Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · 2025
Prenatal alcohol exposure impairs offspring cognition through oxidative stress disrupting CREB/BDNF/TrkB signaling and GABAergic neuron deficits.
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Zeng Xingdong, Wu Mengyan, Cai Yongle, Chen Haonan, Sun Miao, Yang Hao
Аннотация
BACKGROUND: Prenatal alcohol exposure (PAE) is the leading cause of adverse developmental and behavioral disorders, largely attributable to alcohol-induced oxidative stress injury. Cognitive deficits resulting from PAE in offspring are clinically characterized as fetal alcohol syndrome (FAS). Nonetheless, the exact pathogenic mechanisms underlying these deficits have not been fully elucidated.
METHODS: We established C57BL/6J disease models of FAS with doses of PAE (5 g/kg) and primary cultured neuronal cell models (2.5 g/kg, 5 g/kg) to study cognitive impairments and investigate the impacts and underlying mechanisms of FAS. Reactive oxygen species (ROS) in neurons were detected using dihydroethidium staining. The expression of gamma-aminobutyric acid (GABA) and glutamate (Glu) were examined. Furthermore, the activity of the CREB/BDNF/TrkB signaling pathway in offsprings was assessed. Concomitantly, the superoxide dismutase (SOD) analogue 2,2,6,6-tetramethylpiperidinoxy (Tempol, 0.1 mM) was introduced to the primary cultured neurons to reduce ROS levels, and subsequent changes in the CREB/BDNF/TrkB pathway and GABAergic neurons were evaluated.
RESULTS: FAS offspring with cognitive impairment exhibited elevated levels of ROS and malondialdehyde (MDA), indicating PAE-induced oxidative stress. Moreover, PAE markedly decreased the expression of brain-derived neurotrophic factor (BDNF) in offspring, consequently attenuating the activity of the CREB/BDNF/TrkB signaling pathway. Strikingly, the proportion of GABA-positive neurons rather than Glu-positive neurons substantially reduced in the offspring cortex. This decrease in GABAergic expression might be attributed to oxidative stress-mediated downregulation of BDNF, ultimately resulting in cognitive impairment in the progeny. Interestingly, Tempol treatment reduced ROS and MDA content, restored BDNF levels, and counteracted alcohol-induced oxidative damage to GABAergic neurons, suggesting that ROS scavenging could alleviate PAE-related impairments.
CONCLUSION: Oxidative stress impairs GABAergic neuronal development via disruption of CREB/BDNF/TrkB signaling cascades, providing new molecular insights into neurodevelopmental pathology in FAS offspring following PAE. These findings also highlight antioxidants as a potential therapeutic strategy for children with FAS.
METHODS: We established C57BL/6J disease models of FAS with doses of PAE (5 g/kg) and primary cultured neuronal cell models (2.5 g/kg, 5 g/kg) to study cognitive impairments and investigate the impacts and underlying mechanisms of FAS. Reactive oxygen species (ROS) in neurons were detected using dihydroethidium staining. The expression of gamma-aminobutyric acid (GABA) and glutamate (Glu) were examined. Furthermore, the activity of the CREB/BDNF/TrkB signaling pathway in offsprings was assessed. Concomitantly, the superoxide dismutase (SOD) analogue 2,2,6,6-tetramethylpiperidinoxy (Tempol, 0.1 mM) was introduced to the primary cultured neurons to reduce ROS levels, and subsequent changes in the CREB/BDNF/TrkB pathway and GABAergic neurons were evaluated.
RESULTS: FAS offspring with cognitive impairment exhibited elevated levels of ROS and malondialdehyde (MDA), indicating PAE-induced oxidative stress. Moreover, PAE markedly decreased the expression of brain-derived neurotrophic factor (BDNF) in offspring, consequently attenuating the activity of the CREB/BDNF/TrkB signaling pathway. Strikingly, the proportion of GABA-positive neurons rather than Glu-positive neurons substantially reduced in the offspring cortex. This decrease in GABAergic expression might be attributed to oxidative stress-mediated downregulation of BDNF, ultimately resulting in cognitive impairment in the progeny. Interestingly, Tempol treatment reduced ROS and MDA content, restored BDNF levels, and counteracted alcohol-induced oxidative damage to GABAergic neurons, suggesting that ROS scavenging could alleviate PAE-related impairments.
CONCLUSION: Oxidative stress impairs GABAergic neuronal development via disruption of CREB/BDNF/TrkB signaling cascades, providing new molecular insights into neurodevelopmental pathology in FAS offspring following PAE. These findings also highlight antioxidants as a potential therapeutic strategy for children with FAS.