RESEARCH ARTICLE Xanthohumol ameliorates 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin– induced cellular toxicity in cultured MC3T3‐E1 osteoblastic cells Kwang Sik Suh 1 | Eun Mi Choi 1 | Hyun‐Sook Kim 2 | So Young Park 3 | Sang Ouk Chin 1 | Sang Youl Rhee 1 | Youngmi Kim Pak 4 | Wonchae Choe 5 | Joohun Ha 5 | Suk Chon 1 1 Department of Endocrinology & Metabolism, School of Medicine, Kyung Hee University, Seoul 130‐702, Republic of Korea 2 Department of Biomedical Laboratory Science, College of Health Sciences, Cheongju University, Cheongju, Chungbuk 360‐764, Republic of Korea 3 Department of Medicine, Graduate School, Kyung Hee University, Seoul 130‐702, Republic of Korea 4 Department of Physiology, Kyung Hee University, College of Medicine, Seoul 130‐ 701, Republic of Korea 5 Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130‐ 701, Republic of Korea Correspondence Suk Chon, Department of Endocrinology and Metabolism, School of Medicine, Kyung Hee University 1, Hoegi‐dong, Dongdaemun‐gu, Seoul 130‐701, Republic of Korea. Email: cemsuh@gmail.com Funding information Basic Science Research Program, Grant/Award Number: HI14C2700 Abstract 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) is an environmental contaminant. Xanthohumol is a prenylated flavonoid found in hops (Humulus lupulus) and beer. The aim of the current study was to explore the role of xanthohumol in modulating the toxicity of TCDD in MC3T3‐E1 osteoblastic cells. In cells treated with TCDD alone, intracellular Ca 2+ concentrations, mitochon- drial membrane potential disruption, reactive oxygen species production, cardiolipin peroxidation, nitric oxide release and cytochrome P450 1A1 expression were significantly increased. TCDD treatment increased the mRNA levels of extracellular signal‐regulated kinase 1 and nuclear factor kappa B, and significantly decreased the level of protein kinase B (AKT) in MC3T3‐E1 osteoblastic cells. However, the presence of xanthohumol alleviated the pathological effects of TCDD. In addition, xanthohumol treatment significantly increased the expression of genes associated with osteoblast differentiation (alkaline phosphatase, osteocalcin, osteoprotegerin and osterix). We conclude that xanthohumol has a beneficial influence and may antagonize TCDD toxicity in osteoblastic cells. KEYWORDS 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin, mitochondrial function, osteoblast, oxidative stress, xanthohumol 1 | INTRODUCTION The environmental contaminant 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) is considered to be one of the most toxic chemicals in exis- tence (Poland & Knutson, 1982). TCDD causes immunological abnor- malities, teratogenic and carcinogenic effects, wasting syndrome, alterations to the endocrine system and hepatotoxicity in several spe- cies (Aly & Khafagy, 2011; Bock & Kohle, 2006). Humans are gener- ally exposed to such compounds that are incorporated in food, drinking water, soil, dust, smoke and air. TCDD biodegrades very slowly and thus is persistent in the environment. It has been reported that the mechanism of TCDD toxicity is mediated by the aryl hydrocarbon receptor (AhR) and oxidative stress. TCDD is a pro- nounced cytochrome P450 inducer that can trigger cellular oxidative stress and lipid peroxidation (Bagchi et al., 2002; Barouki & Morel, 2001). Exposure of mice and rats to various doses of TCDD results in increased production of reactive oxygen species (ROS), lipid perox- idation and DNA damage (Jin, Hong, Lee, Kang, & Han, 2008; Reyes‐ Hernande et al., 2010). The AhR is a cytoplasmic protein that, once bound to a ligand, translocates to the nucleus and forms a heterodi- mer with the AhR nuclear translocator. The AhR/AhR nuclear translocator heterodimer then interacts with the promoter regions of Ah‐responsive genes to regulate transcription, resulting in the majority of the observed toxic effects of TCDD (Mandal, 2005). In addition to the classical mechanism described above, Enan and Matsumura (1995) demonstrated that ligand‐bound AhR activates Kwang Sik Suh and Eun Mi Choi contributed equally to this work. Received: 9 December 2017 Revised: 29 January 2018 Accepted: 30 January 2018 DOI: 10.1002/jat.3613 J Appl Toxicol. 2018;1–11. Copyright © 2018 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/jat 1