Prenatal Exposure to Gutkha, a Globally Relevant Smokeless Tobacco Product, Induces Hepatic Changes in Adult Mice.

Shannon Doherty Lyons,Daniel J J Conklin,Francesca Gany,M Isabel Fiel,Jason L Blum,Carol Hoffman-Budde,Joseph A Odin,Pamela B Tijerina,Judith T Zelikoff

doi:10.3390/ijerph17217895

Abstract

Maternal exposures during pregnancy affect the onset and progression of adult diseases in the offspring. A prior mouse study indicated that maternal tobacco smoke exposure affects hepatic fibrosis in adult offspring. Gutkha, a broadly used smokeless tobacco (ST) product, is widely used by pregnant woman in many countries. The objective of this murine study was to evaluate whether oral maternal exposure to gutkha during pregnancy alters non-alcoholic fatty liver disease (NAFLD) in adult offspring: risk factors for the progression of NAFLD to cirrhosis in adults remain elusive. Buccal cavity ‘painting’ of pregnant mice with gutkha began on gestational days (GD) 2–4 and continued until parturition. Beginning at 12 weeks of age, a subset of offspring were transitioned to a high-fat diet (HFD). Results demonstrated that prenatal exposure to gutkha followed by an HFD in adulthood significantly increased the histologic evidence of fatty liver disease only in adult male offspring. Changes in hepatic fibrosis-related cytokines (interleukin (IL)-1b and IL-6) and in hepatic collagen mRNA expression were observed when comparing adult male offspring exposed to gutkha in utero to those not exposed. These findings indicate that maternal use of gutkha during pregnancy affects NAFLD in adult offspring in a sex-dependent manner.

Highlights

The estimated global prevalence of non-alcoholic liver disease (NAFLD) is currently 25% in the adult population [1] which parallels the increase in obesity and the spread of high-fat western diets.The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis, through steatohepatitis (SH; fatty liver with inflammation), to cirrhosis
Maternal serum cotinine levels were measured on gestational days (GD) 16 and used as a biomarker of gutkha exposure
Hepatic cytokine levels were significantly affected by prenatal gutkha exposure in the adult male offspring on the control diet

Summary

Introduction

The estimated global prevalence of non-alcoholic liver disease (NAFLD) is currently 25% in the adult population [1] which parallels the increase in obesity and the spread of high-fat western diets. The spectrum of NAFLD ranges from simple steatosis (i.e., fatty liver), through steatohepatitis (SH; fatty liver with inflammation), to cirrhosis (i.e., liver inflammation with fibrosis). Of those with NAFLD have non-alcoholic steatohepatitis (NASH) [1]. It remains unclear why only a proportion of those with NAFLD have more advanced NASH. Cytokine activation of collagen-producing hepatic stellate cells leads to increased hepatic inflammation and fibrosis characteristic of NASH [2]. Res. Public Health 2020, 17, 7895; doi:10.3390/ijerph17217895 www.mdpi.com/journal/ijerph

Methods

Discussion

Conclusion