OBJECTIVE: To study the association of exposure to polycyclic aromatic hydrocarbons (PAH) during pregnancy and autism spectrum disorder (ASD)-related behaviors in toddlers. METHODS: A total of 348 toddlers who had accepted the measurement of PAH-DNA adduct in umbilical cord blood and evaluation of behavior problems at the age of 36 months were enrolled in this birth cohort study. Child Behavior Checklist (CBCL) and Autism Behavior Checklist (ABC) were used to evaluate behavior problems at the age of 36 months. The correlation of the concentration of PAH-DNA adduct in umbilical cord blood with CBCL and ABC scores at the age of 36 months were analyzed. RESULTS: The detection rate of PAH-DNA adduct in umbilical cord blood was 52.3%, and the median concentration was 0.68 ng/mL. The median total scores of CBCL and ABC scales were 23 and 8 respectively. In children aged 36 months, the concentration of PAH-DNA adduct was positively correlated with the score of social withdrawal in the CBCL scale (r=0.205, P<0.05), the total score of the ABC scale (r=0.412, P<0.05), and the self-care score of the ABC scale (r=0.355, P<0.05). The concentration of PAH-DNA adduct was closely associated with the total score of the ABC scale in children aged 36 months (β=0.122, P<0.05). CONCLUSIONS PAH exposure during pregnancy may be a risk factor for ASD-related behaviors in toddlers. Effective reduction of PAH exposure during pregnancy and detection of PAH-DNA adduct in neonatal umbilical cord blood are of vital importance for early prevention, screening and intervention of ASD.
Autism Spectrum Disorder ; chemically induced ; Child Behavior ; Child, Preschool ; Cohort Studies ; Female ; Fetal Blood ; Humans ; Polycyclic Aromatic Hydrocarbons ; adverse effects ; Pregnancy ; Prenatal Exposure Delayed Effects ; chemically induced

OBJECTIVE: To investigate the mechanism of valproic acid (VPA) -induced impairment of the dendritic spines and synapses in the prefrontal cortex (PFC) for causing core symptoms of autism spectrum disorder (ASD) in mice. METHODS: Female C57 mice were subjected to injections of saline or VPA on gestational days 10 and 12, and the male offspring mice in the two groups were used as the normal control group and ASD model group (n=10), respectively. Another 20 male mice with fetal exposure to VPA were randomized into two groups for stereotactic injection of DMSO or Wortmannin into the PFC (n=10). Open field test, juvenile play test and 3-chamber test were used to evaluate autistic behaviors of the mice. The density of dendrite spines in the PFC was observed with Golgi staining. Western blotting and immunofluorescence staining were used to detect the expressions of p-PI3K, PI3K, p-AKT, AKT, p-mTOR, mTOR and the synaptic proteins PSD95, p-Syn, and Syn in the PFC of the mice. RESULTS: Compared with the normal control mice, the mice with fetal exposure to VPA exhibited obvious autism-like behaviors with significantly decreased density of total, mushroom and stubby dendritic spines (P < 0.05) and increased filopodia dendritic spines (P < 0.05) in the PFC. The VPA-exposed mice also showed significantly increased expressions of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR (P < 0.01) and lowered expressions of PSD95 and p-Syn/Syn in the PFC (P < 0.05 or 0.001). Wortmannin injection into the PFC obviously improved the ASD-like phenotype and dendritic spine development, down-regulated PI3K/Akt/mTOR signaling pathway and up-regulated the synaptic proteins in VPA-exposed mice. CONCLUSION In male mice with fetal exposure to VPA, excessive activation of PI3K/Akt/mTOR signaling pathway and decreased expressions of the synaptic proteins PSD95 and p-Syn cause dendritic spine damage and synaptic development disturbance in the PFC, which eventually leads to ASD-like phenotype.
Animals ; Autism Spectrum Disorder/chemically induced* ; Autistic Disorder/chemically induced* ; Dendritic Spines ; Disease Models, Animal ; Female ; Male ; Mice ; Phosphatidylinositol 3-Kinases ; Prefrontal Cortex ; Prenatal Exposure Delayed Effects ; Valproic Acid/adverse effects*