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OBJECTIVES: Cannabis legalization has triggered an increase in prenatal cannabis use. Given that tobacco is commonly co-used with cannabis, determining outcomes associated with prenatal cannabis and tobacco co-exposure is crucial. While literature exists regarding the individual effects of prenatal cannabis and tobacco exposure on childhood behaviour, there is a gap regarding their combined use, which may have interactive effects. Therefore, we investigated whether prenatal cannabis and tobacco co-exposure was associated with greater externalizing and internalizing problems in middle childhood compared to prenatal exposure to either substance alone or no exposure. METHODS: Baseline data from the Adolescent Brain Cognitive Development (ABCD) Study (collected in children ages 9-11) were used to explore differences in externalizing and internalizing scores derived from the Childhood Behavior Checklist across four groups: children with prenatal cannabis and tobacco co-exposure (CT, n = 290), children with prenatal cannabis-only exposure (CAN, n = 225), children with prenatal tobacco-only exposure (TOB, n = 966), and unexposed children (CTL, n = 8,311). We also examined if the daily quantity of tobacco exposure modulated the effect of cannabis exposure on outcomes. RESULTS: Adjusting for covariates, a 2 × 2 ANCOVA revealed significant main effects for prenatal cannabis (p = 0.03) and tobacco exposure (p < 0.001), and a significant interaction effect on externalizing scores (p = 0.032); no significant main effects or interactions were found for internalizing scores. However, interactions between daily quantity of cannabis and tobacco exposure significantly predicted both externalizing and internalizing scores (p < 0.01). CONCLUSIONS: These findings indicate that co-exposure is associated with greater externalizing problems than exposure to either substance alone, which did not differ from each other. Further, greater tobacco exposure may amplify the negative effect of cannabis exposure on both externalizing and internalizing behaviours in children. These findings underscore the need for interventions that target cannabis and tobacco co-use in pregnant women to circumvent their adverse impact on middle childhood behaviour.
Prenatal Cannabis and Tobacco Co-exposure and its Association with Middle Childhood BehavioursPlain Language SummaryGiven the high rates of both cannabis and tobacco use during pregnancy, we explored if their combined use was associated with greater problematic behaviour in 10-year-old children compared to either substance alone or no substance use. We found that children with prenatal co-exposure had greater externalizing behaviours, such as attention problems and aggression, compared to children with prenatal exposure to one of the substances or no exposure. Prenatal co-exposure, cannabis-only exposure and tobacco-only exposure had no effect on childhood internalizing behaviours (e.g., depression, anxiety). However, the amount of tobacco consumed by the mother amplified the negative effect of cannabis on both childhood externalizing and internalizing behaviours. These findings emphasize the need for specialized treatment for cannabis and tobacco co-use in pregnant women to circumvent the adverse impact of these substances on externalizing behaviours in middle childhood.
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Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2α phosphorylation (p-eIF2α), is suppressed in excitatory, but not inhibitory, neurons in a mouse model of fragile X syndrome (FXS; Fmr1-/y). We further show that the decrease in p-eIF2α is mediated via activation of mTORC1. Genetic reduction of p-eIF2α only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1-/y mice, restoration of p-eIF2α solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis, and core phenotypes reminiscent of autism in a mouse model of FXS.