1. Benson S, Bender AM, Wickenheiser H, Naylor A, Clarke M, Samuels CH, Werthner P. {{Differences in sleep patterns, sleepiness, and physical activity levels between young adults with autism spectrum disorder and typically developing controls}}. {Dev Neurorehabil}. 2018: 1-10.
OBJECTIVE: To investigate the differences in sleep, sleepiness, and physical activity (PA) between young adults with autism spectrum disorder (ASD) and typically developing controls (TDC). METHOD: Actigraphic data and questionnaires on sleep, sleepiness, and PA were compared between fifteen adults with ASD (ADOS range 7-19; ages 22.8 +/- 4.5 years) and TDC. RESULTS: In comparison to the TDC group, the ASD group slept longer on average per night but took longer to fall asleep. In relationship to PA levels, the objective PA levels were lower in the ASD group than the TDC group. Fewer wake minutes during the sleep period in the ASD sample were associated with more PA the following day. CONCLUSION: The findings support previous research that demonstrates differences in sleep parameters and PA between ASD and TDC. Interventions aimed at increasing PA in an ASD population may be beneficial for improved sleep.
Lien vers le texte intégral (Open Access ou abonnement)
2. Cherskov A, Pohl A, Allison C, Zhang H, Payne RA, Baron-Cohen S. {{Polycystic ovary syndrome and autism: A test of the prenatal sex steroid theory}}. {Translational psychiatry}. 2018; 8(1): 136.
Elevated levels of prenatal testosterone may increase the risk for autism spectrum conditions (autism). Given that polycystic ovary syndrome (PCOS) is also associated with elevated prenatal testosterone and its precursor sex steroids, a hypothesis from the prenatal sex steroid theory is that women with PCOS should have elevated autistic traits and a higher rate of autism among their children. Using electronic health records obtained from the Clinical Practice Research Datalink (CPRD) in the UK between 1990 and 2014, we conducted three matched case-control studies. Studies 1 and 2 examined the risk of PCOS in women with autism (n = 971) and the risk of autism in women with PCOS (n = 26,263), respectively, compared with matched controls. Study 3 examined the odds ratio (OR) of autism in first-born children of women with PCOS (n = 8588), matched to 41,127 controls. In Studies 1 and 2 we found increased prevalence of PCOS in women with autism (2.3% vs. 1.1%; unadjusted OR: 2.01, 95% CI: 1.22-3.30) and elevated rates of autism in women with PCOS (0.17% vs. 0.09%, unadjusted OR: 1.94 CI: 1.37-2.76). In Study 3 we found the odds of having a child with autism were significantly increased, even after adjustment for maternal psychiatric diagnoses, obstetric complications, and maternal metabolic conditions (unadjusted OR: 1.60, 95% CI: 1.28-2.00; adjusted OR: 1.35, 95% CI: 1.06-1.73). These studies provide further evidence that women with PCOS and their children have a greater risk of autism.
Lien vers le texte intégral (Open Access ou abonnement)
3. Grimaldi R, Gibson GR, Vulevic J, Giallourou N, Castro-Mejia JL, Hansen LH, Leigh Gibson E, Nielsen DS, Costabile A. {{A prebiotic intervention study in children with autism spectrum disorders (ASDs)}}. {Microbiome}. 2018; 6(1): 133.
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(R) galactooligosaccharide (B-GOS(R)) 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(R) 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.
Lien vers le texte intégral (Open Access ou abonnement)
4. Howsmon DP, Vargason T, Rubin RA, Delhey L, Tippett M, Rose S, Bennuri SC, Slattery JC, Melnyk S, James SJ, Frye RE, Hahn J. {{Multivariate techniques enable a biochemical classification of children with autism spectrum disorder versus typically-developing peers: A comparison and validation study}}. {Bioengineering & translational medicine}. 2018; 3(2): 156-65.
