Autism spectrum disorders (ASD) are complex conditions that stem from a combination of genetic, epigenetic and environmental influences during early pre- and postnatal childhood. The review focuses on the cerebellum and the striatum, two structures involved in motor, sensory, cognitive and social functions altered in ASD. We summarize clinical and fundamental studies highlighting the importance of these two structures in ASD. We further discuss the relation between cellular and molecular alterations with the observed behavior at the social, cognitive, motor and gait levels. Functional correlates regarding neuronal activity are also detailed wherever possible, and sexual dimorphism is explored pointing to the need to apprehend ASD in both sexes, as findings can be dramatically different at both quantitative and qualitative levels. The review focuses also on a set of three recent papers from our laboratory where we explored motor and gait function in various genetic and environmental ASD animal models. We report that motor and gait behaviors can constitute an early and quantitative window to the disease, as they often correlate with the severity of social impairments and loss of cerebellar Purkinje cells. The review ends with suggestions as to the main obstacles that need to be surpassed before an appropriate management of the disease can be proposed.

/pdf/cerebellar-and-striatal-implications-in-autism-spectrum-35p5c8yk.pdf

Cerebellar and Striatal Implications in Autism Spectrum Disorders: From Clinical Observations to Animal Models

The prediction of harmful effects can guide research on the health hazards of environmental pollutants. The development of a computer-aided drug design in pharmacological technology and omics database remarkably facilitates the prediction of the possible harmful effects of hazardous substances. In this study, the pharmacophore target database based on molecular structure served as a bridge between pollutants and genes and combined with the omics database and molecular pathway enrichment technology to predict the potential prostatic cancer-promoting effect of dibutyl phthalate. Cell experiments and gene expression were carried out to verify the previous prediction, and the characteristics of harmful effects were further explored. Low concentrations of dibutyl phthalate may have androgen-independent prostate cancer-promoting effects, which may put patients receiving androgen deprivation therapy in danger. This study suggests the potential negative effects of phthalates on prostate cancer and a method for predicting harmful effects on the basis of pharmacology technology.

Pharmacophore based in silico study with laboratory verification—environmental explanation of prostate cancer recurrence

Previous studies aiming at relating exposure to phenols and phthalates with child social behavior characterized exposure using one or a few spot urine samples, resulting in substantial exposure misclassification. Moreover, early infancy exposure was rarely studied.We aimed to examine the associations of phthalates and phenols with child social behavior in a cohort with improved exposure assessment and to a priori identify the chemicals supported by a higher weight of evidence.Among 406 mother-child pairs from the French Assessment of Air Pollution exposure during Pregnancy and Effect on Health (SEPAGES) cohort, 25 phenols/phthalate metabolites were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (∼21 samples/trimester) and at 2 months and 1-year of age (∼7 samples/period). Social behavior was parent-reported at 3 years of age of the child using the Social Responsiveness Scale (SRS). A structured literature review of the animal and human evidence was performed to prioritize the measured phthalates/phenols based on their likelihood to affect social behavior. Both adjusted linear regression and Bayesian Weighted Quantile Sum (BWQS) regression models were fitted. False discovery rate (FDR) correction was applied only to nonprioritized chemicals.Prioritized compounds included bisphenol A, bisphenol S, triclosan (TCS), diethyl-hexyl phthalate (ΣDEHP), mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), and mono-benzyl phthalate (MBzP). With the exception of bisphenols, which showed a mixed pattern of positive and negative associations in pregnant mothers and neonates, few prenatal associations were observed. Most associations were observed with prioritized chemicals measured in 1-y-old infants: Each doubling in urinary TCS (β=0.78; 95% CI: 0.00, 1.55) and MEP (β=0.92; 95% CI: -0.11, 1.96) concentrations were associated with worse total SRS scores, whereas MnBP and ΣDEHP were associated with worse Social Awareness (β=0.25; 95% CI: 0.01, 0.50) and Social Communication (β=0.43; 95% CI: -0.02, 0.89) scores, respectively. BWQS also suggested worse total SRS [Beta 1=1.38; 95% credible interval (CrI): -0.18, 2.97], Social Awareness (Beta 1=0.37; 95% CrI: 0.06, 0.70), and Social Communication (Beta 1=0.91; 95% CrI: 0.31, 1.53) scores per quartile increase in the mixture of prioritized compounds assessed in 1-y-old infants. The few associations observed with nonprioritized chemicals did not remain after FDR correction, with the exception of benzophenone-3 exposure in 1-y-old infants, which was suggestively associated with worse Social Communication scores (corrected p=0.07).The literature search allowed us to adapt our statistical analysis according to the weight of evidence and create a corpus of experimental and epidemiological knowledge to better interpret our findings. Early infancy appears to be a sensitive exposure window that should be further investigated. https://doi.org/10.1289/EHP11798. 

