Male Autism Spectrum Disorder Research Articles

Association of low 25-OH-vitamin D levels and peripheral inflammatory markers in patients with autism spectrum disorder: Vitamin D and inflammation in Autism

Inflammatory mechanisms and Vitamin D are reported to play important roles in the pathophysiology of Autism Spectrum Disorders (ASD). There are ample evidences that vitamin D has an anti-inflammatory effect. In this study, we aimed, for the first time, to investigate the 25-OH-vitamin D with inflammation markers in ASD patients. The study included 154 patients with ASD and 98 healthy subjects. 25-OH-Vitamin D levels and simple peripheral inflammatory markers such as Neutrophil-Lymphocyte ratio (NLR), C-reactive protein (CRP) and, sedimentation were measured in all subjects. K-SADS-PL-DSM 5 were administered to all subjects to evaluate the psychiatric diagnosis. Childhood Autism Rating Scale was used to asses severity of autism. In the patient group, high CRP rate, leukocyte, neutrophil and NLR were significantly high compared to the healthy control group. 25-OH-Vitamin D levels were found to be statistically significantly lower in the ASD group. While a significant negative correlation was found between 25-OH-Vitamin D and CRP, NLR, neutrophil counts in ASD patients, a positive correlation was found between lymphocyte counts. Especially in male ASD patients, the relationship between 25-OH-Vitamin D and inflammation markers was more pronounced. Our findings support the association of vitamin D and inflammation in ASD.

Odor identification impairment in autism spectrum disorder might be associated with mitochondrial dysfunction.

Deficits in olfactory function in autism spectrum disorder (ASD) have already been reported. However, the results of previous studies are not consistent, and the pathophysiological mechanisms of olfactory dysfunction in ASD are not clear. Fifty-three male ASD children or teenagers aged 9-16 years were recruited for the study. The identification and discrimination portion of the Sniffin' Sticks test (SST) was used to assess the olfactory function of the enrolled subjects. The severity of ASD core symptoms and the intelligence quotient (IQ) of participants were assessed. In addition, to explore the potential mechanism underlying olfactory dysfunction, a series of plasma biochemical indicators of oxidative stress, mitochondrial function and inflammation were measured. The mean raw scores on the SST identification and discrimination test of the study subjects were significantly lower than those of typically developing subjects reported in normative data studies. After adjusting for IQ, the odor identification score was not significantly associated with any ASD symptoms. Odor identification was found to be significantly associated with the ratio of L-lactate (L)/pyruvate (P) but not with other measured indicators. The current study validates the impairment of odor identification and discrimination in Chinese ASD children. Odor identification dysfunction may be an independent clinical symptom of ASD. The plasma L/P ratio was found to be significantly associated with odor identification performance, which suggests that mitochondrial dysfunction may be a potential mechanism underlying odor identification impairment in ASD.

The female protective effect against autism spectrum disorder

Autism spectrum disorder (ASD) is diagnosed three to four times more frequently in males than in females. Genetic studies of rare variants support a female protective effect (FPE) against ASD. However, sex differences in common inherited genetic risk for ASD are less studied, particularly within families. Leveraging the Danish iPSYCH resource, we found siblings of female ASD cases (n= 1,707) had higher rates of ASD than siblings of male ASD cases (n= 6,270; p<1.0×10-10). In the Simons Simplex and SPARK collections, mothers of ASD cases (n= 7,436) carried more polygenic risk for ASD than fathers of ASD cases (n= 5,926; 0.08 polygenic risk score [PRS] SD; p= 7.0×10-7). Further, male unaffected siblings under-inherited polygenic risk (n= 1,519; p= 0.03). Using both epidemiologic and genetic approaches, our findings strongly support an FPE against ASD's common inherited influences.

Sex Differences in Autism Spectrum Disorder: Diagnostic, Neurobiological, and Behavioral Features.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a worldwide prevalence of about 1%, characterized by impairments in social interaction, communication, repetitive patterns of behaviors, and can be associated with hyper- or hypo-reactivity of sensory stimulation and cognitive disability. ASD comorbid features include internalizing and externalizing symptoms such as anxiety, depression, hyperactivity, and attention problems. The precise etiology of ASD is still unknown and it is undoubted that the disorder is linked to some extent to both genetic and environmental factors. It is also well-documented and known that one of the most striking and consistent finding in ASD is the higher prevalence in males compared to females, with around 70% of ASD cases described being males. The present review looked into the most significant studies that attempted to investigate differences in ASD males and females thus trying to shade some light on the peculiar characteristics of this prevalence in terms of diagnosis, imaging, major autistic-like behavior and sex-dependent uniqueness. The study also discussed sex differences found in animal models of ASD, to provide a possible explanation of the neurological mechanisms underpinning the different presentation of autistic symptoms in males and females.

