Exposure to endocrine disrupting chemicals including phthalates, phenols, and parabens in infancy: Associations with neurodevelopmental outcomes in the MARBLES study.

BACKGROUND: Endocrine disrupting chemicals (EDCs) are widely used compounds with the potential to affect child neurodevelopmental outcomes including autism spectrum disorders (ASD). We aimed to examine the urinary concentrations of biomarkers of EDCs, including phthalates, phenols, and parabens, and investigate whether exposure during early infancy was associated with increased risk of later ASD or other non-typical development (Non-TD) or adverse cognitive development. METHODS: This analysis included infants from the Markers of Autism Risks in Babies-Learning Early Signs (MARBLES) study, a high-risk ASD cohort (n = 148; corresponding to 188 urine samples). Thirty-two EDC biomarkers were quantified in urine among infants 3 and/or 6 months of age. Trends in EDC biomarker concentrations were calculated using least square geometric means. At 36 months of age, children were clinically classified as having ASD (n = 36), nontypical development (Non-TD; n = 18), or typical development (TD; n = 81) through a clinical evaluation. Trinomial logistic regression analysis was used to test the associations between biomarkers with ASD, or Non-TD, as compared to children with TD. In single analyte analysis, generalized estimating equations were used to investigate the association between each EDC biomarkers and longitudinal changes in cognitive development using the Mullen Scales of Early Learning (MSEL) over the four assessment time points (6, 12, 24, and 36 months of age). Additionally, quantile g-computation was used to test for a mixture effect. RESULTS: EDC biomarker concentrations generally decreased over the study period, except for mono-2-ethyl-5-carboxypentyl terephthalate. Overall, EDC biomarkers at 3 and/or 6 months of age were not associated with an increased risk of ASD or Non-TD, and a few showed significant inverse associations. However, when assessing longitudinal changes in MSEL scores over the four assessment time points, elevated monoethyl phthalate (MEP) was significantly associated with reduced scores in the composite score (ß = -0.16, 95% CI: 0.31, -0.02) and subscales of fine motor skills (ß = -0.09, 95%CI: 0.17, 0.00), and visual reception (ß = -0.11, 95% CI: 0.23, 0.01). Additionally, the sum of metabolites of di (2-ethylhexyl) terephthalate (Æ©DEHTP) was associated with poorer visual reception (ß = -0.09, 95% CI: 0.16, -0.02), and decreased composite scores (ß = -0.11, 95% CI: 0.21, -0.01). Mixtures analyses using quantile g-computation analysis did not show a significant association between mixtures of EDC biomarkers and MSEL subscales or composite scores. CONCLUSION: These findings highlight the potential importance of infant exposures on cognitive development. Future research can help further investigate whether early infant exposures are associated with longer-term deficits and place special attention on EDCs with increasing temporal trends and whether they may adversely affect neurodevelopment.

Exposure to heavy metals in utero and autism spectrum disorder at age 3: a meta-analysis of two longitudinal cohorts of siblings of children with autism.

BACKGROUND: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized. METHODS: In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, urinary metals concentrations during two pregnancy time periods (< 28 weeks and ≥ 28 weeks of gestation) were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. In an exposure-wide association framework, using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, age at pregnancy, race/ethnicity and education. We meta-analyzed across the two cohorts. RESULTS: In EARLI (n = 170) 17% of children were diagnosed with ASD, and 44% were classified as having non-neurotypical development (Non-TD). In MARBLES (n = 231), 21% were diagnosed with ASD, and 14% classified as Non-TD. During the first and second trimester period (< 28 weeks), having cadmium concentration over the level of detection was associated with 1.69 (1.08, 2.64) times higher risk of ASD, and 1.29 (0.95, 1.75)times higher risk of Non-TD. A doubling of first and second trimester cesium concentration was marginally associated with 1.89 (0.94, 3.80) times higher risk of ASD, and a doubling of third trimester cesium with 1.69 (0.97, 2.95) times higher risk of ASD. CONCLUSION: Exposure in utero to elevated levels of cadmium and cesium, as measured in urine collected during pregnancy, was associated with increased risk of developing ASD.

Urine manganese, cadmium, lead, arsenic, and selenium among autism spectrum disorder children in Kuala Lumpur.