Early-Life Exposure to a Mixture of Phenols and Phthalates in Relation to Child Social Behavior: Applying an Evidence-Based Prioritization to a Cohort with Improved Exposure Assessment

Abstract Background Gestational sleep apnea is a hypoxic sleep disorder that affects 8–26% of pregnancies and increases the risk for central nervous system dysfunction in offspring. Specifically, there are sex differences in the sensitivity of the fetal hippocampus to hypoxic insults, and hippocampal impairments are associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. Yet, it is unclear whether gestational sleep apnea impacts these hippocampal-associated functions and if sex and age modify these effects. To examine the relationship between gestational sleep apnea and hippocampal-associated behaviors, we used chronic intermittent hypoxia (CIH) to model late gestational sleep apnea in pregnant rats. We hypothesized that late gestational CIH would produce sex- and age-specific social, anxiety-like, repetitive, and cognitive impairments in offspring. Methods Timed pregnant Long-Evans rats were exposed to CIH or room air normoxia from GD 15–19. Behavioral testing of offspring occurred during either puberty or young adulthood. To examine gestational hypoxia-induced behavioral phenotypes, we quantified hippocampal-associated behaviors (social function, repetitive behaviors, anxiety-like behaviors, and spatial memory and learning), hippocampal neuronal activity (glutamatergic NMDA receptors, dopamine transporter, monoamine oxidase-A, early growth response protein 1, and doublecortin), and circulating hormones in offspring. Results Late gestational CIH induced sex- and age-specific differences in social, repetitive, and memory functions in offspring. In female pubertal offspring, CIH impaired social function, increased repetitive behaviors, and elevated circulating corticosterone levels but did not impact memory. In contrast, CIH transiently induced spatial memory dysfunction in pubertal male offspring but did not impact social or repetitive functions. Long-term effects of gestational CIH on social behaviors were only observed in female offspring, wherein CIH induced social disengagement and suppression of circulating corticosterone levels in young adulthood. No effects of gestational CIH were observed in anxiety-like behaviors, hippocampal neuronal activity, or circulating testosterone and estradiol levels, regardless of sex or age of offspring. Conclusions Our results indicate that hypoxia-associated pregnancy complications during late gestation can increase the risk for behavioral and physiological outcomes in offspring, such as social dysfunction, repetitive behaviors, and cognitive impairment, that are dependent on sex and age. 

Sex and age differences in social and cognitive function in offspring exposed to late gestational hypoxia

/pdf/exposure-to-environmentally-relevant-doses-of-plasticizers-2gpq1euz.pdf

Exposure to environmentally relevant doses of plasticizers alters maternal behavior and related neuroendocrine processes in primiparous and multiparous female mice.