Autism spectrum disorder (ASD) is a developmental disorder which is currently only diagnosed through behavioral testing. Impaired folate-dependent one carbon metabolism (FOCM) and transsulfuration (TS) pathways have been implicated in ASD, and recently a study involving multivariate analysis based upon Fisher Discriminant Analysis returned very promising results for predicting an ASD diagnosis. This article takes another step toward the goal of developing a biochemical diagnostic for ASD by comparing five classification algorithms on existing data of FOCM/TS metabolites, and also validating the classification results with new data from an ASD cohort. The comparison results indicate a high sensitivity and specificity for the original data set and up to a 88% correct classification of the ASD cohort at an expected 5% misclassification rate for typically-developing controls. These results form the foundation for the development of a biochemical test for ASD which promises to aid diagnosis of ASD and provide biochemical understanding of the disease, applicable to at least a subset of the ASD population.
Lien vers le texte intégral (Open Access ou abonnement)
5. Keith JM, Jamieson JP, Bennetto L. {{The Importance of Adolescent Self-Report in Autism Spectrum Disorder: Integration of Questionnaire and Autonomic Measures}}. {Journal of abnormal child psychology}. 2018.
Anxiety and sensory symptoms are highly prevalent and meaningful in the daily lives of individuals with autism spectrum disorder (ASD). Despite the importance of carefully measuring, researching, and treating these symptoms, current methods in ASD seldom include self-report. This study investigated the consistency of adolescent and parent reports of anxiety and auditory sensitivity in individuals with ASD, and examined their validity via comparisons with sympathetic arousal at baseline and in response to an auditory challenge. Fifty adolescent-parent dyads (n = 26 ASD, n = 24 typically developing; 12-16 years old; IQ>80) completed parallel versions of both anxiety and auditory hypersensitivity scales, which were compared to heart rate collected at rest and during an aversive noise task. Adolescents with ASD exhibited greater anxiety and auditory hypersensitivity than their peers, based on both self and parent report. Across groups, self-report was higher than parent report. In individuals with ASD, a significant relationship was found between self-reported anxiety and autonomic arousal at rest, and between self-reported auditory sensitivity and autonomic reactivity during the noise task. These relationships were not significant for parent-report. These findings extend past work by demonstrating greater self-reported (than parent-reported) anxiety and sensory symptoms. Furthermore, the presence of significant correlations between self-reported symptoms and sympathetic arousal supports the validity of self-report in adolescents with ASD with average or above average cognitive abilities. This indicates that adolescents with ASD have a unique perspective on their internal experience, which can complement parent reports and provide a more comprehensive assessment of symptoms in research and clinical settings.
Lien vers le texte intégral (Open Access ou abonnement)
6. Lauber E, Filice F, Schwaller B. {{Dysregulation of Parvalbumin Expression in the Cntnap2-/- Mouse Model of Autism Spectrum Disorder}}. {Front Mol Neurosci}. 2018; 11: 262.
Due to the complex and heterogeneous etiology of autism spectrum disorder (ASD), identification of convergent pathways and/or common molecular endpoints in the pathophysiological processes of ASD development are highly needed in order to facilitate treatment approaches targeted at the core symptoms. We recently reported on decreased expression of the Ca(2+)-binding protein parvalbumin (PV) in three well-characterized ASD mouse models, Shank1-/-, Shank3B-/- and in utero VPA-exposed mice. Moreover, PV-deficient mice (PV+/- and PV-/-) were found to show behavioral impairments and neuroanatomical changes closely resembling those frequently found in human ASD individuals. Here, we combined a stereology-based approach with molecular biology methods to assess changes in the subpopulation of PV-expressing (Pvalb) interneurons in the recently characterized contactin-associated protein-like 2 (Cntnap2-/-) knockout mouse model of ASD. The CNTNAP2 gene codes for a synaptic cell adhesion molecule involved in neurodevelopmental processes; mutations affecting the human CNTNAP2 locus are associated with human ASD core symptoms, in particular speech and language problems. We demonstrate that in Cntnap2-/- mice, no loss of Pvalb neurons is evident in ASD-associated brain regions including the striatum, somatosensory cortex (SSC) and medial prefrontal cortex (mPFC), shown by the unaltered number of Pvalb neurons ensheathed by VVA-positive perineuronal nets. However, the number of PV-immunoreactive (PV(+)) neurons and also PV protein levels were decreased in the striatum of Cntnap2-/- mice indicating that PV expression levels in some striatal Pvalb neurons dropped below the detection limit, yet without a loss of Pvalb neurons. No changes in PV(+) neuron numbers were detected in the cortical regions investigated and also cortical PV expression levels were unaltered. Considering that Cntnap2 shows high expression levels in the striatum during human and mouse embryonic development and that the cortico-striato-thalamic circuitry is important for speech and language development, alterations in striatal PV expression and associated (homeostatic) adaptations are likely to play an important role in Cntnap2-/- mice and, assumingly, in human ASD patients with known Cntnap2 mutations.