Background: The development of autism spectrum disorder (ASD) may stem from exposure to environmental pollutants such as heavy metals. The primary objective of this study is to determine the role of heavy metals of concern such as manganese (Mn), cadmium (Cd), lead (Pb), arsenic (As), and essential trace element selenium (Se) among ASD children in Kuala Lumpur, Malaysia. Method: A total of 155 preschoolers in Kuala Lumpur between the ages 3 to 6 participated in an unmatched case-control study, comprising ASD children (n = 81) recruited from an early intervention program for autism, and 74 children without autism who were recruited from public preschools. Urine samples were collected at home, delivered to the study site, and transported to the environmental lab within 24 hours. Inductively coupled plasma mass spectrometry (ICP-MS) was applied to measure the concentration of heavy metals in the samples. Data were analysed using bivariate statistical tests (Chi-square and T-test) and logistic regression models. Result: This study demonstrated that Cd, Pb, and As urine levels were significantly greater in children without autism relative to those affected with ASD (p < 0.05). No significant difference was in the levels of Se (p = 0.659) and Mn (p = 0.875) between children with ASD and the control group. The majority of children in both groups have urine As, Pb, and Cd values lower than 15.1 µg/dL, 1.0 µg/dL, and 1.0 µg/dL, respectively which are the minimal risk values for noncarcinogenic detrimental human health effect due to the heavy metal's exposure . Factors associated with having an ASD child included being a firstborn, male, and higher parental education levels (adjusted odds ratios (aOR) > 1, p < 0.05). Conclusion: Preschoolers in this study demonstrated low levels of heavy metals in their urine samples, which was relatively lower in ASD children compared to the healthy matched controls. These findings may arise from the diminished capacity to excrete heavy metals, especially among ASD children, thereby causing further accumulation of heavy metals in the body. These findings, including the factors associated with having an ASD child, may be considered by healthcare professionals involved in child development care, for early ASD detection. Further assessment of heavy metals among ASD children in the country and interventional studies to develop effective methods of addressing exposure to heavy metals will be beneficial for future reference.

Androgen levels in autism spectrum disorders: a systematic review and meta-analysis.

Background: Accumulating evidence suggests that the autism spectrum disorder (ASD) population exhibits altered hormone levels, including androgens. However, studies on the regulation of androgens, such as testosterone and dehydroepiandrosterone (DHEA), in relation to sex differences in individuals with ASD are limited and inconsistent. We conducted the systematic review with meta-analysis to quantitatively summarise the blood, urine, or saliva androgen data between individuals with ASD and controls. Methods: A systematic search was conducted for eligible studies published before 16 January 2023 in six international and two Chinese databases. We computed summary statistics with a random-effects model. Publication bias was assessed using funnel plots and heterogeneity using I2 statistics. Subgroup analysis was performed by age, sex, sample source, and measurement method to explain the heterogeneity. Results: 17 case-control studies (individuals with ASD, 825; controls, 669) were assessed. Androgen levels were significantly higher in individuals with ASD than that in controls (SMD: 0.27, 95% CI: 0.06-0.48, P=0.01). Subgroup analysis showed significantly elevated levels of urinary total testosterone, urinary DHEA, and free testosterone in individuals with ASD. DHEA level was also significantly elevated in males with ASD. Conclusion: Androgen levels, especially free testosterone, may be elevated in individuals with ASD and DHEA levels may be specifically elevated in males.

Early childhood exposures to phthalates in association with attention-deficit/hyperactivity disorder behaviors in middle childhood and adolescence in the ReCHARGE study.