The salience of competing nonsocial objects reduces gaze toward social stimuli, but not the eyes, more in typically developing than autistic boys.

Decreased attention to social information is considered an early emerging symptom of autism spectrum disorder (ASD), although the underlying causes remain controversial. Here we explored the impact of nonsocial object salience on reduced attention to social stimuli in male ASD compared with typically developing (TD) children. Correlations with blood concentrations of neuropeptides linked with social cognition were also investigated. Eye-tracking was performed in 102 preschool-aged boys (50 ASD, 52 TD) using a paradigm with social (faces) versus nonsocial (objects) stimuli presented in pairs in two conditions where nonsocial stimulus salience was varied. Basal oxytocin (OXT) and vasopressin concentrations were measured in blood. Compared with TD boys those with ASD viewed social stimuli less only when they were paired with low-salience nonsocial objects. Additionally, boys with ASD spent less time than TD ones viewing facial features, particularly the eyes. In TD boys, OXT concentrations and cognitive development scores were positively associated with time spent viewing the eye region, whereas for boys with ASD associations with time spent viewing faces were negative. Reduced gaze toward social stimuli in ASD relative to TD individuals may therefore be influenced by how salient the paired nonsocial objects are for the latter. On the other hand, reduced interest in the eyes of faces in boys with ASD is not influenced by how salient competing nonsocial stimuli are. Basal OXT concentrations and cognitive development scores are predictive of time spent viewing social stimuli in TD boys (eyes) and those with ASD (faces) but in the opposite direction. LAY SUMMARY: Children with autism exhibit reduced attention to social paired with nonsocial stimuli compared to typically developing children. Using eye-tracking we show this difference is due to typically developing rather than autistic boys being more influenced by how interesting competing nonsocial objects are. On the other hand, reduced time looking at the eyes in autistic relative to typically developing boys is unaffected by nonsocial object salience. Time spent viewing social stimuli is associated with cognitive development and blood levels of oxytocin.

Transdiagnostic and sex differences in cognitive profiles of autism spectrum disorder and attention-deficit/hyperactivity disorder.

An increasing number of studies have shown that autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share symptoms and aetiologies. However, transdiagnostic comparisons between ASD and ADHD is complicated due to the sex differences within each condition. To clarify the similarities and differences in the cognitive functioning between ASD and ADHD, while considering potential sex differences, this study compared cognitive profiles assessed by the WAIS-III between the four groups created by orthogonally combining diagnosis and sex based on the data from 277 ASD males, 86 ASD females, 99 ADHD males and 64 ADHD females. The analysis revealed three major findings. First, performance IQ and perceptual organization index were higher in ADHD males than in ASD males and ADHD females. Second, Gaussian mixture model fitting revealed two clusters underlying the distribution of subindex scores. The percentage of being classified into the cluster that scored lower in all the subindices was higher in females than in males irrespective of diagnosis. Third, feature importance for classification of ASD and ADHD yielded by random forest classifier, a supervised machine learning algorithm, revealed that autism quotient was most informative feature in classifying ASD and ADHD in males, while the discrepancy between verbal and performance intelligence quotient was in females, indicating that the set of behavioral features contributing to classification differs between males and females. Thus, these findings indicate that sex as well as diagnosis is critical in determining the cognitive profiles of people with ASD and ADHD. LAY SUMMARY: The present study compared profiles of cognitive functions measured by Wechsler Adult Intelligence Scale between males and females with ASD and ADHD. The analyses revealed clear sex differences in cognitive functions in both ASD and ADHD and that the set of cognitive functions useful in classifying ASD and ADHD differed between males and females. Thus, biological sex seems to be a critical factor in determining the cognitive profiles of people with ASD and ADHD.