Lien vers le texte intégral (Open Access ou abonnement)
7. Lee J, Hayat MJ, Spratling R, Sevcik RA, Clark PC. {{Relationship of Mothers’ Mental and Physical Health to Characteristics of Mothers and Their Children with Developmental Disabilities}}. {Nursing research}. 2018.
BACKGROUND: While empirical evidence shows that mothers of children with developmental disabilities (DDs) are at risk for poor mental and physical health, the relative contribution of maternal and child characteristics, including sleep quality, remain unclear. OBJECTIVES: The aims of this study were to compare select maternal (sleep quality, caregiving stress, and other sociodemographic variables) and child characteristics (sleep and behavior problems) between mothers with worse mental and physical health and those with better mental and physical health and to determine the contribution of selected characteristics on mental and physical health in mothers of school-age children (ages 6-12) with DDs. METHODS: This cross-sectional, correlational study included a convenience sample of 40 mothers of children with DDs. Mothers completed a set of questionnaires, including the Pittsburgh Sleep Quality Index, the Zarit Burden Interview, the Center for Epidemiologic Studies Depression Scale, and the SF-36v2 Health Survey. RESULTS: Results from bivariate logistic regression modeling showed that mothers with high depressive symptoms and worse physical health, as compared to mothers with low depressive symptoms and better physical health, reported significantly higher caregiving stress, poor sleep quality, and more chronic health conditions, and more behavior and sleep problems in children with DDs. A multivariable logistic regression model showed mother’s sleep quality was significantly associated with increased risk of high levels of depression (OR = 1.934, 95% CI = [1.106, 3.385], p = 0.021) and increased risk of worse physical health (OR = 1.920, 95% CI = [1.086, 3.393], p = 0.025). DISCUSSION: Sleep health assessment may be beneficial when providing care to families of children with developmental disabilities.
Lien vers le texte intégral (Open Access ou abonnement)
8. Lord C, Elsabbagh M, Baird G, Veenstra-Vanderweele J. {{Autism spectrum disorder}}. {Lancet (London, England)}. 2018; 392(10146): 508-20.
Autism spectrum disorder is a term used to describe a constellation of early-appearing social communication deficits and repetitive sensory-motor behaviours associated with a strong genetic component as well as other causes. The outlook for many individuals with autism spectrum disorder today is brighter than it was 50 years ago; more people with the condition are able to speak, read, and live in the community rather than in institutions, and some will be largely free from symptoms of the disorder by adulthood. Nevertheless, most individuals will not work full-time or live independently. Genetics and neuroscience have identified intriguing patterns of risk, but without much practical benefit yet. Considerable work is still needed to understand how and when behavioural and medical treatments can be effective, and for which children, including those with substantial comorbidities. It is also important to implement what we already know and develop services for adults with autism spectrum disorder. Clinicians can make a difference by providing timely and individualised help to families navigating referrals and access to community support systems, by providing accurate information despite often unfiltered media input, and by anticipating transitions such as family changes and school entry and leaving.