BACKGROUND: Early-life exposure to phthalates alters behaviors in animals. However, epidemiological evidence on childhood phthalate exposure and attention-deficit/hyperactivity disorder (ADHD) behaviors is limited. METHODS: This study included 243 children from the ReCHARGE (Revisiting Childhood Autism Risks from Genetics and Environment) study, who were previously classified as having autism spectrum disorder (ASD), developmental delay, other early concerns, and typical development in the CHARGE case-control study. Twenty phthalate metabolites were measured in spot urine samples collected from children aged 2-5 years. Parents reported on children's ADHD symptoms at ages 8-18 years using Conners-3 Parent Rating Scale. Covariate-adjusted negative binomial generalized linear models were used to investigate associations between individual phthalate metabolite concentrations and raw scores. Weighted quantile sum (WQS) regression with repeated holdout validation was used to examine mixture effects of phthalate metabolites on behavioral scores. Effect modification by child sex was evaluated. RESULTS: Among 12 phthalate metabolites detected in >75% of the samples, higher mono-2-heptyl phthalate (MHPP) was associated with higher scores on Inattentive (ß per doubling = 0.05, 95% confidence interval [CI]: 0.02, 0.08) and Hyperactive/Impulsive scales (ß = 0.04, 95% CI: 0.00, 0.07), especially among children with ASD. Higher mono-carboxy isooctyl phthalate (MCiOP) was associated with higher Hyperactivity/Impulsivity scores (ß = 0.07, 95% CI: -0.01, 0.15), especially among typically developing children. The associations of the molar sum of high molecular weight (HMW) phthalate metabolites and a phthalate metabolite mixture with Hyperactivity/Impulsivity scores were modified by sex, showing more pronounced adverse associations among females. CONCLUSION: Exposure to phthalates during early childhood may impact ADHD behaviors in middle childhood and adolescence, particularly among females. Although our findings may not be broadly generalizable due to the diverse diagnostic profiles within our study population, our robust findings on sex-specific associations warrant further investigations.

Determination of modified nucleosides in the urine of children with autism spectrum disorder.

Metabolic disorders and nutritional deficiencies in ASD children may be identified by the determination of urinary-modified compounds. In this study, levels of selected seven modified compounds: O-methylguanosine, 7-methylguanosine, 1-methyladenosine, 1-methylguanine, 7-methylguanine, 3-methyladenine, and 8-hydroxy-2`-deoxyguanosine in the group of 143 ASD children and 68 neurotypical controls were analyzed. An ancillary aim was to verify if the reported levels differed depending on the pathogenetic scoring of ASD (mild deficit, moderate deficit, severe deficit). Elevated O-methylguanosine and 7-methylguanosine levels and significantly lower levels of 3-methyladenine, 1-methylguanine, 1-methyladenosine, 7-methylguanine, and 8-hydroxy-'2'-deoxyguanosine were observed in ASD children compared to controls. O-methylguanosine levels were elevated in the mild and moderate groups, while the levels of 1-methylguanine, 1-methyladenosine, 7-methylguanine, and 8-hydroxy-'2'-deoxyguanosine in the same groups were lower than in neurotypical controls. The reported evidence shows that modified nucleosides/bases can play a potential role in the pathophysiology of ASD and that each nucleoside/base shows a unique pattern depending on the degree of the deficit.

Association of autism with toxic metals: A systematic review of case-control studies.

Environmental factors have been associated with the etiology of autism spectrum disorder ASD in recent times. The involvement of toxic metals in the generation of reactive oxygen species and their epigenetics effects have been implicated in ASD. This systemic review examines the association of toxic metals with autism in children. A systematic literature search was performed in scientific databases such as PubMed, Google scholar, and Scopus. Case-control studies evaluating toxic metal levels in different tissues of ASD children and comparing them to healthy children (control group) were identified. The Newcastle-Ottawa Scale was used to evaluate the risk of bias of the included studies. Six case-control studies with 425 study subjects met our inclusion criteria. A total of four studies indicated higher levels of As, Pb, Hg, Cd, Al, Sn, Sb, Ba, TI, W, and Zr in whole blood, RBC, in whole blood, RBC, and hair samples of children with autism compared with control suggestive of a greater toxic metal exposure (immediate and long-term). Three studies identified significantly higher concentrations of Cd, Pb and Hg in urine and hair samples of autistic children compared to control suggesting decreased excretion and possible high body burden of these metals. The findings from this review demonstrate that high levels of toxic metals are associated with ASD, therefore, critical care is necessary to reduce body burden of these metals in children with ASD as a major therapeutic strategy.

Urine metabolic phenotyping in children with nocturnal enuresis and comorbid neurobehavioral disorders.

