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

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.

Toxic effects of smokeless tobacco on female reproductive health: A review

“…Long term consequences of prenatal exposure to gutkha were demonstrated in mice, where the adult male offspring exposed to a high fat diet developed histological evidence of non-alcoholic fatty liver disease in addition to significant alterations in hepatic fibrosis-related cytokines (interleukin (IL)-1b and IL-6) and in hepatic collagen mRNA expression levels compared to control (non-exposed) group ( Doherty Lyons et al, 2020 ). A mouse model for prenatal nicotine exposure from sources such as smoking and ST was used by Zhu et al (2012) to investigate predisposition of offspring to cognitive disabilities such as deficit hyperactivity disorder (ADHD) and conduct disorder later in life.…”

“… Name of Product Country/Region of prevalent use Product composition Reference Afzal Oman Tobacco leaves in crushed powder form Al-Mukhaini et al, 2016 Chimo Venezuela Tobacco, sodium bicarbonate, brown sugar, Mamón tree ashes Stanfill et al, 2011 Gutkha India Iran Mixture of betel leaf, areca nut, slaked lime, catechu, spices, sweet or savory flavorings (aka betel quid) and dried tobacco. Doherty Lyons et al, 2020 Iq'mik Alaska, USA A homemade mixture of tobacco leaves and tree fungus ash Patten et al, 2020 Khaini India Nepal Tobacco and slaked lime mixture Zhao et al, 2021 Maras Turkey Tobacco leaves mixed with the ashes of wood – especially oak, walnut, or grapevine –, in approximate ratios of 1:2 or 1:3. Taş and Güre, 2020 Mishri India Tobacco roasted on a hot metal plate until it is uniformly black and made in to powder Ganganahalli et al, 2017 Moist snuff USA Tobacco, flavoring, inorganic salts, humectants Wang et al, 2021 Nass Iran Afghanistan Pakistan A mixture of tobacco leaves and substances such as lime and ash Sighaldeh and Charkazi, 2018 Naswar Pakistan Iran A mixture of tobacco, ash and slaked lime added with condiments like green cardamom and mint Ahmad et al, 2021 Nuffa/nafha Northern Africa (Tunisia, Libya, Algeria, Mororcco, Algeria) Finely powdered tobacco IARC, 2007 Qiwam Bangladesh India A thick tobacco paste mixed with powdered spices (saffron, cardamom, aniseed and musk) …”