Maternal Nicotine Exposure Alters Hippocampal Microglia Polarization and Promotes Anti-inflammatory Signaling in Juvenile Offspring in Mice

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.

Maternal smoking during pregnancy and type 1 diabetes in the offspring: A nationwide register-based study with family-based designs

“…Nicotine induced immunosuppression is associated with preserved insulin content and reduced incidence of diabetes in T1D-prone mice models 42 . Experimental studies indicate that the immunosuppressive and anti-inflammatory effects of prenatal smoking exposure remain also postnatally 43 44 . The hypothesis of immunosuppression is partly supported by the fact that autoantibodies of T1D mostly appear within the first two years after birth, close to the time of fetal exposure 2 .…”

Combined Exposure to Diazinon and Nicotine Exerts a Synergistic Adverse Effect In Vitro and Disrupts Brain Development and Behaviors In Vivo

“…Developmental nicotine exposure has resulted in adverse outcomes in vitro and in vivo [ 14 , 15 , 16 , 17 ]. Even though test protocols and drug concentrations vary from those in our study, the previous studies support our major observations: (1) reduced motor learning, (2) compulsive behavior, (3) decreased cognition, and (4) alternation in social interaction patterns.…”

“…Lee and Picciotto (2019) reported that nicotine exposure (delivered thorough drinking water; 200 μg/mL) during development impairs learning behaviors and motor tasks via the modification of cortical synaptic plasticity. Zhou (2021) revealed that maternal nicotine exposure (via drinking water; 200 μg/mL) resulted in increased moving distance in an open field test for offspring mice [ 17 ]. Moreover, Alkam (2013) reported that maternal nicotine exposure (via drinking water; 200 μg/mL, ad libitum ) weakened the emotional behaviors of offspring mice, including those displayed in the marble-burying test.…”

Maternal smoking during pregnancy and type 1 diabetes in the offspring: a nationwide register-based study with family-based designs

“…Nicotine-induced immunosuppression is associated with preserved insulin content and reduced incidence of diabetes in type 1 diabetes-prone mice models [49]. Experimental studies indicate that the immunosuppressive and anti-inflammatory effects of prenatal smoking exposure remain also postnatally [50,51]. The hypothesis of immunosuppression is partly supported by the fact that autoantibodies of type 1 diabetes mostly appear within the first 2 years after birth, close to the time of fetal exposure [2].…”