Chlorinated persistent organic pollutants, obesity, and type 2 diabetes

Abstract

Persistent organic pollutants (POPs) are lipophilic compounds that travel with lipids and accumulate mainly in adipose tissue. Recent human evidence links low-dose POPs to an increased risk of type 2 diabetes (T2D). Because humans are contaminated by POP mixtures and POPs possibly have nonmonotonic dose-response relations with T2D, critical methodological issues arise in evaluating human findings. This review summarizes epidemiological results on chlorinated POPs and T2D, and relevant experimental evidence. It also discusses how features of POPs can affect inferences in humans. The evidence as a whole suggests that, rather than a few individual POPs, background exposure to POP mixtures-including organochlorine pesticides and polychlorinated biphenyls-can increase T2D risk in humans. Inconsistent statistical significance for individual POPs may arise due to distributional differences in POP mixtures among populations. Differences in the observed shape of the dose-response curves among human studies may reflect an inverted U-shaped association secondary to mitochondrial dysfunction or endocrine disruption. Finally, we examine the relationship between POPs and obesity. There is evidence in animal studies that low-dose POP mixtures are obesogenic. However, relationships between POPs and obesity in humans have been inconsistent. Adipose tissue plays a dual role of promoting T2D and providing a relatively safe place to store POPs. Large prospective studies with serial measurements of a broad range of POPs, adiposity, and clinically relevant biomarkers are needed to disentangle the interrelationships among POPs, obesity, and the development of T2D. Also needed are laboratory experiments that more closely mimic real-world POP doses, mixtures, and exposure duration in humans.

Figure 1.

Interaction between BMI and POPs estimating the prevalence of T2D. A, United States (37): The summary measure of six POPs was calculated by summing individual rank of six POPs (1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin, p,p′-DDE, oxychlordane, trans-nonachlor, and PCB153). The summary measure was classified into five quintiles from Q1 to Q5. Among persons with the lowest quintile (Q1) of the summary POPs, BMI was not associated with the risk of T2D, and T2D itself was very rare even among obese. In addition, the risk of diabetes increased with increasing concentrations of POPs even among lean persons. The highest risk was observed in persons with high POPs and high BMI. B, Finland (40): Because only results based on individual POP, not summary measures of POPs, were presented in the paper, we selected trans-nonachlor, which showed the strongest association with T2D for this figure. Serum concentrations of trans-nonachlor were divided into <0th, 10-<50th, 50-<90th, and ≥ 90th percentiles. The positive associations of T2D with POPs became stronger as BMI increased, similar to those in the United States. However, obesity was associated with T2D even among persons with the lowest levels of trans-nonachlor. C, Spain (41): The summary measure of four PCBs was calculated by summing individual rank of four PCBs (PCB118, PCB138, PCB153, and PCB180). The summary measure was classified into four quartiles from Q1 to Q4. All odds ratios were computed with Q1 and normal weight as the reference category, with models adjusted by age, sex, total cholesterol, and triglycerides. Results were similar with those from Finland.

Figure 2.

Comparison of strength of associations with T2D between a summary measure of 19 POPs and gender-specific waist circumference in the PIVUS (the Prospective Investigation of the Vasculature in Uppsala Seniors) cohort study (44). The summary measure was calculated by summing the individual rank of 19 POPs. Results were recalculated using the raw dataset because the original article (44) reported results on summary measures of subclasses of POPs (PCBs or OC pesticides), not all POPs. These findings use the methodology described in the original article (44) but have not been published before. Both POPs and gender-specific waist circumference were included in the same model and adjusted for gender, physical activity, cigarette smoking, alcohol consumption, total cholesterol, and triglyceride. Statistically significant odds ratios are indicated with asterisks.

Figure 3.

Comparison of quartile vs sextile approaches to the associations between a summary measure of 31 POPs on T2D in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study (45). The summary measure was calculated by summing individual rank of 31 POPs. When the summary measure was classified into quartiles, there was no association between POPs and T2D. However, with classification into sextiles, low-dose POPs significantly predicted the future risk of T2D. The authors interpret this finding to have occurred because the sextile reference group was closer to a true hypothetical reference group without exposure to POPs than the quartile reference group. Results were adjusted for age, gender, race, BMI, total cholesterol, and triglyceride. Statistically significant odds ratios are indicated with an asterisk.