Exploring social emotion processing in autism: evaluating the reading the mind in the eyes test using network analysis

BackgroundFeatures of autism spectrum disorder (ASD) include difficulties in processing and interpreting socioemotional information. The "Reading the Mind in the Eyes" test (RMET) is a validated measurement for processing socioemotional ability. However, previous RMET studies did not explore patterns of incorrect answers and the emotional valence of the test items. This study used the Taiwanese version of the RMET and the network analysis methods to examine the differences in underlying mechanisms of socioemotional processes between 30 males with autism spectrum disorder (ASD) (mean age = 18 years) and 30 healthy control males (mean age = 17 years). For each test item, a picture of a person's eyes and partial face was shown with four words describing the emotional status on picture corners. Participants were instructed to choose one of the four words that best matched the person's thinking or feeling. We further classified the words into three valences of emotional categories to examine socioemotional processes.ResultsOur results showed that ASD males performed poorer on the RMET than the controls. ASD males had higher network density and in-degree scores, especially in negative words, than control males.ConclusionsThe findings suggest that males with ASD might have deficits in mapping the best emotional concept words to the target item, especially for processing negative emotion.

Association between ultrasonography foetal anomalies and autism spectrum disorder.

Multiple pieces of evidence support the prenatal predisposition of autism spectrum disorder (ASD). Nevertheless, robust data about abnormalities in foetuses later developing into children diagnosed with ASD are lacking. Prenatal ultrasound is an excellent tool to study abnormal foetal development as it is frequently used to monitor foetal growth and identify foetal anomalies throughout pregnancy. We conducted a retrospective case-sibling-control study of children diagnosed with ASD (cases); their own typically developing, closest-in-age siblings (TDS); and typically developing children from the general population (TDP), matched by year of birth, sex and ethnicity to investigate the association between ultrasonography foetal anomalies and ASD. The case group was drawn from all children diagnosed with ASD enrolled at the National Autism Research Center of Israel. Foetal ultrasound data from the foetal anatomy survey were obtained from prenatal ultrasound clinics of Clalit Health Services in southern Israel. The study comprised 659 children: 229 ASD, 201 TDS and 229 TDP. Ultrasonography foetal anomalies were found in 29.3% of ASD cases versus only 15.9% and 9.6% in the TDS and TDP groups [adjusted odds ratio (aOR) = 2.23, 95% confidence interval (CI) = 1.32-3.78, and aOR = 3.50, 95%CI = 2.07-5.91, respectively]. Multiple co-occurring ultrasonography foetal anomalies were significantly more prevalent among ASD cases. Ultrasonography foetal anomalies in the urinary system, heart, and head and brain were the most significantly associated with ASD diagnosis (aORUrinary = 2.08, 95%CI = 0.96-4.50 and aORUrinary = 2.90, 95%CI = 1.41-5.95; aORHeart = 3.72, 95%CI = 1.50-9.24 and aORHeart = 8.67, 95%CI = 2.62-28.63; and aORHead&Brain = 1.96, 95%CI = 0.72-5.30 and aORHead&Brain = 4.67, 95%CI = 1.34-16.24; versus TDS and TDP, respectively). ASD females had significantly more ultrasonography foetal anomalies than ASD males (43.1% versus 25.3%, P = 0.013) and a higher prevalence of multiple co-occurring ultrasonography foetal anomalies (15.7% versus 4.5%, P = 0.011). No sex differences were seen among TDS and TDP controls. ASD foetuses were characterized by a narrower head and a relatively wider ocular-distance versus TDP foetuses (ORBPD = 0.81, 95%CI = 0.70-0.94, and aOROcular distance = 1.29, 95%CI = 1.06-1.57). Ultrasonography foetal anomalies were associated with more severe ASD symptoms. Our findings shed important light on the multiorgan foetal anomalies associated with ASD.

Randomized clinical trial shows no substantial modulation of empathy-related neural activation by intranasal oxytocin in autism