Lien vers le texte intégral (Open Access ou abonnement)
9. Nickel K, Tebartz van Elst L, Domschke K, Glaser B, Stock F, Endres D, Maier S, Riedel A. {{Heterozygous deletion of SCN2A and SCN3A in a patient with autism spectrum disorder and Tourette syndrome: a case report}}. {BMC Psychiatry}. 2018; 18(1): 248.
BACKGROUND: Mutations in voltage-gated sodium channel (SCN) genes are supposed to be of importance in the etiology of psychiatric and neurological diseases, in particular in the etiology of seizures. Previous studies report a potential susceptibility region at the chromosomal locus 2q including SCN1A, SCN2A and SCN3A genes for autism spectrum disorder (ASD). To date, there is no previous description of a patient with comorbid ASD and Tourette syndrome showing a deletion containing SCN2A and SCN3A. CASE PRESENTATION: We present the unique complex case of a 28-year-old male patient suffering from developmental retardation and exhibiting a range of behavioral traits since birth. He received the diagnoses of ASD (in early childhood) and of Tourette syndrome (in adulthood) according to ICD-10 and DSM-5 criteria. Investigations of underlying genetic factors yielded a heterozygous microdeletion of approximately 719 kb at 2q24.3 leading to a deletion encompassing the five genes SCN2A (exon 1 to intron 14-15), SCN3A, GRB14 (exon 1 to intron 2-3), COBLL1 and SCL38A11. CONCLUSIONS: We discuss the association of SCN2A, SCN3A, GRB14, COBLL1 and SCL38A11 deletions with ASD and Tourette syndrome and possible implications for treatment.
Lien vers le texte intégral (Open Access ou abonnement)
10. Padilha IG, Nunes RH, Scortegagna FA, Pedroso JL, Marussi VH, Rodrigues Goncalves MR, Barsottini OGP, da Rocha AJ. {{MR Imaging Features of Adult-Onset Neuronal Intranuclear Inclusion Disease May Be Indistinguishable from Fragile X-Associated Tremor/Ataxia Syndrome}}. {AJNR American journal of neuroradiology}. 2018.
Lien vers le texte intégral (Open Access ou abonnement)
11. Poquerusse J, Pastore L, Dellantonio S, Esposito G. {{Alexithymia and Autism Spectrum Disorder: A Complex Relationship}}. {Front Psychol}. 2018; 9: 1196.
Alexithymia is a personality construct characterized by altered emotional awareness which has been gaining diagnostic prevalence in a range of neuropsychiatric disorders, with notably high rates of overlap with autism spectrum disorder (ASD). However, the nature of its role in ASD symptomatology remains elusive. Here, we distill research at the intersection of alexithymia and ASD. After a brief synopsis of the studies that plaid a pioneering role in the identification of the overlapping fields between alexithymia and ASD, we comb the literature for evidence of its overlap with ASD in terms of prevalence, etiology, and behaviors. Through a formalized framework of the process of emotional interpretation and expression, we explore evidence for where and how deficits arise in this complex network of events. We portray how these relate to the dynamic interplay between alexithymic and autistic traits and find emerging evidence that alexithymia is both a cause and consequence of autistic behaviors. We end with a strategic proposal for future research and interventions to dampen the impacts of alexithymia in ASD.
Lien vers le texte intégral (Open Access ou abonnement)
12. Singh J, Santosh P. {{Key issues in Rett syndrome: emotional, behavioural and autonomic dysregulation (EBAD) – a target for clinical trials}}. {Orphanet journal of rare diseases}. 2018; 13(1): 128.