Nocturnal enuresis (NE) is a common problem among 10% school-aged children. The etiologies underlying childhood NE is complex and not fully understood nowadays. Nevertheless, increasing evidence suggests a potential link between neurobehavioral disorders and enuresis in children. In this study, we aimed to explore novel metabolomic insights into the pathophysiology of NE and also, its association with pediatric psychiatric problems. Urine collected from 41 bedwetting children and 27 healthy control children was analyzed by using 1H-nuclear magnetic resonance spectroscopy from August 2017 to December 2018. At regular follow-up, there were 14 children with refractory NE having a diagnosis of attention deficient hyperactivity disorder (ADHD) or anxiety. Eventually, we identified eight significantly differential urinary metabolites and particularly increased urinary excretion of betaine, creatine and guanidinoacetate linked to glycine, serine and threonine metabolism were associated with a comorbidity of neurobehavioral disorders in refractory bedwetting children. Notably, based on physiological functions of betaine acting as a renal osmolyte and methyl group donor, we speculated its potential role in modulation of renal and/or central circadian clock systems, becoming a useful urinary metabolic marker in diagnosis of treatment-resistant NE in children affected by these two disorders.

Urinary Metabonomic Profiling Discriminates Between Children with Autism and Their Healthy Siblings.

BACKGROUND Autism spectrum disorder (ASD) is a complicated neuropsychiatric disease that displays significant heterogeneity. The diagnosis of ASD is currently primarily dependent upon descriptions of clinical symptoms, and it remains urgent to find biological markers for the detection and diagnosis of autism. The current study applied the urinary metabolic profiling approach to characterize metabolic phenotypes in ASD. MATERIAL AND METHODS Urine was obtained from children with ASD and their matched healthy siblings. Samples were analyzed using 1H NMR-based methods designed to measure a broad range of metabolites. Partial least-square-discriminant analysis (PLS-DA) was used to develop models to identify metabonomic variations that can be used to distinguish between individuals with ASD and their unaffected siblings. RESULTS A significant difference was observed between the metabolomic profiles of children with ASD and that of their healthy siblings. An increase in the levels of tryptophan, hippurate, glycine, and creatine, and a decrease in trigonelline, melatonin, pantothenate, serotonin, and taurine were observed compared to the control group. We conclude that several metabolic pathways are affected by autism, which suggests that a gut-brain link may be important in the pathophysiology of ASD. CONCLUSIONS 1H NMR-based metabonomic analysis of the urine can determine perturbations of specific metabolic pathways related to ASD and help identify a characteristic metabolic fingerprint to better understand the disease and its causes.

A metabolomics approach to investigate urine levels of neurotransmitters and related metabolites in autistic children.

Since recently metabolic abnormalities in autistic children have been associated with ASD disturbs, the aim of this study is to determine the neurotransmitter levels in urine samples of autistic children and to analyse the altered metabolic pathway involved in their production. Thus, ASD-specific urinary metabolomic patterns were explored in 40 ASD children and 40 matched controls using untargeted metabolomics through UHPLC-mass spectrometry (Q-exactive analyser), and by using XCMS Metlin software for data interpretation. Through this new advanced technique, a more considerable number of urinary altered metabolites were recorded in autistic children, than in the previous investigations, which allowed us to collect metabolites involved in neurotransmitter production. In these subjects, a high amount of dopamine was revealed and an increased amount of homovanillic acid, to the detriment of noradrenaline and adrenaline production, as well as MHPG and vanillylmandelic acid, which were found lower. This indicates that the accumulation of dopamine is not due to its greater production, but its lesser biotransformation into noradrenaline, due to the blockage of the dopamine ß-hydroxylase enzyme by 4-cresol and vitamin C, both found in high quantities in autistic subjects. Finally, a decreased amount of the active form of vitamin B6, pyridoxal phosphate (P5P), implicated in biotransformation of glutamate into γ-aminobutyric acid (GABA), was also detected, justifying the lower levels of latter. All of these alterations are correlated with a peculiar intestinal microbiome in autistic subjects, supporting the idea of a microbiota-gut-brain axis, then altered levels of neurotransmitters and altered neuronal transmission exist.

Neurotoxicity by mercury is not associated with autism spectrum disorders in Spanish children.

BACKGROUND: The pathophysiological etiologies related with the development of Autism Spectrum Disorders (ASD) remain controversial. Different authors have studied neurotoxins such as mercury (Hg) and their relationship with ADS. The objective of this study was to assess the levels of Hg in hair in a group of ASD children (chronic exposure) and in urinary excretion (acute exposure), in comparison to a healthy group. METHODS: A case-control study was conducted in Spanish children. We compared 54 ASD children (aged 2-6) with no other associated pathology to a normally-developing control group (54 subjects). RESULTS: There were no differences in urine (p:0.631) and hair (p:1.000) samples percentages below the limits of detection between the control and the ASD groups, and also between patients in the regression ASD subgroup (AMR) (p:0.08) and the non-regression ASD subgroup (ANMR) (p:0.705). When the analysis was adjusted for age and sex, the differences between Hg levels maintained not significant. There were no correlations between Hg concentrations in the ASD group as a whole (p: 0.739), or when they were subdivided into ASD-AMR (p: 0.739) and ASD-ANMR (p: 0.363). CONCLUSIONS: The present study shows no evidence in our geographical area to support an association between mercury neurotoxicity and the etiopathogenesis of ASD.

