-Dawley rats were intraperitoneally injected with VPA during gestation to establish an autism model in their offspring. Some offspring prenatally exposed to VPA were randomly treated with MS-275, one histone deacetylase (HDAC) inhibitor, or retinoic acid (RA) after birth. Behavioral tests were conducted on the offspring 6 weeks after birth. Electrophysiological experiments were performed to investigate long-term potentiation (LTP) in the prefrontal cortex (PFC). The expression levels of AMPA receptors (GluA1 and 2), NMDA receptors (GluN1 and 2), synapsin 1 (SYN1), HDAC, acetylated histone 3 (AcH3), RA receptor alpha (RARα), and ALDH1A1 in the PFC were measured by Western blotting and quantitative polymerase chain reaction. ALDH enzyme activity in PFC tissue was detected using a Micro ALDH Assay Kit. The RA level in the PFC was measured using ultrahigh-performance liquid chromatography/tandem mass spectrometry. A chromatin immunoprecipitation (ChIP) experiment explored the interaction between the ALDH1A1 gene and AcH3. RESULTS: Offspring prenatally exposed to VPA showed autism-like behavior, upregulated the levels of LTP and GluN2A, GluA1, and SYN1 proteins relevant to synaptic plasticity in the PFC. The expression levels of HDAC3 mRNA and protein were increased. On the other hand, there was a significant reduction in the levels of AcH3, RARα, RA, ALDH1A1 mRNA and protein, the level of ALDH activity and AcH3 enrichment in the ALDH1A1 promoter region in VPA-induced offspring. Administration of MS-275 in VPA offspring significantly elevated the levels of AcH3, ALDH1A1 mRNA and protein, ALDH activity, RA, the level of RARα protein and the binding of AcH3 to the ALDH1A1 promoter. In addition, the GluA1 protein level and LTP were reduced, and most behavioral deficits were reversed. After RA supplementation in the VPA-treated offspring, the RA and RARα protein levels were significantly upregulated, GluA1 protein and LTP were downregulated, and most autism-like behavioral deficits were effectively reversed. CONCLUSION: These findings suggest that VPA impairs histoneacetylation of ALDH1A1 and downregulates the RA-RARα pathway. Such epigenetic modification of ALDH1A1 by VPA leads to autism-like synaptic and behavioral deficits.

Vitamin A supplementation ameliorates motor incoordination via modulating RORα in the cerebellum in a valproic acid-treated rat autism model with vitamin A deficiency.

Motor dysfunctions are common comorbidities among autism spectrum disorder (ASD) patients. Abnormal cerebellar development throughout critical periods may have an effect on motor functions and result in motor impairments. Vitamin A (VA) plays a crucial role in the developing process of the nervous system. The correlation of VA deficiency (VAD) and ASD with motor dysfunctions, however, is not clear. Therefore, we built rat models with different VA levels based on the valproic acid (VPA)-treated autism model. ASD rats with VAD showed aggravated motor coordination abnormalities, Purkinje cell loss and impaired dendritic arborization of Purkinje cells compared to ASD rats with normal VA levels (VA normal, VAN). Additionally, the expression levels of retinoid-related orphan receptor α (RORα) and retinoic acid receptor α (RARα) were lower in the cerebellum of ASD rats with VAD than in those of ASD rats with VAN. VA supplementation (VAS) effectively improved motor coordination and cerebellar Purkinje cell abnormalities in ASD rats with VAD. Furthermore, the results of chromatin immunoprecipitation (ChIP) assays confirmed that the enrichment of RARα was detected on the RORα promoter in the cerebellum and that VAS could upregulate the binding capacity of RARα for RORα promoters. These results showed that VAD in autism might result in cerebellar impairments and be a factor aggravating a subtype of ASD with motor comorbidities. The therapeutic effect of VAS on motor deficits and Purkinje neuron impairments in autism might be due to the regulation of RORα by RARα.

Vitamin A deficiency increases the risk of gastrointestinal comorbidity and exacerbates core symptoms in children with autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder, and many individuals with ASD have gastrointestinal (GI) comorbidities. Vitamin A (VA) is an essential micronutrient that plays an important role in brain development and GI function. METHODS: A total of 323 children with ASD and 180 control children were enrolled in this study. Symptoms of ASD were assessed with the Child Autism Rating Scale (CARS), the Social Responsiveness Scale (SRS), and the Autism Behavior Checklist (ABC). Caregivers of the children completed questionnaires about GI symptoms. Serum retinol levels were detected with high-performance liquid chromatography (HPLC). RESULTS: Children with ASD and with GI comorbidity and constipation had considerably lower serum VA levels than autistic children without these symptoms. VA level was associated with CARS, SRS, and ABC scores, whereas GI symptoms were associated some SRS and ABC scores. The interaction of VAD and GI symptoms appeared to aggravate some of the core symptoms of children with ASD. CONCLUSIONS: VAD exacerbates core symptoms in children with ASD, and ASD children with GI comorbidities also have more serious core symptoms than ASD children without GI comorbidities. VAD comorbid with GI symptoms aggravates autistic children's core symptoms. IMPACT: VAD exacerbates core symptoms in children with ASD. ASD children with GI comorbidities have more serious core symptoms than ASD children without GI comorbidities. VAD comorbid with GI symptoms aggravates autistic children's core symptoms. We speculate that VAD might be related to a subtype of ASD that involves GI comorbidities. We believe that our findings will be of fundamental importance to the scientific community.

