Biometals DOI 10.1007/s10534-015-9823-2 Mercury and metabolic syndrome: a review of experimental and clinical observations Alexey A. Tinkov • Olga P. Ajsuvakova • Margarita G. Skalnaya • Elizaveta V. Popova • Anton I. Sinitskii • Olga N. Nemereshina • Evgenia R. Gatiatulina • Alexandr A. Nikonorov • Anatoly V. Skalny Received: 17 November 2014 / Accepted: 15 January 2015 Ó Springer Science+Business Media New York 2015 Abstract A significant interrelation between heavy oxidative stress may occur due to both prooxidant metal exposure and metabolic syndrome (MetS) action of the metal and decrease in antioxidant development has been demonstrated earlier. Despite enzymes. Despite the absence of direct indications, it the presence of a number of works aimed at the can be proposed that mercury may induce endoplas- investigation of the role of Hg in MetS development, mic reticulum stress. As it is seen from both in vivo the existing data remain contradictory. Therefore, the and in vitro studies, mercury is capable of inducing primary objective of the current work is to review the inflammation. The reviewed data demonstrate that existing data regarding the influence of mercury on mercury affects universal pathogenetic mechanisms of universal mechanisms involved in the pathogenesis of MetS development. Moreover, multiple investigations the development of MetS and its components. The have indicated the role of mercury in pathogenesis of brief chemical characterization of mercury is pro- MetS components: dyslipidemia, hypertension, insu- vided. The role of mercury in induction of oxidative lin resistance, and obesity to a lesser extent. The stress has been discussed. In particular, Hg-induced present state of data regarding the interrelation & A. A. Tinkov ( ) Á A. V. Skalny M. G. Skalnaya Á A. V. Skalny Laboratory of Biotechnology and Applied Russian Society of Trace Elements in Medicine, ANO Bioelementology, Yaroslavl State University, Sovetskaya ‘‘Centre for Biotic Medicine’’, Zemlyanoy Val st. 46, st., 14, Yaroslavl 150000, Russia Moscow 105064, Russia e-mail: [email protected] A. I. Sinitskii A. A. Tinkov Á E. V. Popova Á O. N. Nemereshina Á Department of Chemistry of the Pharmaceutical Faculty, E. R. Gatiatulina Á A. A. Nikonorov South Ural State Medical University, Vorovskogo st., 64, Department of Biochemistry, Orenburg State Medical Chelyabinsk 453092, Russia Academy, Sovetskaya st., 6, Orenburg 460000, Russia A. V. Skalny O. P. Ajsuvakova Institute of Bioelementology (Russian Satellite Centre of Department of Chemistry, Orenburg State Agrarian Trace Element—Institute for UNESCO), Orenburg State University, Chelyuskintsev st., 18, Orenburg 460014, University, Pobedy Ave. 13, Orenburg 460352, Russia Russia O. P. Ajsuvakova Department of Chemistry and Methods of Chemistry Teaching, Orenburg State Pedagogical University, Sovetskaya st., 19, Orenburg 460014, Russia 123 Biometals between mercury and MetS denotes the following universal mechanisms taking part both in development perspectives: (1) Further clinic-epidemiologic and of MetS itself and its components. Particularly, a tight experimental studies are required to estimate the relationship between MetS and oxidative stress has association between mercury exposure and the devel- been demonstrated (Furukawa et al. 2004; Roberts and opment of MetS components, especially obesity; (2) Sindhu 2009; Youn et al. 2014). This process also plays Additional investigations of the possible effect of a significant role in pathogenesis of obesity (Matsuz- organism’s mercury content modulation on MetS awa-Nagata et al. 2008; Ferna´ndez-Sa´nchez et al. pathogenesis should be undertaken. 2011), insulin resistance (Matsuzawa-Nagata et al. 2008; Ceriello and Motz 2004), hypertension (Zalba Keywords Mercury Á Toxicity Á Obesity Á Insulin et al. 2001; Vaziri and Rodrı´guez-Iturbe 2006) and resistance Á Hypertension Á Dyslipidemia Á dyslipidemia (Rizzo et al. 2009; Matsuda and Shi- Atherosclerosis momura 2013). Endoplasmic reticulum stress (ERS) is also postulated to be a universal mechanism playing a significant role in the development of a number of MetS-related pathologies (Ba´nhegyi et al. 2007). Introduction Despite limited data indicating its role in MetS (Sage et al. 2012; Xia et al. 2012), a wide number of works Metabolic syndrome (MetS) is a complex metabolic have demonstrated the importance of ERS in patho- disturbance associated with obesity (Eckel et al. genesis of individual components of MetS (Ozcan et al. 2005). Final understanding of MetS was formed by 2004; Young et al. 2012; Cnop et al. 2012; Basseri and Reaven in 1988 (Reaven 1988; 1993), while the Austin 2012; Santos et al. 2014). At the same time, conception of MetS existed for more than 80 years due inflammatory reaction