An induced pluripotent stem cells line (SDQLCHi014-A) derived from urine cells of a patient with ASD and hyperactivity carrying a 303 kb de novo deletion at chr3p26.1 implicating GRM7 gene.

Autism spectrum disorder (ASD) is a childhood-onset neurodevelopmental disorder challenged in social reciprocity and restrictive repetitive behaviors. Here, we generated an induced pluripotent stem cell (iPSC) line SDQLCHi014-A from a patient with ASD and hyperactivity, carrying a 303 kb de novo deletion at chr3p26.1 implicating GRM7 gene by reprogramming urine cells with non-integrating vectors. SDQLCHi014-A have shown full pluripotency, differentiation capacity and genetic stability. This iPSC line provides a valuable resource to study the molecular mechanisms underlying ASD.

Identification of gender-related metabolic disturbances in autism spectrum disorders using urinary metabolomics.

Autism spectrum disorders (ASD) are a highly heterogeneous group of neurodevelopmental disorders that are more commonly diagnosed in boys than in girls. The reasons for gender differences in ASD are unknown and no definitive current evidence can explain male predominance. Therefore, in search for laboratory biomarkers responsible for ASD, a comprehensive metabolomics study was performed by metabolic profiling of urine samples in 51 ASD subjects and 51 age- and sex-matched children with typical development. Orthogonal partial least-squares discriminant analysis (OPLS-DA) models with poor quality failed to perform the analysis based on gender in the ASD and control groups. OPLS-DA models based on single-sex samples, especially in female subjects, had better clustering between the ASD and control groups with an increase in the R2 and Q2 values compared with those in the whole group. Significantly increased levels of adenine, 2-Methylguanosine, creatinine, and 7alpha-hydroxytestololactone and a decrease in creatine were observed in the female ASD subjects. In particular, 7alpha-hydroxytestololactone, which has a structure similar to that of testolactone, was positively correlated with adenine (Pearson correlation coefficient, r = 0.738, p < 0.01), creatinine (r = 0.826, p < 0.01), and 2-Methylguanosine (r = 0.757, p < 0.01) and negatively correlated with creatine (r=-0.413, p < 0.05). A receiver operating characteristic curve analysis using the creatinine:creatine ratio yielded an area under the curve of 0.913 (95% CI: 0.806-1). These metabolites may be sex-related or sex-sensitive to an extent and can be valuable for identification of the molecular pathways involved in the gender bias in manifestation of ASD. The creatinine:creatine ratio has a potential to be a good predictor of ASD in the female subjects.

The concomitant lower concentrations of vitamins B6, B9 and B12 may cause methylation deficiency in autistic children.

Autism spectrum disorder (ASD) is characterized by severe and persistent difficulties in social communication and social interaction at multiple levels. Recently, metabolic disorders have been associated with most cases of patients with ASD. The aim of this study was to investigate, through a new and more sophisticated mass technique, such as UHPLC-mass spectrometry (Q-exactive analyzer), alteration in metabolisms analyzing ASD children urine samples from children showing simultaneous vitamin B6, B9 and B12 deficiencies. This in order to study how these concurrent deficiencies may influence some phenotypic aspects of autistic disorder. Thus, urinary metabolic patterns specific to ASD were explored at an early age in 60 children with ASD, showing lower three vitamins levels, and 60 corresponding controls (age group 3-8, M: F=42:18). The results showed significant block of cystathionine formation with consequent accumulation of homocysteine. A lower glutathione levels (GSH), with reduction of essential intracellular reducing environment required for normal immune function, detoxification capacity and redox-sensitive enzyme activity. Increased concentration of 5-methyltetrahydrofolate, which leads to a lower availability of methyl group and significant decrease in urinary methionine and S-adenosyl-L-methionine (SAM) concentrations, the major methyl donor. The latter justify the well-known reduction in protein and DNA methylation reported in autistic children. As a final consideration, the concomitant deficiencies of all three B vitamins, recorded in a significant number of autistic children, suggests that intestinal dysbiosis in these patients may be the main cause of a reduction in their absorption, in addition to the genetic mutation of a specific gene.