Vitamin A deficiency exacerbates autism-like behaviors and abnormalities of the enteric nervous system in a valproic acid-induced rat model of autism.

The manifestations of autism spectrum disorder (ASD) are highly heterogeneous. As many individuals with ASD have gastrointestinal (GI) comorbidities, ASD with GI problems is considered to be a subtype of ASD. Vitamin A (VA) plays an important role in the development of both the central and peripheral nervous system. However, the relationship between VA deficiency (VAD) and ASD with GI comorbidities is still unclear. We established rat models with different VA levels based on the valproic acid-induced autism model. Compared to autism model rats with VA normal (VAN), autism model rats with gestational VAD showed more severe autism-like behavior, increased GI transit time, and impairment of the enteric nervous system (ENS). Besides, the expression levels of retinoic acid receptor α (RARα) and Ret in autism model rats with VAD were decreased compared with those in rats with VAN. Supplementation with VA was found to effectively ameliorate autism-like behaviors and impairments of GI motility and the ENS in autism model rats with VAD. Chromatin immunoprecipitation results suggested that RARa can bind to the promoter region of the Ret gene and regulate the Ret signaling pathway. We speculate that VAD in autism might lead to impairments of both the brain and ENS. VAD might be a factor that causes individuals to be more susceptible to ASD-related risk factors and aggravates a subtype of ASD with GI comorbidities.

[Role of exercise in asthma management in children].

OBJECTIVE: To study the role of exercise in asthma management in children and formulate exercise prescriptions for asthmatic children. METHODS: A total of 112 asthmatic children aged 7-14 years were randomized into control group (n=56, with medications only) and exercise group (n=56, with medications and exercise prescription) for a trial lasting for 4 months. An asthma diary was used for all children to record the morning and evening peak expiratory flow (PEF), daytime and nighttime asthma symptom score, use of short-acting beta agonists, participation in physical activity, and exercise-induced asthma symptoms. RESULTS: Of the 112 children, 5 dropped out before the trial completion. From the 13th week, PEF variation in exercise group was significantly lowered compared to that in the control group (P<0.05). Upon the completion of the trial, the daytime and nighttime symptoms score and emergency medication score were all significantly lower in the exercise group than in the control group (P<0.05). No severe adverse events occurred in the children during the trial. CONCLUSION: Exercise for no less than 20 min, 3 days a week for 4 months is safe and beneficial for asthma control in children.

A cross-sectional survey of participation of asthmatic children in physical activity.

BACKGROUND: Physical exercise has been proven to be beneficial to children with asthma, but the traditional view in China is that asthmatic children should not take part in sports. This study was undertaken to investigate the current status of children with asthma taking part in exercise in China. METHODS: One hundred and twenty-three asthmatic children (7-14 years old) who had visited our asthma control center between February 2009 and June 2009 were enrolled in this cross-sectional study. Each child had a pulmonary function test and his/her health-related quality of life was assessed. The children also finished a questionnaire about their physical activity. As a control group, 109 nonasthmatic children from a primary school were surveyed about their level of activity. RESULTS: Asthmatic children took part in less exercise than their healthy peers, and 62.6% (77/123) of the children with asthma never reached the criteria of exercise prescription for patients with asthma advised by the American College of Sports Medicine. The asthmatic children were divided into two groups based on the level of activity; compared with the group with a higher physical activity level, more children in the group with lower activity believed that exercise could make asthma worse, more parents and teachers restricted the children's exercise, and fewer doctors approved them participating in exercise. All of the parameters of basic lung function were higher in the group with higher activity level. Moreover, the children with a higher exercise level had a higher score on all parts of the pediatric asthma quality-of-life questionnaire. About 78.5% (96/123) of children ever experienced coughing, chest distress, dyspnea, or gasping during exercise, but 49.6% (61/123) had these symptoms occasionally. CONCLUSIONS: Our study reveals that children with asthma do not have enough exercise in China. The concept that children, parents, teachers and doctors have about exercise for patients with asthma is urgent to be updated. We need to prescribe appropriate exercise for children with asthma.