Complex neurodevelopmental disorders need multi-disciplinary treatment approaches for optimal care. The clinical effectiveness of treatments is limited in patients with rare genetic syndromes with multisystem morbidity. Emotional and behavioural dysregulation is common across many neurodevelopmental disorders. It can manifest in children across multiple diagnostic groups, including those on the autism spectrum and in rare genetic syndromes such as Rett Syndrome (RTT). There is, however a remarkable scarcity in the literature on the impact of the autonomic component on emotional and behavioural regulation in these disorders, and on the longer-term outcomes on disorder burden.RTT is a debilitating and often life-threatening disorder involving multiple overlapping physiological systems. Autonomic dysregulation otherwise known as dysautonomia is a cardinal feature of RTT characterised by an imbalance between the sympathetic and parasympathetic arms of the autonomic nervous system. Unlocking the autonomic component of emotional and behavioural dysregulation would be central in reducing the impairment seen in patients with RTT. In this vein, Emotional, Behavioural and Autonomic Dysregulation (EBAD) would be a useful construct to target for treatment which could mitigate burden and improve the quality of life of patients.RTT can be considered as a congenital dysautonomia and because EBAD can give rise to impairments occurring in multiple overlapping physiological systems, understanding these physiological responses arising out of EBAD would be a critical part to consider when planning treatment strategies and improving clinical outcomes in these patients. Biometric guided pharmacological and bio-feedback therapy for the behavioural and emotional aspects of the disorder offers an attracting perspective to manage EBAD in these patients. This can also allow for the stratification of patients into clinical trials and could ultimately help streamline the patient care pathway for optimal outcomes.The objectives of this review are to emphasise the key issues relating to the management of EBAD in patients with RTT, appraise clinical trials done in RTT from the perspective of autonomic physiology and to discuss the potential of EBAD as a target for clinical trials.
Lien vers le texte intégral (Open Access ou abonnement)
13. Sunamura N, Iwashita S, Enomoto K, Kadoshima T, Isono F. {{Loss of the fragile X mental retardation protein causes aberrant differentiation in human neural progenitor cells}}. {Sci Rep}. 2018; 8(1): 11585.
Fragile X syndrome (FXS) is caused by transcriptional silencing of the FMR1 gene during embryonic development with the consequent loss of the encoded fragile X mental retardation protein (FMRP). The pathological mechanisms of FXS have been extensively studied using the Fmr1-knockout mouse, and the findings suggest important roles for FMRP in synaptic plasticity and proper functioning of neural networks. However, the function of FMRP during early development in the human nervous system remains to be confirmed. Here we describe human neural progenitor cells (NPCs) as a model for studying FMRP functions and FXS pathology. Transcriptome analysis of the NPCs derived from FMR1-knockout human induced pluripotent stem cells (iPSCs) showed altered expression of neural differentiation markers, particularly a marked induction of the astrocyte marker glial fibrillary acidic protein (GFAP). When induced to differentiate, FMRP-deficient neurons continued to express GFAP, and showed less spontaneous calcium bursts than the parental iPSC-derived neurons. Interestingly, the aberrant expression of GFAP and the impaired firing was corrected by treatment with the protein kinase inhibitor LX7101. These findings underscore the modulatory roles of FMRP in human neurogenesis, and further demonstrate that the defective phenotype of FXS could be reversed at least partly by small molecule kinase inhibitors.
Lien vers le texte intégral (Open Access ou abonnement)
14. Taylor SE, Taylor RD, Price J, Andreae LC. {{Single-molecule fluorescence in-situ hybridization reveals that human SHANK3 mRNA expression varies during development and in autism-associated SHANK3 heterozygosity}}. {Stem cell research & therapy}. 2018; 9(1): 206.
BACKGROUND: Deletions and mutations in the SHANK3 gene are strongly associated with autism spectrum disorder and underlie the autism-associated disorder Phelan-McDermid syndrome. SHANK3 is a scaffolding protein found at the post-synaptic membrane of excitatory neurons. METHODS: Single-molecule fluorescence in-situ hybridization (smFISH) allows the visualization of single mRNA transcripts in vitro. Here we perform and quantify smFISH in human inducible pluripotent stem cell (hiPSC)-derived cortical neurons, targeting the SHANK3 transcript. RESULTS: Both smFISH and conventional immunofluorescence staining demonstrated a developmental increase in SHANK3 mRNA and protein, respectively, in control human cortical neurons. Analysis of single SHANK3 mRNA molecules in neurons derived from an autistic individual heterozygous for SHANK3 indicated that while the number of SHANK3 mRNA transcripts remained comparable with control levels in the cell soma, there was a 50% reduction within neuronal processes, suggesting that local, dendritic targeting of SHANK3 mRNA may be specifically affected in SHANK3 haploinsufficiency. CONCLUSION: Human SHANK3 mRNA shows developmentally regulated dendritic localization in hiPSC-derived neurons, which is reduced in neurons generated from a haploinsufficient individual with autism. Although further replication is needed, given the importance of local mRNA translation in synaptic function, this could represent an important early abnormality.