Role of mycotoxins in the pathobiology of autism: A first evidence.

Objectives: Gene-environment interaction is an emerging hypothesis to expound not only the autism pathogenesis but also the increased incidence of neurodevelopmental disorders (such as autistic spectrum disorder, attention-deficit, hyperactivity disorder). Among xenobiotics, mycotoxins are worldwide contaminants of food that provoke toxicological effects, crucially resembling several symptoms associated with autism such as oxidative stress, intestinal permeability, and inflammation. Here, we focused on a group of mycotoxins to test their role in the manifestation of autism, try to explain their mechanism of action, and discuss possible preventive and therapeutic interventions. Methods: Autistic children (n = 52) and healthy children [n = 58 (31 siblings and 27 unrelated subjects)] were recruited and body fluids and clinical data collected. The diagnosis of autism was made according to DSM V criteria, then with GMDS 0-2, WPPSI, and ADOS. Ochratoxin A (OTA), gliotoxin, zearalenone, and sphingosine/sphinganine ratio were determined by LC analysis in sera and urines. Statistical analysis was performed by the Wilcoxon Rank Sum (Mann-Whitney) test and Spearman test. Results: By comparing the results of autistic patients with those of unrelated controls, a significant association was found for OTA levels in urines (P = 0.0002) and sera (P = 0.0017), and also comparing patients with siblings and unrelated controls together (P = 0.0081). Discussion: Our results are the first describing a possible role of OTA in the pathobiology of autism. Recalling the male prevalence of ASD (male/female = 4-5/1), it is noted that, in animal models, OTA exerts its neurotoxicity especially in males. Moreover, in vitro, OTA increases microRNA-132 that is dysregulated in autistic patients and involved in reciprocal regulation of the autism-related genes MeCP2 and PTEN. A personalized diet coupled with probiotic administration, especially OTA adsorbing Lactobacillus, could ameliorate autistic symptoms in OTA-positive patients.

Diagnostic and Severity-Tracking Biomarkers for Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder afflicting about one in every 68 children. It is behaviorally diagnosed based on a triad of symptoms, including impairment in communication, impairment in sociability and abnormal and stereotypic behavior. The subjectivity of behavioral diagnosis urges the need for clinical biomarker tests to improve and complement ASD diagnosis and treatment. Over the past two decades, researchers garnered a broad range of biomarkers associated with ASD and often correlating with the severity of ASD, which includes metabolic and genetic biomarkers or neuroimaging abnormalities. Metabolic biomarkers are either involved in key pathways such as a trans-sulfuration pathway or produced due to the derangement of these pathways in the case of oxidative stress. Recent studies reported several genetic abnormalities related to ASD, encompassing various mechanisms, from copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) to chromosomal anomalies. However, it is still premature to consider these genetic variants as true biomarkers for ASD, due to their low reproducibility and regional-specific nature. Herein, we comprehensively review state of the art about major biomarkers reported in ASD and the association of some biomarkers with ASD symptoms and severity. It is important to establish those biomarkers to be able to help in the diagnosis and to optimize the treatment of ASD.

A prebiotic intervention study in children with autism spectrum disorders (ASDs).

BACKGROUND: Different dietary approaches, such as gluten and casein free diets, or the use of probiotics and prebiotics have been suggested in autistic spectrum disorders in order to reduce gastrointestinal (GI) disturbances. GI symptoms are of particular interest in this population due to prevalence and correlation with the severity of behavioural traits. Nowadays, there is lack of strong evidence about the effect of dietary interventions on these problems, particularly prebiotics. Therefore, we assessed the impact of exclusion diets and a 6-week Bimuno® galactooligosaccharide (B-GOS®) prebiotic intervention in 30 autistic children. RESULTS: The results showed that children on exclusion diets reported significantly lower scores of abdominal pain and bowel movement, as well as lower abundance of Bifidobacterium spp. and Veillonellaceae family, but higher presence of Faecalibacterium prausnitzii and Bacteroides spp. In addition, significant correlations were found between bacterial populations and faecal amino acids in this group, compared to children following an unrestricted diet. Following B-GOS® intervention, we observed improvements in anti-social behaviour, significant increase of Lachnospiraceae family, and significant changes in faecal and urine metabolites. CONCLUSIONS: To our knowledge, this is the first study where the effect of exclusion diets and prebiotics has been evaluated in autism, showing potential beneficial effects. A combined dietary approach resulted in significant changes in gut microbiota composition and metabolism suggesting that multiple interventions might be more relevant for the improvement of these aspects as well as psychological traits. TRIAL REGISTRATION: NCT02720900 ; registered in November 2015.

