Cadmium Burden and Blood Pressure

Background Hypertension, or high blood pressure (BP) affects 1 in 3 adults worldwide and is a leading cause of cardiovascular disease. A growing body of literature has implicated toxic heavy metals, such as cadmium (Cd), as contributors to higher BP and hypertensive disorders. Cd is extensively used in production of consumer products such as batteries, pigments, coatings, metal plating, and plastic stabilizers. Cd exposure in the general population is mainly through diet (leafy greens and root vegetables) and tobacco smoke. Importantly, the human body does not have an efficient means of eliminating Cd and thus it is accumulated in the kidneys for up to 40 years. Mechanisms of Cd’s cardiovascular toxicity are not well-understood, however, the accumulation of Cd in kidney tissue increases oxidative stress through depletion of glutathione, resulting in damage to the kidney tissue and blood vessels. In addition, even though the placenta acts as a partial barrier to fetal Cd exposure, maternal Cd may damage the placenta, causing growth impairment and/or fetal programming of adverse life course cardiovascular outcomes. Existing epidemiological studies on maternal Cd burden-offspring BP as well as adult Cd burden-BP associations have been limited by a lack of longitudinal data, inadequate control of important confounders, and limited assessment of potential modifiers (e.g., genetic susceptibility or exposure to other heavy metals). More specifically, the few studies that have examined impacts of prenatal Cd burden on childhood BP in the offspring have reported inconsistent findings. No study has examined how genetic variations impact fetal susceptibility to offspring Cd-related blood pressure changes. Furthermore, studies of Cd and BP in adults are mostly cross-sectional. This dissertation aims to address these gaps in the current literature.

Objectives The three aims of the dissertation project were 1) to determine the associations between prenatal Cd burden (as measured by maternal urinary Cd (UCd)), birthweight, and blood pressure in middle childhood, 2) to examine whether associations of maternal UCd burden with offspring BP differ by offspring genotypes 3) to investigate associations between Cd (measured in toenails) and longitudinal changes in BP, as well as risk of hypertension among adults and examine for potential effect modification by zinc (Zn).

Methods This dissertation utilized data from two large cohort studies – ELEMENT and CARDIA. ELEMENT (Early Life Exposure in Mexico to Environmental Toxicants) is a birth cohort study based in Mexico City, Mexico, designed to assess the effects of environmental toxicants on pregnancy outcomes and child development. CARDIA (Coronary Artery Risk Development in Young Adults) recruited young adults (18-25 years) at four centers in the United States to study determinants and development of clinical and subclinical cardiovascular disease. Analyses to address aim #1 used a subset of the ELEMENT cohort (N=202) for which information on maternal urinary Cd and childhood BP among the offspring (age 7-15) was available. To address aim #2, we identified 113 mother-child dyads in ELEMENT with available offspring genetic data in addition to maternal urinary Cd (UCd) and offspring BP measurement in childhood. To address aim #3, we used data from 3745 participants in CARDIA, free of hypertension at baseline, with available measures of Cd in toenails, and longitudinal BP measures and the development of hypertension. To estimate associations of maternal UCd and child BP in ELEMENT, we used linear and logistic models, adjusted for covariates (child sex, age, height, postnatal UCd, maternal SES). To estimate associations of toenail Cd with BP and hypertension, we used estimating equations (GEE) and Cox proportional hazards models with interaction terms, adjusted for covariates (sex, race, education, study center, BMI, smoking status, alcohol use, physical activity). Effect modification was assessed with interaction terms and stratified analyses.

Results In ELEMENT, prenatal cadmium was not associated with birthweight (β=-41.47 grams, 95%CI: -128.03, 45.08), offspring SBP (β=-1.01 mmHg, 95%CI: -3.04, 1.00), DBP (β=-1.22 mmHg, 95%CI: -2.75, 0.29), or high BP (OR=0.65, 95%CI: 0.34, 1.23). In a subset of ELEMENT participants, we found evidence of maternal UCd and offspring genotype interaction on SBP and DBP for eight and two SNPs, respectively (interaction p-values<0.10). Maternal UCd was inversely associated with SBP among those with 0 copies of the rs5909 (HMGCR) minor allele (β=-4.61 mmHg, 95%CI: -8.84, -0.38), at least one copy of the rs10497900 (PTH2R) minor allele (β=-5.02 mmHg, 95%CI: -8.67, -1.38), and 0 copies of the rs3771452 (ADD2) minor allele (β=-9.82 mmHg, 95%CI: -17.30, -2.35, p-value < 0.05) (interaction pvalues 0.05, 0.05, and 0.02, respectively). There were suggestive (borderline) inverse associations of maternal UCd with lower DBP among those with at least one copy of the rs208272 (HMGCR) minor allele (β=-5.57 mmHg, 95%CI: -11.17, 0.03, p-value=0.05) and 0 copies of the rs4984 (ADD2) minor allele (β=-2.86 mmHg, 95%CI: -6.01, 0.29, p-value=0.07) (interaction p-values, 0.07 and 0.03, respectively). In CARDIA, toenail Cd concentration (logµg/g) was not associated with SBP (b=0.09, 95%CI: -0.18, 0.35), DBP (b=-0.06, 95%CI: -0.26, 0.15), or risk of hypertension (HR=1.02, 95%CI: 0.98,1.07). We observed evidence of potential effect modification by sex in the association of Cd with hypertension (interaction p-value =0.05). The risk of hypertension was marginally positively associated with toenail Cd among females (HR=1.06, 95%CI: 0.99, 1.13), but not males (HR=0.98, 95%CI: 0.90, 1.05). There was no interaction of Zn and Cd in associations with hypertension, SBP, or DBP (p for interaction 0.72, 0.80, 0.53, respectively).

Conclusion We did not observe a statistically significant association between maternal UCd and childhood BP in all ELEMENT participants, however, contrary to our hypothesis, we observed an inverse association between maternal UCd and SBP and DBP in a subset of the populations defined by offspring genotypes of genes associated with oxidative stress and calcium (Ca) homeostasis. We did not find an association between toenail Cd concentration and longitudinal BP changes or risk of hypertension among adults, however, there was some indication of potential effect modification by sex. Future larger studies are needed to confirm and expand on our findings. If confirmed, our findings may lead to strategies for targeting interventions and BP screening efforts.