Prenatal cigarette exposure induces offspring hyperactivity and affective alterations via gut -brain axis metabolic...

Prenatal cigarette exposure (PCE) is a major preventable risk factor for neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD), but the underlying mechanisms extending beyond direct developmental neurotoxicity remain poorly defined. This study investigated the long-term integrative effects of PCE on offspring behavior, neuronal activation, and gut metabolome using an established mouse model. Pregnant C57BL/6 mice were randomly assigned to whole-body cigarette smoke or control air exposure from pre-mating until birth. Compared to controls, PCE offspring exhibited a transient reduction in early postnatal weight gain, followed by a robust hyperactive phenotype in adolescence and adulthood, accompanied by increased despair-like behavior without deficits in social interaction. These behavioral alterations were associated with region-specific neuronal hyperactivation, characterized by a significant increase in c-Fos-positive cells in the paraventricular area (PVA) and basal ganglia (BG) - regions implicated in stress integration and motor regulation, respectively, while no significant changes were detected in the medial prefrontal cortex, hippocampus, basolateral amygdala, or nucleus accumbens. Furthermore, PCE induced selective microglial activation in the PVA, accompanied by impaired intestinal barrier integrity as evidenced by reduced colonic Claudin-5 expression. Untargeted fecal metabolomics revealed a persistent reprogramming of gut metabolic pathways, including glycerophospholipid metabolism, phosphatidylinositol signaling, and arachidonic acid metabolism. Together, these findings demonstrate that prenatal cigarette exposure induces enduring behavioral and metabolic abnormalities that correlate with selective neuroimmune and neuronal alterations, highlighting region-specific gut-brain axis correlates of PCE-induced neurobehavioral alterations.