Association of Dioxin and Dioxin-like Congeners With Hypertension
Elderly in Sweden
In a study of 1,016 Swedish men and women who were aged 70 years or older and were living in Uppsala, Sweden, Lind and colleagues calculated average supine BP from 3 sphygmomanometer measurements after 30 minutes of rest.14 The researchers used high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS) to measure the serum levels of a set of 23 POPs—16 PCB congeners, 5 OC pesticides, 1 brominated biphenyl ether congener, and octachloro-p-dibenzodioxin—and lipid-normalized the values. They used logistic regression to assess POP levels and prevalent hypertension (BP ≥ 140/90 mm Hg or use of antihypertensives), adjusting for sex, BMI, smoking status, exercise, and education. Among the COIs with the highest circulating lipid-normalized POP levels were PCB congeners 180, 138, and 170 and DDE. There was no clear relationship between toxic equivalents and hypertension; after multivariate adjustments, only DDE showed a statistically significant OR: 1.25 (95% CI, 1.07-1.47).
Organic Pollutants and Hypertension
Using National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2002, Ha and colleagues conducted a cross-sectional study of a 524-adult subset of patients who were exposed to background levels of POPs and had newly diagnosed hypertension (≥ 140/90 mm Hg).15 In the NHANES study, the CDC collected standardized patient history information, physical examination findings, and venous blood sample results. Recorded BP data points were the averages of 3 separate SBP and DBP readings from a sphygmomanometer, as recommended by the AHA. The NHANES study recorded POPs with HRGC/HRMS.
Ha and colleagues selected 12 POPs, and standardized the COI concentrations against lipid concentration. The lipid-standardized POP concentrations used were at a higher level of detection and found in at least 60% of the study patients. The researchers used a logistic regression model to calculate multivariate-adjusted OR separately in men and women, adjusting for race/ethnicity, smoking/alcohol use, physical activity, BMI, cotinine level, and income level. Among the 56 men and 67 women with newly diagnosed prevalent hypertension, PCDD levels in women were positively associated with hypertension but not correlated with higher or lower toxic equivalency factors. Dioxin and NDL-PCBs were positively associated with hypertension in men but negatively in women. Ha and colleagues postulated that this approach of studying a US population subset of patients with background exposure to POPs, instead of groups with high concentrations of exposure (eg, Vietnam War veterans or those exposed occupationally or in industrial accidents), provides an alternative observable effect of long-term, low-dose exposure of a blend of POPs.15
Discussion
In vivo and in vitro studies have found that dioxins induce a subset of 35 genes, including microsomal P450 enzymes, kinases and phosphates, and DNA repair proteins. A microarray profile of cardiovascular murine tissue and cultured vascular smooth muscle cells exposed to TCDD found known dioxin-inducible genes Cyp1b1, a phase 1 drug metabolism enzyme, and Aldh3A1, another drug metabolism gene up-regulated, among lectin-related natural killer cell receptor, insulin-like growth factor binding protein, and cyclin G2.16
Dioxins bind avidly to the aryl hydrocarbon receptor (AhR), a cytosolic transcription factor that also interacts with other xenobiotic compounds with varying affinities. TCDD is one of the most potent ligands for AhR, and other DL compounds have a lower binding affinity. AhR dimerizes in the nucleus with the AhR nuclear translocator and then binds genomic dioxin response elements and induces the expression of cytochrome P450 genes, such as CYP1A1.17
The AhRs are highly expressed in the vascular endothelium.17 Agbor and colleagues found that mice with endothelial AhR knockouts showed decreased baseline SBP and DBP.18 When challenged with angiotensin II, a potent vasoconstrictor, AhR-/- mice failed to show an increase in DBP. AhR-/- exhibited reduced ex vivo aortic contraction in the presence of angiotensin II in aortas with perivascular adipose tissue. Notably, compared with wild-type mice, AhR-/- mice had reduced renin-angiotensinsystem gene expression in the visceral adipose, linking the AhR receptor with the endogenous renin-angiotensin-aldosterone system (RAAS).
Early studies have shown that mice lacking AhR do not demonstrate TCDD toxicity.20 More recently, Kopf and colleagues found that TCDD exposure in mice led to increased BP and cardiac hypertrophy, possibly linked to increased superoxide production in the vasculature.21 When exposed to TCDD, mice showed enhanced CYP1A1 mRNA expression in the left ventricle, kidney, and aorta by day 35 and increased CYP1B1 mRNA expression in the left ventricle after 60 days. Within the first week of TCDD exposure, the mean arterial pressure for the exposure group was statistically significantly increased, showing a trend of peaks and plateaus. Mice exposed to TCDD also showed left ventricular concentric hypertrophy, which is typical of systemic hypertension.8,21 Kerley-Hamilton and colleagues found that AhR ligand activation increased atherosclerosis.22
Most hypertension is idiopathic. Research into the downstream effects of AhR suggests it induces vascular oxidative stress and increases atherosclerosis.22 It is unclear whether this is an initiating or synergistic factor in the development of hypertension. The study results described here indicate that dioxins initiate BP changes through the endothelial AhR receptor, but this mechanism has been proved only in an animal model. Ongoing studies are needed to examine the molecular changes in humans. Clinicians can be advised that dioxin exposure, rather than being an initiating factor, would at most contribute to an accumulating series of assaults, including genetics, lifestyle, and environmental factors, and that these assaults progress to hypertension only after passing a threshold.23 Moreover, many of the studies described here categorized hypertension under the guideline of 140/90 mm Hg. Future studies may use the newer guideline, which will affect their results.