Evidence suggests that intranasal application of oxytocin facilitates empathy and modulates its underlying neural processes, which are often impaired in individuals with autism spectrum disorders (ASD). Oxytocin has therefore been considered a promising candidate for the treatment of social difficulties in ASD. However, evidence linking oxytocin treatment to social behavior and brain function in ASD is limited and heterogeneous effects might depend on variations in the oxytocin-receptor gene (OXTR). We examined 25 male ASD patients without intellectual disability in a double-blind, cross-over, placebo-controlled fMRI-protocol, in which a single dose of oxytocin or placebo was applied intranasally. Patients performed three experiments in the MRI examining empathy for other’s physical pain, basic emotions, and social pain. All participants were genotyped for the rs53576 single-nucleotide polymorphism of the OXTR. Oxytocin increased bilateral amygdala responsiveness during the physical pain task for both painful and neutral stimuli. Other than that, there were no effects of oxytocin treatment. OXTR genotype did not significantly interact with oxytocin treatment. Our results contribute to the growing body of empirical literature suggesting heterogenous effects of oxytocin administration in ASD. To draw clinically relevant conclusions regarding the usefulness of oxytocin treatment, however, empirical studies need to consider methods of delivery, dose, and moderating individual factors more carefully in larger samples.

Brief report: the effect of gender on teachers’ perceptions of behaviours in students with Autism Spectrum Disorder (ASD)

ABSTRACT Objective It has been suggested that gender stereotypes can influence social perception and how people perceive behaviours in Autism Spectrum Disorder (ASD) based on the individual’s gender. This study aimed to investigate the effect of student’s gender on teachers’ perceptions of ASD behaviours in regular school settings. Method The sample consisted of 60 primary school teachers with a mean of 11.82 years (SD = 7.34) of teaching experience. Participants read a total of 20 vignettes depicting students’ behaviours and were asked to rate the featured student’s behaviour using a 5-point Likert scale (i.e., 1 = Strongly Negative to 5 = Strongly Positive). The survey vignettes were presented in a randomised order and participants were randomly assigned to either the female gender group or the male gender group. Results Results indicated that teachers rated the male ASD student’s social behaviours but not the repetitive and restricted behaviours significantly more negatively than the female ASD student. Using multiple regression analysis, teachers’ prior awareness of ASD affected their ratings for the social behaviours. Conclusion Findings from this study would have implications for teacher training in understanding and supporting students with ASD.

Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

Polish Adaptation of the Social Communication Questionnaire (SCQ) and Female Autism Phenotype: An Investigation of Potentially Sex-Biased Items in the Screening Assessment and Their Impact on Scores.

Standardized screening assessments and sex differences in autism spectrum disorder (ASD) are still under-explored in Poland. This study investigated the differences between Polish ASD females and males based on the responses provided by parents/caregivers to a Polish adaptation of the Social Communication Questionnaire, SCQ Lifetime and SCQ Current. The study included 90 ASD participants from Mental Health Services and Autism Clinics in Poland with no intellectual disability and no profound communication difficulties. Parents provided information on the SCQ items which were compared under three domains of the Autism Diagnostic Interview-Revised (ADI-R). Four SCQ items with the examples were investigated. No significant differences were found between the two sexes in the three domains. The repetitive use of objects declined with age in ASD males. Although the findings of the present study did not reveal substantial gender biases in the Polish adaptation of the SCQ, it is necessary to take into account potential gender differences in the clinical presentation of ASD and in the adaptation of screening and diagnostic tools.

Evaluation of Zn, Cu, and Se Levels in the North American Autism Spectrum Disorder Population

Metal ion dyshomeostasis and disparate levels of biometals like zinc (Zn), copper (Cu), and selenium (Se) have been implicated as a potential causative factor for Autism Spectrum Disorder (ASD). In this study, we have enrolled 129 children (aged 2–4 years) in North America, of which 64 children had a diagnosis of ASD and 65 were controls. Hair, nail, and blood samples were collected and quantitatively analyzed for Zn, Cu and Se using inductively coupled plasma mass spectrometry (ICP-MS). Of the analyzed biometals, serum Se (116.83 ± 14.84 ng/mL) was found to be significantly lower in male ASD cases compared to male healthy controls (128.21 ± 9.11 ng/mL; p < 0.005). A similar trend was found for nail Se levels in ASD (1.01 ± 0.15 mcg/g) versus that of controls (1.11 ± 0.17 mcg/g) with a p-value of 0.0132 using a stratified Wilcoxon rank sum testing. The level of Se in ASD cohort was co-analyzed for psychometric correlation and found a negative correlation between total ADOS score and serum Se levels. However, we did not observe any significant difference in Zn, Cu, and Zn/Cu ratio in ASD cases versus controls in this cohort of North American children. Further studies are recommended to better understand the biology of the relationship between Se and ASD status.

A neurogenetic analysis of female autism.

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8–17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts.

