Carotid Intima-Media Thickness and Plasma Asymmetric Dimethylarginine in Mexican Children Exposed to Inorganic Arsenic

Abstract

Background: Arsenic exposure is a risk factor for atherosclerosis in adults, but there is little information on arsenic and early risk biomarkers for atherosclerosis in children. Carotid intima-media thickness (cIMT) is an indicator of subclinical atherosclerotic burden that has been associated with plasma asymmetric dimethylarginine (ADMA), a predictor of cardiovascular disease risk.Objectives: The aim of this study was to investigate associations of arsenic exposure with cIMT, ADMA, and endothelial adhesion molecules [soluble intercellular cell adhesion molecule-1 (sICAM-1); soluble vascular cell adhesion molecule-1 (sVCAM-1)] in children who had been exposed to environmental inorganic arsenic (iAs).Methods: We conducted a cross-sectional study in 199 children 3–14 years of age who were residents of Zimapan, México. We evaluated cIMT using ultrasonography, and plasma lipid profiles by standard methods. We analyzed ADMA, sICAM-1, and sVCAM-1 by ELISA, and measured the concentrations of total speciated arsenic (tAs) in urine using hydride generation cryotrapping atomic absorption spectrometry.Results: In the multiple linear regression model for cIMT, tAs categories were positively associated with cIMT increase. The estimated cIMT diameter was greater in 35- to 70-ng/mL and > 70-ng/mL groups (0.035 mm and 0.058 mm per 1-ng/mL increase in urinary tAs, respectively), compared with the < 35-ng/mL group. In addition to tAs level, plasma ADMA was a significant predictor of cIMT. In the adjusted regression model, cIMT, percent iAs, and plasma sVCAM-1 were significant predictors of ADMA levels (e.g., 0.419-μmol/L increase in ADMA per 1-mm increase in cIMT).Conclusions: Arsenic exposure and plasma ADMA levels were positively associated with cIMT in a population of Mexican children with environmental arsenic exposure through drinking water.Citation: Osorio-Yáñez C, Ayllon-Vergara JC, Aguilar-Madrid G, Arreola-Mendoza L, Hernández-Castellanos E, Barrera-Hernández A, De Vizcaya-Ruíz A, Del Razo LM. 2013. Carotid intima-media thickness and plasma asymmetric dimethylarginine in Mexican children exposed to inorganic arsenic. Environ Health Perspect 121:1090–1096; http://dx.doi.org/10.1289/ehp.1205994

Mechanisms of action for arsenic in cardiovascular toxicity and implications for risk assessment

“…Numerous studies have assessed subclinical and intermediate cardiovascular endpoints that are surrogate endpoints commonly utilized in cardiovascular research, such as blood pressure/ hypertension (e.g., Guha Mazumder et al, 2012;Islam et al, 2012;Kim and Lee 2011;Jones et al, 2011;Chen et al, 2007;Kwok et al, 2007), QT prolongation (the QT interval on a surface electrocardiogram represents the depolarization and subsequent repolarization of the heart's ventricles, and as the interval lengthens, an individual is at greater risk for ventricular tachyarrhythmias) and other arrhythmic changes (e.g., Wang et al, 2009;Mordukhovich et al, 2009;Yildiz et al, 2008;Chen et al, 2007a), and intima media thickness (iMT) (e.g., Wang et al, 2009;Chen et al, 2006Chen et al, , 2013cOsorio-Yáñez et al, 2013). For each of the aforementioned changes, results are inconsistent, even at moderate to high exposure levels.…”

Arsenic Exposure and Subclinical Endpoints of Cardiovascular Disease

“…These increases were also seen with increasing proportion of urinary monomethylarsonic acid (MMA%), the most toxic arsenic metabolite, and every 10% increase in MMA% was related to an increase of 12.1 μm (95% CI: 0.4, 23.8) in cIMT. More recently, in a cross-sectional study of 199 children 3–14 years of age in México, total urinary arsenic was positively associated with increases in cIMT, with a 35-μm and 58-μm increase in cIMT among children exposed to 35–70 μg/L and > 70 μg/L total urinary arsenic, respectively, compared with those exposed to < 35 μg/L [55]. Although cross-sectional, these data strongly support a role for arsenic exposure in subclinical atherosclerosis, at both high and low-to-moderate levels.…”

“…A recent study in West Bengal ( n = 91) showed that individuals chronically exposed to arsenic (mean 218 μg/L in well water) had significantly higher MPO activities in serum than the unexposed group, however, no further dose-response relation was found among the exposed group [85]. The only study among children from México found that the proportion of InAs was significantly associated with asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase that could lead to endothelial dysfunction and cardiovascular events [55]. However, total arsenic levels were not associated with ADMA.…”

“…Conversely, another study found a dose-response relationship between serum levels of TC, HDL, LDL, and TG, and carotid atherosclerosis in this high exposure area of Taiwan [50]. In the pediatric population of México, plasma lipids were not correlated with total urinary arsenic [55], indicating that arsenic-mediated early effects on atherogenesis may be independent of the lipid profiles.…”

Effect of Celergen, a marine derivative, on in vitro hepatocarcinogenesis

“…This data is in contrast with the albeit isolated clinical report of Chua et al (14) suggesting an arsenic-related hepatocarcinogenesis effect of the same compound. However, that study bears the main methodological bias in that the authors measured the whole arsenic content, while the literature has clearly demonstrated that only the inorganic component is the one with the noxious effect (28) and the only one deserving monitoring from major epidemiological studies (29,30). On the contrary, the organic one is regarded as safe (31) and its concentration may also vary (32) as probably occurred in their study.…”