Abstract
Accumulating evidence reveal that maternal smoking or perinatal nicotine replacement therapy impairs hippocampal neurogenesis, neural development, and cognitive behaviors in the offspring. Microglia is a source of non-neural regulation of neuronal development and postnatal neurogenesis. In this study, we explored the impact of nicotine on the microglia during the development of hippocampus. Developmental nicotine exposure in a mouse model was conducted by supplementing nicotine in the drinking water to mother mice during gestation and lactation period. We found that juvenile offspring with maternal nicotine exposure presented physical and neurobehavioral development delay and an increase in anxiety-like behavior in the open field test on postnatal day (PND) 20. To further detect possible developmental neurotoxic effects of nicotine in offspring and underlying mechanism, whole genome microarray analysis of the expression profile of the hippocampus was performed on postnatal day 20. Significant alterations in the expression of genes related to inflammatory, neurotransmitter, and synapsis were observed in the hippocampus after maternal nicotine exposure, as compared to the vehicle control. Concurrently, an increase in microglial markers and the presence of M2 polarity state in the hippocampus of the nicotine offspring were observed by histological analysis and confocal z-stacking scanning. The M2 microglial polarization state was further confirmed with in vitro primary microglia culture by cytokine array, and double-positive expression of BDNF/Iba1 in microglia by immunohistochemical staining in the juvenile offspring hippocampus was visualized. We also found that nicotine offspring showed an increase of neurite length in the molecular layer and CA1 by Tuj1 staining, as well as an increase in the expression of synapse associated protein, PSD95, but the expression of NeuroD1 in CA1 and CA3 reduced. In summary, maternal nicotine exposure dysregulates immune-related genes expression by skewing the polarity of M2 microglia in the hippocampus, which may cause abnormal cognitive and behavioral performance in the offspring.
Highlights
Tobacco smoking, nicotine replacement therapy (NRT), e-cigarettes, as well as other nicotine exposure remain a major public health issue across the world (Guerby et al, 2020), and the trend of nicotine usage and exposure continues increasing over the past decades (Dai and Leventhal, 2019; Kapaya et al, 2019)
Developmental nicotine exposure is associated with much neuronal dysplasia in offspring
It is not clear what role microglia plays in the hippocampal impairment caused by developmental nicotine exposure, and what is the effect of nicotine on the differentiation of neural stem cells in the hippocampus
Summary
Nicotine replacement therapy (NRT), e-cigarettes, as well as other nicotine exposure remain a major public health issue across the world (Guerby et al, 2020), and the trend of nicotine usage and exposure continues increasing over the past decades (Dai and Leventhal, 2019; Kapaya et al, 2019). Nicotine exposure during pregnancy is associated with numerous fetal consequences including pre-mature birth, low birth weight, and Sudden Infant Death Syndrome (Salihu and Wilson, 2007; Knopik et al, 2016b; King et al, 2018; Buck et al, 2019), as well as neurodevelopmental disorders, such as attention deficit hyperactivity disorder, autism, and schizophrenia in developing children (Knopik et al, 2016a; Niemela et al, 2016; Golding et al, 2017; He et al, 2017; Quinn et al, 2017; Huang et al, 2018; Marceau et al, 2018). Understanding the unique effects of nicotine use on offspring is critical for treating and preventing the adverse consequences that follow
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