Associations between urinary cotinine and symptoms of attention deficit/hyperactivity disorder and autism spectrum disorder.

BACKGROUND: The present study investigated associations between urinary cotinine levels as a biomarker of secondhand smoke exposure and symptoms of attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). METHODS: A total of 520 child participants (200 with ADHD, 67 with ASD, and 253 normal control subjects) were assessed using the Korean version of the ADHD rating scale (K-ARS), Autism spectrum screening questionnaire (ASSQ), and Behavioral Assessment System for Children, second edition (BASC-2). The Korean version of the computer-based continuous performance test was used to assess cognitive function. Urinary cotinine was evaluated as a biomarker of secondhand smoke exposure. RESULTS: Urinary cotinine levels were significantly and positively associated with K-ARS score (B = 4.00, p < 0.001), ASSQ score (B = 1.71, p = 0.030), the behavioral problem subscales of the BASC-2 (B = 1.68-3.52, p < 0.001-0.045), and omission and commission errors in the continuous performance test (B = 6.21-8.42, p < 0.001-0.019). Urinary cotinine levels were also associated with the increased odds ratio of ADHD (OR = 1.55, 95% CI 1.05-2.30, p = 0.028) and ASD (OR = 1.89, 95% CI 1.12-3.21, p = 0.018). CONCLUSION: Urinary cotinine levels were associated with lower behavioral adaptation and cognitive function and increased odds ratios of ADHD and ASD, indicating a negative effect of secondhand smoke exposure on the symptomatic manifestation of ADHD and ASD.

Decreased levels of urinary free amino acids in children with autism spectrum disorder.

Autism spectrum disorder (ASD) is a range of neurodevelopmental problems without certain causes. Conventional diagnostic or screening tools for ASD rely on the observation of children's behavioral presentations. Novel methods are focused on the alterations of some important biochemical matters in ASD patients, which are applicable in the screening for ASD. This study investigated and compared amino acids in the first morning urine from age and sex matched ASD and non-ASD children using high performance liquid chromatography. Significantly lower urinary free methionine, phenylalanine, valine, tryptophan, and leucine plus isoleucine were observed in ASD children. The effects of using urinary free amino acids (UFAAs) singly or conjointly to classify participants into ASD or control group were analyzed and compared. ROC curves on these UFAAs singly in classification performed the sensitivity of 0.593-0.889 and the specificity of 0.704-0.963. Binary-logistic regression analysis of these UFAAs obtained a final regression model comprised of urinary free valine and tryptophan. The ROC curve established by the linear combination of the two amino acids achieved a sensitivity of 0.926 and a specificity of 0.889, which showed superiority to single UFAA and comparability to existing diagnostic or screening tools. It was suggested that the multivariate model based on UFAAs was possibly applicable in screening for children at higher risk of ASD.

Homocysteine Levels in Autism Spectrum Disorder: A Clinical Update.

BACKGROUND AND OBJECTIVE: Homocysteine (Hcy) is a non-protein α-amino acid, which plays several important roles in human physiology and in the central nervous system. Although Hcy has several known biological properties in one-carbon metabolism, its overproduction might be harmful, and could add to the pathophysiology associated with ASD. We reviewed the current evidence about changes in Hcy concentration in ASD and tried to correlate its changes with the clinical profile Discussion: The concentration of the amino acid in biological fluids (blood and urine) in children/ youngs with ASD is increased in the majority of studies when comparing to typically developing control subjects. Some report demonstrated a significant association between the severity of the disorder and the abnormalities in Hcy levels. CONCLUSION: Further research is needed to correlate the increase in Hcy with specific symptoms/ deficits in ASD and to evaluate the clinical impact of strategies that can reduce Hcy concentration in ASD.