Postnatal Smoke Exposure Further Increases the Hepatic Nicotine Metabolism in Prenatally Smoke Exposed Male Offspring and Is Linked with Aberrant Cyp2a5 Methylation.

Khosbayar Lkhagvadorj,Machteld N Hylkema,Zhijun Zeng,Karolin F Meyer,Torsten Plösch,Wierd Kooistra,Inge A M De Graaf,Laura P Verweij,Henk W Dijkhuizen,Marjan Reinders-Luinge

doi:10.3390/ijms22010164

Abstract

Prenatal smoke exposure (PreSE) is a risk factor for nicotine dependence, which is further enhanced by postnatal smoke exposure (PostSE). One susceptibility gene to nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine in the liver. Higher CYP2A6 activity is associated with nicotine dependence and could be regulated through DNA methylation. In this study we investigated whether PostSE further impaired PreSE-induced effects on nicotine metabolism, along with Cyp2a5, orthologue of CYP2A6, mRNA expression and DNA methylation. Using a mouse model where prenatally smoke-exposed adult offspring were exposed to cigarette smoke for 3 months, enzyme activity, mRNA levels, and promoter methylation of hepatic Cyp2a5 were evaluated. We found that in male offspring, PostSE increased PreSE-induced cotinine levels and Cyp2a5 mRNA expression. In addition, both PostSE and PreSE changed Cyp2a5 DNA methylation in male groups. PreSE however decreased cotinine levels whereas it had no effect on Cyp2a5 mRNA expression or methylation. These adverse outcomes of PreSE and PostSE were most prominent in males. When considered in the context of the human health aspects, the combined effect of prenatal and adolescent smoke exposure could lead to an accelerated risk for nicotine dependence later in life.

Highlights

University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, University of Groningen, 9713 AV Groningen, The Netherlands
In males, postnatal smoke exposure (PostSE) further enhanced the Prenatal smoke exposure (PreSE)-induced cotinine levels, (positive interaction, (p = 0.002, Figure 1A), while no interactive effects were observed between PreSE and PostSE female offspring (Figure 1B)
Cyp2a5 mRNA levels in PostSE groups (p = 0.012, Figure 1C) were increased, while no PostSE effect on mRNA was seen in female offspring (Figure 1D)

Summary

Introduction

In this study we investigated whether PostSE further impaired PreSE-induced effects on nicotine metabolism, along with Cyp2a5, orthologue of CYP2A6, mRNA expression and DNA methylation. We found that in male offspring, PostSE increased PreSE-induced cotinine levels and Cyp2a5 mRNA expression. PreSE decreased cotinine levels whereas it had no effect on Cyp2a5 mRNA expression or methylation. These adverse outcomes of PreSE and PostSE were most prominent in males. When considered in the context of the human health aspects, the combined effect of prenatal and adolescent smoke exposure could lead to an accelerated risk for nicotine dependence later in life. Human studies indicated that prenatal smoke exposure (PreSE) is associated with a higher probability of nicotine addiction [3], and a greater daily consumption of nicotine [4], as nicotine is the most prominent toxicant and psychoactive component in cigarette smoke

Methods

Results

Discussion

Conclusion