is considered to be one of the to multiple observations (Cameron et al. 2004). key mechanisms of MetS development (Romeo et al. Despite the presence of a great number of MetS 2012). It is also important to note that inflammation is definitions (Oda 2012), general criteria for this state interrelated both with oxidative (Pillarisetti and Sax- are dyslipidemia, arterial hypertension, glucose dy- ena 2004) and ERS (Zhang and Kaufman 2008). shomeostasis and insulin resistance, and obesity During a long period of time genetic predisposition, (Kassi et al. 2011). Some classifications propose a excessive caloric consumption and sedentary lifestyle number of other additive criteria like impaired uric were considered to be the main risk factors of MetS acid metabolism, prothrombotic factors, inflammatory development (Zhang et al. 2009). However, recent and endothelial dysfunction markers, and microalbu- research indicated a substantial role of environmental minuria (Parikh and Mohan 2012). factors in the development of this syndrome (Lind MetS has a significant socio-economic impact due et al. 2013). Particularly, a significant interrelation to its strong relation to mortality. Particularly, a between heavy metal exposure and MetS development significant association between the presence of MetS has been demonstrated (Moon 2014). and cardio-vascular mortality has been indicated in In particular, a wide investigation of 2,114 adults Russia (Sidorenkov et al. 2010), Finland (Lakka et al. occupationally not exposed to Hg compounds dem- 2002), Japan (Kondo et al. 2011), and USA (Malik onstrated a significant relationship between blood et al. 2004). At the same time, the incidence of MetS mercury levels and body mass index (BMI), waist has been increased rapidly from 1999 to 2006 circumference, systolic and diastolic arterial pressure, (Mozumdar and Liguori 2011). Despite a certain fasting blood glucose and triglycerides (TG) (Eom decrease (from 25.5 to 22.9 %) in 2010 (Beltra´n- et al. 2014). Investigation of hair metal content in 343 Sa´nchez et al. 2013), the incidence of MetS in adults people also indicated that persons suffering from MetS remains high. It is also important to note the preva- are characterized by a significant 70 % increase in hair lence of MetS in children and adolescents also is mercury in comparison to healthy subjects. Moreover, increasing to high levels (Friend et al. 2013). statistical analysis revealed a close relationship Due to a presence of multiple components of the between hair mercury levels and the risk of MetS MetS, its pathogenesis involves a wide number of development (Park et al. 2009). Within the National mechanisms. However, current data allow to mark out Health and Nutrition Examination Survey (NHANES) 123 Biometals 2003–2004 analysis a substantial interrelationship High stability of d10 electron shell determines the between the increasing mercury levels and alanine difficulty of the third electron detachment (Eliav et al. aminotransferase (ALT) has been shown, that can be 1995). A high value of the third ionization potential is indicative of non-alcoholic fatty liver disease (NA- indicative of this property (3,300 kJ/mol). Mercury FLD) (Cave et al. 2010). A close pathogenetic virtually does not form compounds with the unoccu- interplay between NAFLD and MetS (Vanni et al. pied d-sublevel. Consequently, the oxidation rate of 2010) may also be indicative of the role of mercury in ?2 is the most stable for mercury atom. At the same MetS development. At the same time, the Korea time, in contrast to zinc and cadmium, for which ?2 National Health and Nutrition Examination Survey oxidation rate is more characteristic, in a number of (KNHANES) 2005–2010 data have demonstrated the compounds mercury may have the oxidation number lack of significant relationship between blood mercury of ?1 (Kunkely and Vogler 1989). The presence of levels and both MetS and its individual components occupied d-sublevel increases the covalent character (Lee and Kim 2013). Therefore, despite the presence of mercury compounds, particularly halides. The of a number of works aimed at the investigation of the formation of di-, tri- and tetranuclear clusters 2? 2? 2? role of Hg in MetS development, the existing data (Hg2 ,Hg3 ,Hg4 ) (Gillespie et al. 1984)is remain contradictory. characteristic for mercury due to the presence of Moreover, investigation of various aspects of covalent Hg–Hg bonds. In accordance with the mercury toxicology is particularly important due to a expressed ability to form covalent bonds, mercury wide distribution of mercury compounds in the forms a wide spectrum of metalloorganic compounds environment (Bender et al. 2013). In particular, recent (Cotton et al. 1999; Greenwood and Earnshaw 1997). data have