Effects of Inorganic Arsenic, Methylated Arsenicals, and Arsenobetaine on Atherosclerosis in the [apoE.Sup.-/-] Mouse Model and the Role of As3mt-Mediated Methylation

By Silva, Luis Fernando Negro; Lemaire, Maryse et al. | Environmental Health Perspectives, July 2017 | Go to article overview

Effects of Inorganic Arsenic, Methylated Arsenicals, and Arsenobetaine on Atherosclerosis in the [apoE.Sup.-/-] Mouse Model and the Role of As3mt-Mediated Methylation


Silva, Luis Fernando Negro, Lemaire, Maryse, Lemarie, Catherine A., Plourde, Dany, Chiavatti, Alicia M. Bol Christopher, Bohle, D. Scott, Slavkovich, Vesna, Graziano, Joseph H., Lehoux, Stephanie, Mann, Koren K., Environmental Health Perspectives


Introduction

Arsenic exposure in humans is recognized as a major public health issue [Agency for Toxic Substances and Disease Registry (ATSDR) 2013; World Health Organization (WHO) 2001), where tens of millions of people worldwide are exposed at concentrations above maximum contaminant levels (Nordstrom 2002). Chronic exposure through drinking water increases the mortality rate (Argos et al. 2010) owing to the increased incidence of several cancers (Ahsan et al. 2007) (Smith et al. 2012; Tokar et al. 2011), cardiovascular disease (Moon et al. 2013), impairment of lung (Josyula et al. 2006) (Argos et al. 2014) and liver (Mazumder 2005) function, defective immune responses (Andrew et al. 2008; Dangleben et al. 2013), and diabetes (Navas-Acien et al. 2008). Of particular concern is the link between arsenic exposure and atherosclerosis. In fact, people exposed to even low concentrations of arsenic are at risk of developing atherosclerosis (Moon et al. 2013).

Arsenic is biotransformed through a series of oxidation and methylation reactions primarily catalyzed by arsenic (3) methyltransferase (As3MT) (Thomas et al. 2007). As3MT is conserved from bacteria to mammals (Thomas et al. 2007). Thus, humans are exposed to methylated intermediates generated by bacteria found in the environment (Oremland and Stolz 2003). The methylation reaction uses S-adenosyl-L-methionine (SAM) as the methyl donor and produces intermediate compounds that include both monomethylated (MMA V and MMA III) and dimethylated (DMA V and DMA III) forms of arsenate and arsenite. Several different molecular mechanisms have been proposed for the reaction, some involving glutathionylated-arsenic intermediates (Challenger 1947; Dheeman et al. 2014; Hayakawa et al. 2005). Regardless of the exact reaction, there is a consensus regarding the importance of the As3MT enzyme in arsenic methylation. As3mt knockout mice have altered retention and distribution of arsenic, with significantly decreased production of methylated intermediates (Drobna et al. 2009). Historically, this reaction was considered a detoxification process; however, it is now recognized that some intermediate species are more toxic than inorganic arsenic (Styblo et al. 2002). Nevertheless, the relative contribution of each intermediate arsenical to specific outcomes has not been defined.

The capacity to methylate arsenic has been epidemiologically linked to cardiovascular diseases. Lower methylation capacity, indicated by higher urinary MMA% or lower urinary DMA%, was associated with increased risk of fatal and nonfatal cardiovascular disease, including atherosclerosis (Chen et al. 2013b). The same group reported a linear dose-response relationship between urinary MMA% and carotid intima media thickness (cIMT), a surrogate measure of atherosclerosis, and they proposed that incomplete methylation influences atherosclerosis (Chen et al. 2013a). Importantly, human AS3MT polymorphisms were linked to differential arsenic methylation efficacy (Engstrom et al. 2011). An interaction between several AS3MT single nucleotide polymorphisms (SNPs), arsenic content in well-drinking water, and cIMT has been reported (Wu et al. 2014), although it was not statistically significant after adjusting for multiple comparisons. These data are suggestive that certain populations may be at greater risk for cardiovascular consequences of arsenic exposure.

We utilized the [apoE.sup.-/-] mouse model to address the role of arsenic biomethylation in arsenic-induced atherosclerosis. Previously, we observed increased atherosclerotic plaque formation in the [apoE.sup.-/-] mouse model after exposure to 200 ppb (parts per billion; micrograms/liter) inorganic sodium arsenite, an environmentally relevant concentration (Lemaire et al. 2011). Here, we provide data that methylated arsenicals are also proatherogenic. Importantly, we show that As3MT expression is required for arsenic-induced atherosclerosis. …

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