Association between exposures to brominated trihalomethanes, hepatic injury and type II diabetes mellitus Konstantinos C. Makris a, ⁎, Xanthi D. Andrianou a , Pantelis Charisiadis a , James B. Burch b,e,f , Ratanesh K. Seth c , Androniki Ioannou a , Michael Picolos d , Costas A. Christophi a , Saurabh Chatterjee c, ⁎⁎ a Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus b South Carolina Statewide Cancer Prevention & Control Program, University of South Carolina, Columbia, SC, USA c Environmental Health & Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA d Endocrinology Clinic, Nicosia, Cyprus e Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA f Dorn Department of Veterans Affairs Medical Center, Columbia, SC, USA abstract article info Article history: Received 5 January 2016 Received in revised form 7 April 2016 Accepted 8 April 2016 Available online xxxx Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder in the Western world, commonly diagnosed in the majority of obese patients with type 2 diabetes mellitus (T2DM). Metabolic disrupting chemicals with short half-lives, such as those of halogenated structure (trihalomethanes, THM) have been linked with hepatic insulin resistance phenomena in animal studies. However, human studies evalu- ating the role of THM exposure on liver pathogenesis and T2DM disease process are scarce. The objectives of this study were to: i) determine the association of urinary brominated THM (BrTHM) levels and T2DM disease status, and ii) investigate the association between urinary BrTHM levels and serum alanine aminotransferase (ALT) con- centrations, often used as surrogate markers of NAFLD. A pilot case–control study was conducted in Nicosia, Cyprus (n = 95). Cases were physician-diagnosed T2DM patients and controls were healthy individuals. Liver enzymes, leptin and TNF-α were measured in sera, while urinary THM levels were measured using tandem mass spectrometry. Diabetics had higher levels of serum leptin, body mass index and ALT than the controls. Among all study participants those with serum ALT levels above the median (17 IU/L) had higher mean tribromomethane (TBM) concentrations compared to those with serum ALT below 17 IU/L. A significant increase in the odds of having above the median serum ALT levels [OR 6.38, 95% CI: 1.11, 42.84 (p = 0.044)] was observed for each unit increase in creatinine-unadjusted urinary TBM levels, along with BMI and past smoking, after adjusting for possible confounders, such as urinary creatinine, age, sex, and leptin; no other THM compound showed a significant association with serum ALT. Logistic regression models for T2DM using the urinary BrTHM as exposure variables did not reach the predetermined level of significance. The interplay between expo- sures to BrTHM and the initiation of key pathophysiological events relating to hepatic injury (ALT) and inflamma- tion (leptin) was recognized via the use of selected biomarkers of effect. Our evidence that THM could act as hepatic toxins with a further initiation of diabetogenic effects call for additional studies to help us better under- stand the disease process of the two co-morbidities (NAFLD and T2DM). © 2016 Elsevier Ltd. All rights reserved. Keywords: Brominated trihalomethanes Fatty liver Non-alcoholic Diabetes Disinfection byproducts Inflammation Obesity Environment International 92–93 (2016) 486–493 Abbreviations: ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; BDCM, Bromodichloromethane; BrTHM, Brominated THM species; DBCM, Dibromochloromethane; ELISA, Enzyme-linked immunosorbent assay; EU, European Union; LOD, Limit of detection; LOQ, Limit of quantification; NAFLD, Non-alcoholic fatty liver dis- ease; NASH, Non-alcoholic steatohepatitis; T2DM, Type 2 diabetes melllitus; TBM, Tribromomethane; TCM, Trichloromethane; THM, Trihalomethanes; TTHM, Sum of all THM species. ⁎ Correspondence to: K. C. Makris, Water and Health Laboratory, Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Irenes 95, Limassol 3041, Cyprus. ⁎⁎ Correspondence to: S. Chatterjee, Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, 915 Greene Street, Discovery I Bldg., Columbia, SC 29208, USA. E-mail addresses: konstantinos.makris@cut.ac.cy (K.C. Makris), schatt@mailbox.sc.edu (S. Chatterjee). http://dx.doi.org/10.1016/j.envint.2016.04.012 0160-4120/© 2016 Elsevier Ltd. All rights reserved. Contents lists available at ScienceDirect Environment International journal homepage: www.elsevier.com/locate/envint