The gap between IQ and adaptive functioning in autism spectrum disorder: Disentangling diagnostic and sex differences.

Adaptive functioning refers to skills that are vital to success in day-to-day life, including daily living (e.g. grocery shopping, food preparation, transportation use), communication (e.g. verbal expression of needs), and socialization skills (e.g. interpersonal skills, including expressing and recognizing emotions, and understanding turn-taking in conversation). Among autistic individuals without intellectual disability, adaptive functioning is not commensurate with intellectual ability (IQ), and instead a gap exists between these individuals' intellectual ability and their adaptive skills. Further, these autistic individuals show a widening of this gap with increasing age. Existing studies of the gap between IQ and adaptive functioning have studied predominantly male samples. Thus, we do not know if the gap also exists in autistic females. We therefore looked at adaptive functioning and the gap between IQ and adaptive functioning in a large sample of autistic girls and boys without intellectual disability. To disentangle effects of group (autistic vs typically developing) from effects of sex (girls vs boys), we compared autistic girls and boys to one another as well as to their same-sex typically developing peers. Analyses took into consideration differences in IQ between autistic and typically developing youth. We found autistic girls, like autistic boys, show lower adaptive functioning than their same-sex typically developing peers. Results underscore the need to evaluate adaptive functioning in autistic individuals without intellectual disability and to provide necessary supports. The large gap between intellectual ability and socialization skills, in particular, may be of critical importance in improving our understanding of outcomes and mental health difficulties among autistic females.

Survey for caregivers of people in the autism spectrum in Chile: first concerns, age of diagnosis and clinical characteristics.

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders of increasing prevalence. People with ASD have multiple health, education, and community needs, yet there is little information about their situation in Chile. To learn about the demographic and clinical characteristics, caregiver's first concerns, and age of diagnosis of ASD individuals. Participants were parents/caregivers of ASD persons, who answered the Caregiver Needs Survey, developed by Autism Speaks specifically for this purpose, and translated into Spanish. The survey is comprised of 4 sections: demographic information, characteristics of the ASD individual, past and present use of Health and Education Services, and parents/caregivers' perceptions of satisfaction, impact, stigma, and quality of life. Data from the first two sections are reported in this paper. The survey was answered by 291 caregivers (86% mothers) of 291 mostly male ASDs (89%), aged between 1-40 years (X: 10.4 SD: 6.1). The average age of parents' first concerns was 29.2m (SD: 23.8) where the main ones were: interaction difficulties (79.4%), unusual response to sensory stimuli (69.8%), behavioral problems (65.3%), unusual gestures/movements (64.3%), and lack of eye contact (63.6%). The ave rage age of diagnosis was 58m (SD: 36.5), with an average delay of diagnosis of 29m. The diagnosis was most frequently made by pediatric neurologists (44.7%), child psychiatrists (19.2%), and pedia tricians (5.5%). The most frequent comorbidities were language impairment, cognitive deficit, and behavioral problems. The late age of diagnosis of ASD and the large gap between the age of first concerns and diagnosis, represent a critical loss of treatment opportunities and jeopardize the chances of a better long-term outcome.

Derivation of four iPSC lines from a male ASD patient carrying a deletion in the middle coding region of NRXN1α gene (NUIGi039-A and NUIGi039-B) and a male sibling control (NUIGi040-A and NUIGi040-B).

NRXN1 deletions are commonly found in autism spectrum disorder (ASD) and other neurodevelopmental/neuropsychiatric disorders. Derivation of induced pluripotent stem cells (iPSCs) from different diseases involving different deletion regions are essential, as NRXN1 may produce thousands of splicing variants. We report here the derivation of iPSCs from a sibling control and an ASD proband carrying de novo heterozygous deletions in the middle region of NRXN1, using a non-integrating Sendai viral kit. The genotype and karyotype of the iPSCs were validated by whole genome SNP array. All iPSC lines highly expressed pluripotency markers and could be differentiated into three germ layers.