Figure 4.

Hypothetical dose-response relationship between POPs and T2D. For simplicity, monotonically increasing doses are arbitrarily numbered starting from zero: 0–2 entails no significant response; doses 3–9 induce an increased risk of T2D; a decreased risk of T2D is observed from 10–20; toxicity (including strongly adverse effects) starts above dose 20. Let us assume that the dose range 0–20 represents a general population within environmental exposure to concentrations of chemicals within the presumed safety level, determined from the linear viewpoint of toxicology. The shape of the dose-response curve differs depending on the different distributions of POPs across populations. Population A shows an inverted U-shaped association (full range of doses 0–20); population B (doses 0–9) shows a strong positive association; population C (doses 5–15) shows a null association; and population D (doses 10–20) shows an inverse association. In addition, the shape of the dose-response curve can look different depending on the sensitivity of the physiological system. A young population is expected to show a sharper inverted U-shaped association (greater y-axis range), whereas an older population would show a blunted shape (less y-axis range). An additional feature made clear in Figure 4 is attenuation of risk estimation when there is a gradient of risk within the reference category. For example, in a population with exposure doses close to 0–12, relative risk for doses 8–12 (the “at risk” group) would have a much lower relative risk if the reference group were doses 0–7 than if doses 0–2 were taken as the reference group. In epidemiological studies, the most common shape of association we can observe may be the increase of risk within lower range of dose and flattening of the risk at higher doses.

Figure 5.

Summary of postulated POPs and T2D relationship with possible mechanisms. Under the current paradigm (labeled “Traditional risk factors”), lifestyle changes characterized by excess energy intake and a lack of physical activity have led to the obesity and T2D epidemic. Inflammation in adipose tissue, lipotoxicity in liver, muscle, and pancreas, and mitochondrial dysfunction are considered to be primary mechanisms. However, adipose tissue also contains POPs because of the contaminated environment and food web. As depicted under an expanded paradigm (labeled “New risk factors”), POP mixtures consisting of several hundred compounds are stored in adipose tissue, are continuously released to circulation, and reach critical organs along with serum lipids. Human responses to POP mixtures may differ depending on levels of POPs. There can be low-dose POP mixtures that are not high enough to induce any chemical-specific responses. However, even at low doses POPs at least induce physiological responses like phase I, phase II, and phase III xenobiotic metabolism pathways aimed to increase the excretion of POPs. In particular, phase II glutathione conjugation can lead to chronic consumption and depletion of intracellular glutathione. Intracellular glutathione depletion can cause mitochondrial dysfunction that is closely related to inflammation and ectopic fat accumulation; all of these mechanisms are also known to play important roles in the pathogenesis of traditional obesity-related T2D. However, a somewhat increased dose of POP mixtures can activate increased synthesis of cytoprotective and restorative proteins, including glutathione synthesis. This activation may improve mitochondrial function, which in theory might decrease the risk of T2D. Therefore, we can expect the inverted U-shaped associations between POPs and T2D. Importantly, mitochondria function can be improved with other well-accepted health promotion behaviors like exercise, phytochemical consumption, or calorie restriction; they are traditionally known to be beneficial to prevent and/or control T2D. In the range of high-dose POPs, we can expect traditional toxicity responses. Many toxicological studies of POPs deal with this high range of POPs and focus on one specific POP. However, exposure patterns used in experimental settings are very different from human exposure patterns in terms of doses, mixtures, and exposure duration of POPs. Therefore, the relevance of experimental findings to humans is unclear. On the other hand, POPs can increase or decrease adipose hyperplasia and/or hypertrophy depending on dose or kinds of POPs. Various endocrine-disrupting mechanisms may be involved in these relationships. POPs can indirectly induce obesity through the influence on gut microbiota. However, in the risk of T2D, the worst-case scenario could be the combination of antiadipogenic chemicals and excess energy intake. Also, it is important to note that adipose tissue can play dual roles: promoting T2D, and providing a relatively safe place to store POPs.