Phthalates are chemicals interfering with the function of testosterone and are suspected to play a role in the emergence of neurodevelopmental diseases. This could be due to interference with brain development for which optimal testosterone levels are essential. We investigated the effect of prenatal and early postnatal exposure to a phthalate mixture on the anogenital distance (AGD), plasma testosterone levels and social behavior in rats. Pregnant rats were exposed to a mixture of diethylhexyl, diisononyl and dibutyl phthalate, each at a dose of 4.5 mg/kg/day, from gestational day 15 to postnatal day 4. A social interaction test was performed to assess sociability in the three ontogenetic stages (weaning, puberty, adulthood). AGD was measured in adulthood to assess changes in prenatal testosterone levels. Plasma testosterone levels were measured in adults by a radioimmunoassay. The total frequency and time of socio-cohesive interactions were decreased in phthalate exposed females in weaning, puberty and adulthood. Phthalate exposed males showed a decrease in the frequency of social interactions in weaning only. Shorter anogenital distance was observed in adult males exposed to phthalates. Decreased testosterone levels were observed in the exposed group in both sexes. Our results suggest that early developmental phthalate exposure may play an important role in the hormonal and behavioral changes associated with several neurodevelopmental diseases.

/pdf/a-mixture-of-diethylhexyl-diisononyl-and-dibutyl-phthalate-4tjyxy4swq.pdf

A mixture of diethylhexyl, diisononyl and dibutyl phthalate decreased anogenital distance, postnatal testosterone levels, and changed social behavior in Wistar rats

The healthy development of the fetus depends on the exact course of pregnancy and delivery. Therefore, prenatal hypoxia remains between the greatest threats to the developing fetus. Our study aimed to assess the impact of prenatal hypoxia on postnatal development and behavior of the rats, whose mothers were exposed to hypoxia (10.5 % O2) during a critical period of brain development on GD20 for 12 h. This prenatal insult resulted in a delay of sensorimotor development of hypoxic pups compared to the control group. Hypoxic pups also had lowered postnatal weight which in males persisted up to adulthood. In adulthood, hypoxic males showed anxiety-like behavior in the OF, higher sucrose preference, and lower levels of grimace scale (reflecting the degree of negative emotions) in the immobilization chamber compared to the control group. Moreover, hypoxic animals showed hyperactivity in EPM and LD tests, and hypoxic females had reduced sociability compared to the control group. In conclusion, our results indicate a possible relationship between prenatal hypoxia and changes in sociability, activity, and impaired emotion regulation in ADHD, ASD, or anxiety disorders. The fact that changes in observed parameters are manifested mostly in males confirms that male sex is more sensitive to prenatal insults.

/pdf/impact-of-prenatal-hypoxia-on-the-development-and-behavior-3zohogpe14.pdf

Impact of prenatal hypoxia on the development and behavior of the rat offspring.

Phthalates are chemical substances that are widely used to provide flexibility and durability to plastic materials. They leach from products in which they are mixed and reach living organisms. Results from experimental studies suggest that exposure to phthalates can have a negative impact on an individual's neuronal system and behavior. In this regard, exposure during early ontogenesis seems to be particularly dangerous due to the extensive growth and development of body structures and functions. Disruption during this critical time can result in alterations of behavior and the emergence of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Various animal models have been used to elucidate the pathogenesis of this disease. They are fundamental for research, and although the translation of results to humans is difficult, new animal models are being developed. The aim of this review is to summarize laboratory rodent studies in which early developmental phthalate exposure resulted in brain alterations and autistic-like behavioral traits. We also discuss the possibility of using early developmental phthalate exposure in rodents to create a new animal model of autism.

/pdf/autistic-like-traits-in-laboratory-rodents-exposed-to-2tpp105ve7.pdf

Autistic-like traits in laboratory rodents exposed to phthalic acid esters during early development - an animal model of autism?

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A mixture of diethylhexyl, diisononyl and dibutyl phthalate decreased anogenital distance, postnatal testosterone levels, and changed social behavior in Wistar rats

Impact of prenatal hypoxia on the development and behavior of the rat offspring.

Autistic-like traits in laboratory rodents exposed to phthalic acid esters during early development - an animal model of autism?