Anesthesia, sex and miscarriage history may influence the association between cesarean delivery and autism spectrum disorder

BackgroundTo explore the association between cesarean section (CS) and risk of autism spectrum disorder (ASD), and evaluate the possible factors influencing this association.MethodsIn total, 950 patients diagnosed with ASD and 764 healthy controls were recruited in this study. Socio-demographic characteristics and prenatal, perinatal, and neonatal characteristics were compared between the two groups. Univariate and multivariable conditional logistic regression analyses were applied to adjust for confounders. Further stratified analyses based on sex and miscarriage history were similarly performed to explore the factors influencing the association between CS and ASD.ResultsCS was evidently associated with an elevated risk of ASD (adjusted odds ratio [aOR] = 1.606, 95% confidence interval (CI) = 1.311–1.969). Unlike regional anesthesia (RA), only CS performed under general anesthesia (GA) consistently elevated the risk of ASD (aOR = 1.887, 95% CI = 1.273–2.798) in females and males in further stratified analysis. The risk of children suffering from ASD following emergency CS was apparently increased in males (aOR = 2.390, 95% CI = 1.392–5.207), whereas a higher risk of ASD was observed among voluntary CS and indicated CS subgroups (aOR = 2.167, 95% CI = 1.094–4.291; aOR = 2.919, 95% CI = 1.789–4.765, respectively) in females. Moreover, the interaction term of CS and past miscarriage history (β = − 0.68, Wald χ2 = 7.5, df = 1, p = 0.006)) was similarly defined as influencing ASD.ConclusionsThe exposure of children to GA during CS may explain the possible/emerging association between CS and ASD. In addition, sex and miscarriage history could equally be factors influencing the association between CS and ASD.

Sex Differences in Autism Spectrum Disorder: An Investigation on Core Symptoms and Psychiatric Comorbidity in Preschoolers.

Findings regarding sex differences in autism spectrum disorder (ASD), as far as core symptoms and psychiatric comorbidities (PC) are concerned, are inconsistent, inconclusive, or conflicting among studies. The lower prevalence of ASD in females than in males and the age and intelligence quotient (IQ) heterogeneity among samples made it difficult to investigate these differences. This case–control study tries to deepen the impact of sex differences on core symptoms of autism and PC in 214 preschoolers with ASD (mean age, 45.26) without impairment in non-verbal IQ (nvIQ ≥70). A total of 107 ASD females (mean age, 44.51 ± 13.79 months) were matched one by one with 107 males (mean age, 46.01 ± 13.42 months) for chronological age (±6 months) and nvIQ (±6 points). We used the Autism Diagnostic Observation Schedule 2 (ADOS-2) and the Child Behavior Checklist (CBCL) 1.5–5 to explore autism severity and PC. The results highlight that ASD females did not significantly differ from ASD males regarding the severity of autism. Statistically significant lower levels of emotionally reactive (p = 0.005, η2 = 0.04), anxious-depressed (p = 0.001, η2 = 0.05), internalizing problems (p = 0.04, η2 = 0.02), and DSM-Oriented Scales anxiety problems (p = 0.02, η2 = 0.04) in ASD females than in ASD males were also detected. Our findings of no difference in the autism severity and lower internalizing problems in females than males with ASD extend the knowledge of autism in females during preschool years. Compared to other similar studies on this topic, we can state that these results are not supported by differences in nvIQ between sexes nor by the presence of cognitive impairment. It confirms the need for clinicians to consider sex differences when describing autism psychopathology.

Sex differences in the effects of prenatal bisphenol A exposure on autism-related genes and their relationships with the hippocampus functions

Our recent study has shown that prenatal exposure to bisphenol A (BPA) altered the expression of genes associated with autism spectrum disorder (ASD). In this study, we further investigated the effects of prenatal BPA exposure on ASD-related genes known to regulate neuronal viability, neuritogenesis, and learning/memory, and assessed these functions in the offspring of exposed pregnant rats. We found that prenatal BPA exposure increased neurite length, the number of primary neurites, and the number of neurite branches, but reduced the size of the hippocampal cell body in both sexes of the offspring. However, in utero exposure to BPA decreased the neuronal viability and the neuronal density in the hippocampus and impaired learning/memory only in the male offspring while the females were not affected. Interestingly, the expression of several ASD-related genes (e.g. Mief2, Eif3h, Cux1, and Atp8a1) in the hippocampus were dysregulated and showed a sex-specific correlation with neuronal viability, neuritogenesis, and/or learning/memory. The findings from this study suggest that prenatal BPA exposure disrupts ASD-related genes involved in neuronal viability, neuritogenesis, and learning/memory in a sex-dependent manner, and these genes may play an important role in the risk and the higher prevalence of ASD in males subjected to prenatal BPA exposure.