Elsevier

Toxicology Letters

Volume 312, 15 September 2019, Pages 148-156
Toxicology Letters

Biomarkers of cadmium, lead and mercury exposure in relation with early biomarkers of renal dysfunction and diabetes: Results from a pilot study among aging Canadians

https://doi.org/10.1016/j.toxlet.2019.05.014Get rights and content

Highlights

  • Cd, Pb and Hg levels were measured in urine and blood from 70 aging canadians.

  • Metabolomic profiles were determined for T2D-related branched chain amino acids.

  • Biomarkers of early renal dysfunction and risk of T2D were also measured.

  • Linear and structural equation models were performed between measured biomarkers.

  • Results suggest relations between urinary Cd or Hg, with KIM or RBP and adiponectin.

Abstract

Cadmium (Cd), lead (Pb) and mercury (Hg) are known nephrotoxicants that have been associated with the risk of developing type-2 diabetes (T2D). The aim of this pilot study was to explore relations between biomarkers of Cd, Pb and Hg exposure, early urinary biomarkers of renal dysfunction (kidney-injured molecule-1 (KIM-1), N-acetylglucosaminidase and retinol-binding protein (RBP)) and plasma biomarkers deemed predictive of the risk of developing T2D (adiponectin, leptin, branched-chain and aromatic amino acids), among 70 participants (age range: (46–87 yrs)) from the Canadian Longitudinal Study on Aging (CLSA) with normal glycemic control (glycated haemoglobin ≤ 6.5%) in all but four of them. Significant (p < 0.05) Spearman correlation coefficients were obtained between: plasma adiponectin and RBP (r = 0.42), urinary Cd (r = 0.32), blood Cd (r = 0.36); KIM-1 and CdU (r = 0.33) as well as HgU (r = 0.37); RBP and isoleucine (r = -0.28), leucine (r = -0.33), tyrosine (r = -0.3) and valine (r = -0.44); CdU and isoleucine and valine (r = -0.27 for both). Multiple linear regression analyses showed that some T2D-related biomarkers are confounders of associations between RBP and Hg or Cd biomarkers. Path analyses support a mediating effect of adiponectin on the relation between urinary Cd and RBP. Concluding, this pilot study originally investigated a comprehensive set of biomarkers on complex interactions between toxic metal exposure, renal function and T2D in a group of aging Canadians. Its findings warrant further investigation of longitudinal data in a greater number of participants.

Introduction

The aging demography results in elders becoming an ever-growing proportion of the population in western countries. As a result, an always increasing burden of disease is attributable to age-related chronic diseases, such as chronic kidney disease and type-2 diabetes (T2D) (Kirkman et al., 2012; McQueen et al., 2017; Zimbudzi et al., 2016). Although little is known regarding health risks from exposure to environmental toxicants in elders, this subpopulation can reasonably be presumed as more sensitive to chemicals than younger adults. Indeed, pre-existing health conditions (e.g. reduced kidney function, bone demineralization) can influence the determinants of toxicokinetics such that elders may exhibit a greater internal dose of toxicants for a given external exposure (Clewell et al., 2002; Risher et al., 2010). These pre-existing conditions, as well as other age-related diseases, can also be worsen by the intrinsic toxicity of such metals. More specifically, cadmium (Cd), lead (Pb) and mercury (Hg) share the common characteristic to be known nephrotoxicants that have also been associated with T2D or its determinants and other components of the cardiometabolic syndrome in animal studies or epidemiological settings (Barregard et al., 2014; Chen et al., 2013; Edwards and Prozialeck, 2009; Ettinger et al., 2014; Feng et al., 2015; González-Villalva et al., 2016; Huang et al., 2013a, b; Padilla et al., 2010; Schwartz et al., 2003; Tyrrell et al., 2017). However, the overall weight-of evidence appears inconclusive in view of other epidemiological studies in which no such associations were obtained (Barregard et al., 2013; Borné et al., 2014).

Both exposure and adverse health effects can be monitored in humans by means of biomarkers. While urinary β-2-μglobulin is a common marker of kidney damage, concentrations of kidney injury molecule (KIM-1), n-acetylglucosaminidase (NAG) and retinol-binding protein (RBP) in urine are extensively used as biomarkers of early kidney dysfunction (Prozialeck and Edwards, 2010; Ruangyuttikarn et al., 2013). Besides, the ratio of leptin / adiponectin plasma concentrations have been shown to be predictive of the risk of developing T2D later in life, as leptin concentrations represent a risk factor and adiponectin concentrations, a protective factor (Lilja et al., 2012; Thorand et al., 2010). Recent investigations using metabolomics have revealed that plasma concentrations of branched-chain amino acids― (BCAA), namely leucine (Leu), isoleucine (Isol), and valine (Val), as well as aromatic amino acids phenylalanine (Phe) and tyrosine (Tyr) ― constitute early predictors of T2D development (Wang et al., 2011).

The Canadian Longitudinal Study on Aging (CLSA, https://www.clsa-elcv.ca/) will follow, during at least 20 years, approximately 50,000 Canadian men and women aged between 45 and 85 at recruitment (Kirkland et al., 2015). CLSA is collecting information on the several biological and medical characteristics among 30,000 participants who periodically provide biological samples (urine, blood) that are stored in a biorepository for future analyses. This biobank represents a unique opportunity to analyse biomarkers of exposure and effects of toxic metals, therefore contributing to elucidate the role of lifetime exposure to Cd, Pb and Hg in the pathogenesis of T2D, which in turn impacts on the renal function, as people age. Biomonitoring data from the Canadian Health Measures Survey have also shown significantly higher levels of Cd and Pb in participants over 60 yrs old as compared to adults younger than 40, but that was not the case for Hg (Health Canada, 2015). Therefore, we performed a pilot study on a subset of CLSA’s biobanked samples obtained from participants exhibiting adequate glycemic control based on the percentage of glycated haemoglobin (HbA1c), with the objective of exploring the relations between biomarkers of exposure to Cd, Pb and Hg and early effect biomarkers that are predictive of the future risk of diabetes and kidney injury.

Section snippets

Laboratory analyses

Random spot biological samples provided by 70 CLSA participants were accessed via CLSA’s biobank, for a total of 70 blood and 69 urine samples. They were shipped to the Centre de Toxicologie du Québec for laboratory analyses. Metal concentrations in blood and urine were analyzed by inductively coupled plasma mass spectrometry, whereas creatinine in urine was measured using the colorimetric end-point Jaffe method, all of which is further detailed by Health Canada (2010). Limit of detection (LOD)

Results

Table 1 presents the characteristics of the participants. The age span of the participants was 48–82 in men (n = 42) and 46–87 in women (n = 28), which covers the range of age groups targeted by CLSA recruitment. Geometric mean BMI of 28.5 kg in males and 26.6 kg in females suggest a slight overweight in general, and only 4 participants were current smokers (all men) at the time of the sampling. Half of the remaining participants have a history of tobaccoism though. All but one participant had

Discussion

This pilot study investigated for the first time a comprehensive set of biomarkers linked to toxic metal exposure, renal function and T2D in a group of aging Canadians. The incorporation of risk factors for T2D in a study also examining biomarkers for renal injury and known nephrotoxic metals appears as especially novel. In particular, metal exposure biomarkers are hypothesized as “effectors”, in that they are assumed to reflect the metal exposures that may cause an adverse toxic effect.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests.

Acknowledgements

INSPQ’ s internal funds and CTQ laboratory services are acknowledged, as well as Denis Hamel, from BIESP, for his all-around coordination of statistical support. The authors declare they have no conflicts of interests.

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