Lien vers le texte intégral (Open Access ou abonnement)
15. Tomiyama S, Kikuchi M, Yoshimura Y, Hasegawa C, Ikeda T, Saito DN, Kumazaki H, Naito N, Minabe Y. {{Changes in maternal feelings for children with autism spectrum disorder after childbirth: The impact of knowledge about the disorder}}. {PLoS One}. 2018; 13(8): e0201862.
The social interactions between caregivers and their children play a crucial role in childhood development; therefore, caregivers’ feelings for children are critical for the development of social minds. Mothers of children with autism spectrum disorder (ASD) are known to experience higher levels of stress. However, knowledge regarding mothers’ feelings for their children before receiving a clinical diagnosis is limited. This study retrospectively investigated the time course of mothers’ feelings from the time of birth and the effect of protective factors. The participants were 5- to 8-year-old children with an ASD diagnosis and their mothers. The mothers of the children with ASD had less positive feelings toward their children than the mothers of the typically developed (TD) children before receiving a clinical diagnosis. Intriguingly, prior knowledge of ASD may relieve maternal mental distress during the child-rearing years and at the time of diagnosis.
Lien vers le texte intégral (Open Access ou abonnement)
16. Vittal P, Pandya S, Sharp K, Berry-Kravis E, Zhou L, Ouyang B, Jackson J, Hall DA. {{ASFMR1 splice variant: A predictor of fragile X-associated tremor/ataxia syndrome}}. {Neurology Genetics}. 2018; 4(4): e246.
Objective: To explore the association of a splice variant of the antisense fragile X mental retardation 1 (ASFMR1) gene, loss of fragile X mental retardation 1 (FMR1) AGG interspersions and FMR1 CGG repeat size with manifestation, and severity of clinical symptoms of fragile X-associated tremor/ataxia syndrome (FXTAS). Methods: Premutation carriers (PMCs) with FXTAS, without FXTAS, and normal controls (NCs) had a neurologic evaluation and collection of skin and blood samples. Expression of ASFMR1 transcript/splice variant 2 (ASFMR1-TV2), nonspliced ASFMR1, total ASFMR1, and FMR1 messenger RNA were quantified and compared using analysis of variance. Least absolute shrinkage and selection operator (LASSO) logistic regression and receiver operating characteristic analyses were performed. Results: Premutation men and women both with and without FXTAS had higher ASFMR1-TV2 levels compared with NC men and women (n = 135,135, p < 0.0001), and ASFMR1-TV2 had good discriminating power for FXTAS compared with NCs but not for FXTAS from PMC. After adjusting for age, loss of AGG, larger CGG repeat size (in men), and elevated ASFMR1-TV2 level (in women) were strongly associated with FXTAS compared with NC and PMC (combined). Conclusions: This study found elevated levels of ASFMR1-TV2 and loss of AGG interruptions in both men and women with FXTAS. Future studies will be needed to determine whether these variables can provide useful diagnostic or predictive information. Lien vers le texte intégral (Open Access ou abonnement)
17. Xie W, Ge X, Li L, Yao A, Wang X, Li M, Gong X, Chu Z, Lu Z, Huang X, Jiao Y, Wang Y, Xiao M, Chen H, Xiang W, Yao P. {{Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation}}. {Mol Autism}. 2018; 9: 43.
Background: Recent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior. Methods: Experiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERbeta knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing. Results: Eight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERbeta expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERbeta activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERbeta and its target genes by demethylation of DNA and histone on the ERbeta promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior. Conclusions: We conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application.
