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We investigated the effect of lipopolysaccharide (LPS)‐induced maternal immune activation used as a model for producing neurodevelopmental disorders on hippocampal neurogenesis and behaviors in rat offspring by exploring the antioxidant effects of alpha‐glycosyl isoquercitrin (AGIQ). Pregnant Sprague–Dawley rats were intraperitoneally injected with LPS (50 μg/kg body weight) at gestational days 15 and 16. AGIQ was administered in the diet to dams at 0.5% (w/w) from gestational day 10 until weaning at postnatal day 21 and then to offspring until adulthood at postnatal day 77. During postnatal life, offspring of LPS‐injected animals did not show neuroinflammation or oxidative stress in the brain. At weaning, LPS decreased the numbers of type‐2b neural progenitor cells (NPCs) and PCNA+ proliferating cells in the subgranular zone, FOS‐expressing granule cells, and GAD67+ hilar interneurons in the dentate gyrus. In adulthood, LPS decreased type‐1 neural stem cells, type‐2a NPCs, and GAD67+ hilar interneurons, and downregulated Dpysl3, Sst, Fos, Mapk1, Mapk3, Grin2a, Grin2b, Bdnf, and Ntrk2. In adults, LPS suppressed locomotor activity in the open field test and suppressed fear memory acquisition and fear extinction learning in the contextual fear conditioning test. These results indicate that mid‐gestation LPS injections disrupt programming of normal neurodevelopment resulting in progressive suppression of hippocampal neurogenesis and synaptic plasticity of newborn granule cells by suppressing GABAergic and glutamatergic neurotransmitter signals and BDNF/TrkB signaling to result in adult‐stage behavioral deficits. AGIQ ameliorated most aberrations in hippocampal neurogenesis and synaptic plasticity, as well as behavioral deficits. Effective amelioration by continuous AGIQ treatment starting before LPS injections may reflect both anti‐inflammatory and anti‐oxidative stress effects during gestation and neuroprotective effects of continuous exposure through adulthood. [ABSTRACT FROM AUTHOR]

We have previously reported that the valproic acid (VPA)‐induced disruption pattern of hippocampal adult neurogenesis differs between developmental and 28‐day postpubertal exposure. In the present study, we performed brain region‐specific global gene expression profiling to compare the profiles of VPA‐induced neurotoxicity between developmental and postpubertal exposure. Offspring exposed to VPA at 0, 667, and 2000 parts per million (ppm) via maternal drinking water from gestational day 6 until weaning (postnatal day 21) were examined, along with male rats orally administered VPA at 0, 200, and 900 mg/kg body weight for 28 days starting at 5 weeks old. Four brain regions—the hippocampal dentate gyrus, corpus callosum, cerebral cortex, and cerebellar vermis—were subjected to expression microarray analysis. Profiled data suggested a region‐specific pattern of effects after developmental VPA exposure, and a common pattern of effects among brain regions after postpubertal VPA exposure. Developmental VPA exposure typically led to the altered expression of genes related to nervous system development (Msx1, Xcl1, Foxj1, Prdm16, C3, and Kif11) in the hippocampus, and those related to nervous system development (Neurod1) and gliogenesis (Notch1 and Sox9) in the corpus callosum. Postpubertal VPA exposure led to the altered expression of genes related to neuronal differentiation and projection (Cd47, Cyr61, Dbi, Adamts1, and Btg2) in multiple brain regions. These findings suggested that neurotoxic patterns of VPA might be different between developmental and postpubertal exposure, which was consistent with our previous study. Of note, the hippocampal dentate gyrus might be a sensitive target of developmental neurotoxicants after puberty. Global gene expression profiling was performed in four different brain regions in rats after developmental or postpubertal 28‐day valproic acid (VPA) exposure. Developmental VPA exposure had specific effects on each of the four brain regions, while postpubertal VPA exposure had common effects among multiple brain regions. Our results suggested that the neurotoxic pattern of VPA might differ between developmental and postpubertal exposure. They also suggested that the hippocampal dentate gyrus might be particularly vulnerable to postpubertal exposure to developmental neurotoxicants. [ABSTRACT FROM AUTHOR]

We have previously found that maternal exposure to 6‐propyl‐2‐thiouracil (PTU), valproic acid (VPA), or glycidol (GLY) has a sustained or late effect on hippocampal neurogenesis at the adult stage in rat offspring. Herein, we searched for genes with hypermethylated promoter region and downregulated transcript level to reveal irreversible markers of developmental neurotoxicity. The hippocampal dentate gyrus of male rat offspring exposed maternally to PTU, VPA, or GLY was subjected to Methyl‐Seq and RNA‐Seq analyses on postnatal day (PND) 21. Among the genes identified, 170 were selected for further validation analysis of gene expression on PND 21 and PND 77 by real‐time reverse transcription‐PCR. PTU and GLY downregulated many genes on PND 21, reflecting diverse effects on neurogenesis. Furthermore, genes showing sustained downregulation were found after PTU or VPA exposure, reflecting a sustained or late effect on neurogenesis by these compounds. In contrast, such genes were not observed with GLY, probably because of the reversible nature of the effects. Among the genes showing sustained downregulation, Creb, Arc, and Hes5 were concurrently downregulated by PTU, suggesting an association with neuronal mismigration, suppressed synaptic plasticity, and reduction in neural stem and progenitor cells. Epha7 and Pvalb were also concurrently downregulated by PTU, suggesting an association with the reduction in late‐stage progenitor cells. VPA induced sustained downregulation of Vgf and Dpysl4, which may be related to the aberrations in synaptic plasticity. The genes showing sustained downregulation may be irreversible markers of developmental neurotoxicity. Hippocampal dentate gyrus of rat offspring exposed maternally to PTU, VPA, or GLY was subjected to global methylation analysis on PND 21. Genes downregulated on PND 77 were examined. PTU concurrently downregulated Creb, Arc, and Hes5, suggesting an association with the diverse effects on neurogenesis. PTU also concurrently downregulated Epha7 and Pvalb, suggesting an association with progenitor cell reduction. VPA downregulated Vgf and Dpysl4, suggesting an association with the aberrant synaptic plasticity. In contrast, GLY did not induce sustained downregulation. [ABSTRACT FROM AUTHOR]