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Parental habits of betel quids chewing are dose-dependently associated with a risk of metabolic syndrome in offspring

   Betel chewing, a socially important custom, is an addictive habit recognized as causing oropharyngeal and other cancers. Chewers of the chopped nuts of the Areca catechu palm, wrapped in piper betel vine leaves or flowers [‘betel-quids’], take the habit with them across the globe and currently number ~700 million [10% of the world population]. Addictive arecal alkaloids form carcinogenic nitroso-compounds during digestion, and many nitroso-compounds induce type 2 diabetes [T2DM] at low dosages. Betel-feeding of CD1 mice induces obesity and high blood glucose in a proportion of adult mice. A community-based prospective cohort study led by Professor Chen, the Associate Dean of the College of Public Health, National Taiwan University, has revealed the association between betel quid chewing and a series of chronic diseases, including T2DM, with a 1.29-fold increased risk (95% confidence interval [CI]: 1.04, 1.60); metabolic syndrome, with a 1.78-fold increased risk (95% CI: 1.53, 2.08); liver cirrhosis and hepatocellular carcinoma, with a 4.25-fold increased risk (95% CI: 2.9, 6.2); and cardiovascular disease, with a 1.23-fold increased risk (95% CI: 1.11, 1.37), in males in Taiwan (Chen et al, 2004; Tung et al, 2004; Wu et al, 2009; Yen et al, 2006, 2008).

Transgenerational effects of betel quid chewing
   In animal studies, it has been shown that obesity and high blood glucose are induced in many offspring of betel-fed male mice, even though the offspring had never been fed Areca catechu. Similarly, Prof Chen’s team has reported the early onset of metabolic syndrome in the offspring of betel-chewing men in northern Taiwan in ~5000 families. The offspring exposed to paternal betel-quid chewing had a 2.14-fold elevated risk of early manifestations of metabolic syndrome (95% CI: 1.25, 3.66) compared with those not exposed. Moreover, the risk increased with longer or greater amounts of paternal betel chewing. The tendency remained in the absence of metabolic syndrome in either parent, with a 2.53-fold (95% CI: 1.03, 2.64) increased risk among offspring, thereby excluding the likely hereditary predisposition to metabolic syndrome (Chen et al, 2006). In view of the above evidence suggesting the transmission of an increased risk of metabolic disease to offspring by paternal Areca-nut chewing, it is of interest to determine the influence of paternal age at commencement of the betel habit since it may be associated with other risk factors, as well as whether chewing duration affects the likelihood of the offspring developing metabolic syndrome. Professor Chen and the team conducted another study of ~13,000 families across Taiwan and showed that both paternal smoking and betel chewing independently increased early-onset metabolic syndrome risks in offspring. The pre-fatherhood exposure to betel chewing and smoking increased the risk of metabolic syndrome in offspring by 77% (95% CI: 23%, 153%) and 27% (95% CI: 11%, 45%), respectively. The risk of metabolic syndrome in offspring associated with pre-fatherhood betel chewing increased dose-wise, with an elevated risk of 3.28 (95% CI: 1.67, 6.43) for 10+ years of use and 1.42 (95% CI: 0.80, 2.54) for <5 years of use. Interestingly, the group who commenced use at age 20-29 years faced a higher risk (1.95-fold, 95% CI: 1.26, 3.04) than the other age groups. A similar dose relationship was observed for pre-fatherhood smoking (Yen et al, 2016). These data should be useful in designing educational programs aimed at reducing the uptake of the habits of smoking and betel chewing and programs encouraging habit cessation among both smokers and betel chewers globally, as experimental data suggest that transgenerational transmission of early-onset metabolic syndrome, along with the associated risks, due to paternal habits falls to zero over the generations.

Interpretation
   This community-based prospective study used family pedigree-validated information to demonstrate adverse transgenerational effects of Areca nut chewing and paternal smoking, independently, on the risk of metabolic syndrome in never-chewing/smoking offspring. These findings strongly suggest an epigenetic influence attributable to pre-fatherhood Areca nut usage and pre-conception paternal smoking. This postulate is strongly supported by the higher risk of an early manifestation of metabolic syndrome associated with pre-fatherhood versus post-fatherhood exposure to both factors and by the effects of a longer duration of Areca nut and smoking exposure, together with an earlier age of exposure to Areca nuts. These are powerful criteria that support the suggestion of a causal relationship between these environmental risk factors and the adverse health outcomes of offspring metabolic syndrome, with all the associated health risks.

References
1. Chen, T. H., Chiu, Y., Luh, D., Yen, M., Wu, H., Chen, L., . . . Chen, C. (2004). Taiwan Community-based Integrated Screening Group. Community-based multiple screening model: design, implementation, and analysis of 42,387 participants. Cancer, 100(8), 1734-1743. DOI:10.1002/cncr.20171
2. Chen, T. H., Chiu, Y., and Boucher, B. J. (2006). Transgenerational effects of betel-quid chewing on the development of the metabolic syndrome in the Keelung Community-based Integrated Screening Program (KCIS no. 8). The American Journal of Clinical Nutrition, 83(3), 688-692. DOI:10.1093/ajcn.83.3.688
3. Tung, T., Chiu, Y., Chen, L., Wu, H., Boucher, B. J., and Chen, T. H. (2004). A population-based study of the association between areca-nut chewing and type 2 diabetes mellitus in men (KCIS No. 2). Diabetologia, 47(10), 1776-1781. DOI:10.1007/s00125-004-1532-2
4. Wu, G. H., Boucher, B. J., Chiu, Y., Liao, C., and Chen, T. H. (2009). Impact of chewing betel-nut (Areca catechu) on liver cirrhosis and hepatocellular carcinoma: a population-based study from an area with a high prevalence of hepatitis B and C infections. Public Health Nutrition, 12(01), 129. DOI:10.1017/s1368980008002073
5. Yen, A. M., Chiu, Y., Chen, L., Wu, H., Huang, C., Boucher, B. J., and Chen, T. H. (2006). A population-based study on the association between betel quid chewing and the metabolic syndrome in men. The American Journal of Clinical Nutrition, 83(5), 1153-1160. DOI:10.1093/ajcn/83.5.1153
6. Yen, A. M., Chen, L., Chiu, Y., Boucher, B. J., and Chen, T. H. (2008). A prospective community-population-registry based cohort study of the association between betel-quid chewing and cardiovascular disease in men in Taiwan (KCIS no. 19). The American Journal of Clinical Nutrition, 87(1), 70-78. DOI:10.1093/ajcn/87.1.70

Hsiu-Hsi Chen
Professor, Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University
chenlin@ntu.edu.tw

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Parental habits of betel quids chewing are dose-dependently associated with a risk of metabolic syndrome in offspring

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