Increased Fetal Thymocytes Apoptosis Contributes to Prenatal Nicotine Exposure-induced Th1/Th2 Imbalance in Male Offspring Mice.

Ting Chen,You-E Yan,Hui-Yi Yan,Han-Xiao Liu,Li-Fang Hou,Jie Ping,Wen Qu,Sha Liu

doi:10.1038/srep39013

Abstract

Nicotine, a definite risk factor during pregnancy, is an immunomodulator. This study was designed to investigate the effects of prenatal nicotine exposure (PNE) on the balance of Th1/Th2 in offspring, and further explore the developmental origin mechanisms from the perspective of fetal thymocytes apoptosis. Pregnant Balb/c mice were administered 1.5 mg/kg nicotine subcutaneously twice per day from gestational day (GD) 9 to GD18. Results showed that PNE could cause a Th2 shift in male offspring, manifested as increased ratio of IgG1/IgG2a, IL-4 production in serum, and IL-4/IFN-γ expression ratio in spleen. Increased apoptosis of total thymocytes and CD4SP and reduced cell proportion of CD4SP were found in PNE male offspring on postnatal day (PND) 14 and PND 49. In the fetuses, decreased body weight and organ index of fetal thymus, histological changes in fetal thymus, reduced CD4SP proportion and increased fetal thymocyte apoptosis were observed in nicotine group. The increased mRNA expression of genes involved in Fas-mediated apoptotic pathway and protein expression of Fas were also detected. In conclusion, PNE could cause a Th2 shift in male offspring mediated by reduced CD4+ T cells output, which may result from the increasing apoptosis of total thymocytes and CD4SP.

Highlights

Nicotine, a definite risk factor during pregnancy, is an immunomodulator
The results showed that the body weights of male offspring in prenatal nicotine exposure (PNE) group were lower than those of controls from postnatal day (PND)[0] to PND49 (P < 0.01, P < 0.05, Fig. 1A,B), but the growth rates were higher compared with the control (P < 0.01, Fig. 1C)
The results showed that there were no changes in immunoglobulin G1 (IgG1), IgG2a, the ratio of IgG1/IgG2a and IL-4 in serum before and after immunization with S. pneumoniae in control offspring (Fig. 2A–D)

Summary

Introduction

This study was designed to investigate the effects of prenatal nicotine exposure (PNE) on the balance of Th1/Th2 in offspring, and further explore the developmental origin mechanisms from the perspective of fetal thymocytes apoptosis. PNE could cause a Th2 shift in male offspring mediated by reduced CD4+ T cells output, which may result from the increasing apoptosis of total thymocytes and CD4SP. Nicotine can cross the placental barrier because of its low molecular weight and high lipid solubility[7] Both epidemiological and experimental animal studies showed that the increased risks of adult immune diseases was related to prenatal tobacco smoke or nicotine exposure[8,9]. We speculated that fetal thymic hypoplasia induced by PNE might be involved in mediating the abnormal immune responses of peripheral effector T cells in offspring

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Discussion

Conclusion