In this paper we continued our examination of the relationships between serum concentrations of POPs and the prevalence of diabetes  and insulin resistance  by studying associations between POP concentrations and the prevalence of metabolic syndrome among non-diabetic participants. Among five subclasses of POPs, dioxin-like PCBs, non-dioxin-like PCBs and OC pesticides were significantly associated with metabolic syndrome, although dose–response shapes varied depending on POPs subclass. In particular, OC pesticides were most strongly associated with metabolic syndrome with a linear dose–response relationship. Similarly to metabolic syndrome, OC pesticides were also most strongly associated with type 2 diabetes and insulin resistance in our previous studies [5, 6]. However, dioxin-like PCBs showed a dose–response relationship with a plateau, while non-dioxin-like PCBs showed an inverted U-shaped relationship.
The inverted U-shaped associations observed with non-dioxin-like PCBs deserve further discussion. Considering the consistency with all specific POPs belonging to non-dioxin-like PCBs, this association may be real. This observation appears to be consistent with the association between POPs and diabetes, because this association was much steeper across lower background concentrations than across higher background concentrations [5, 7]. In agreement with this concept, others have reported that endocrine disrupters such as bisphenol A can show a non-monotonic dose–response or even an inverted U-shaped association ; POPs are well-known endocrine disrupters. In addition, there was one experimental study in which increasing toxicity with increasing doses of some PCBs was even followed by a plateau or a decrease of toxicity in higher doses of them . There should be further studies of the question whether exposure to low doses of PCBs can be more harmful than the exposure to high doses to PCBs.
However, there were some differences between the association of POPs with metabolic syndrome and the associations of POPs with either insulin resistance or type 2 diabetes. When specific POPs were individually analysed, chlordanes among the OC pesticides (oxychlordane and trans-nonachlor) were most strongly associated with both type 2 diabetes and insulin resistance [5, 6] while, in the case of metabolic syndrome, β-hexachlorocyclohexane was most strongly associated. However, when the five components of metabolic syndrome were separately examined, most OC pesticides appeared to be strongly associated with impaired fasting glucose, consistent with its relationship with insulin resistance or type 2 diabetes. The analysis of the specific and combined effects of POP mixtures and their components may be one of the greatest challenges in this area .
It has long been thought that insulin resistance may be the underlying pathophysiology in metabolic syndrome, as many of the components of the syndrome are associated with insulin resistance [22–24]. However, some recent studies [25–27] have reported that metabolic syndrome is not unequivocally related to insulin resistance. Even in this data-set, only 22.9% of subjects with metabolic syndrome had HOMA-IR ≥90th percentile; in our previous study , that high percentile cut-off point of HOMA-IR showed a stronger association with POPs than did lower cut-off points. Thus, some inconsistency of findings on metabolic syndrome vs those on insulin resistance or type 2 diabetes may be understandable. The findings also suggest that a mixture of POPs may be associated with a reinforcing set of metabolic abnormalities, probably not solely limited to diabetes.
Importantly, subclasses of POPs were differently related to five components of metabolic syndrome. Especially, the POPs associations with blood pressure differed from those with metabolic syndrome traits more closely associated with diabetes. Differently from other components of the metabolic syndrome, high blood pressure was most strongly associated with PCDFs. On the other hand, OC pesticides were significantly associated with waist circumference, elevated triacylglycerol, low HDL-cholesterol and impaired fasting glucose, but showed only a non-significant positive trend with high blood pressure. Interestingly, factor analyses of traits of metabolic syndrome consistently show that blood pressure elevation clusters less closely than other traits in metabolic syndrome .
Although we examined specific POPs to know which were most strongly associated with metabolic syndrome itself or each component of the metabolic syndrome, only very large studies would have the ability to identify which POPs are aetiologically important and which are just correlated bystanders. Furthermore, since mechanistic studies in humans are constrained by ethical principles, knowledge of putative mechanisms for the observed relationships will require a variety of scientific approaches. Thus, our current findings should be regarded as tentative preliminary observations that add to existing knowledge, but require several types of additional confirmation such as mechanistic studies in animals, clinical studies and further epidemiological evidence from longitudinal designs with repeated measures [7, 8].
It may seem paradoxical that the strong associations between serum concentrations of POPs and metabolic syndrome, insulin resistance or type 2 diabetes are found when these clinical outcomes have recently become epidemic, while serum concentrations of some POPs have shown decreasing trends [8, 29]. In our previous studies [5, 6], we hypothesised a possible interaction with obesity to help explain these apparently conflicting trends: the toxicity of POPs may synergistically increase as people get obese. This idea was supported by recent molecular epidemiological evidence for diabetogenic effects of dioxin exposure; an inverse correlation between the ratio of GLUT4 to nuclear factor kappa B and serum dioxin concentrations was particularly significant among those with known risk factors of type 2 diabetes such as obesity and family history of diabetes . In addition, other chemicals with similar properties to POPs, like the brominated flame retardants, perfluorinated compounds, which are still in widespread use today, may be as important as POPs which were measured in the NHANES . The non-linear dose–response with some PCBs may also play a role in the recent epidemic.
A further consideration is that the current generation may be experiencing epigenetic changes due to POPs in utero or even from altered ovum or sperm of their parents or grandparents; the fetal exposure to environmental pollutants such as POPs can cause epigenetic changes with transgenerational effects [32, 33]. Because POPs only began wide use after the Second World War , people who lived during that early time of POPs usage may have had little genetic effect due to in utero exposure to POPs even though their serum concentrations of POPs would be very high. However, in the current era, the cumulating exposure of POPs over several generations could be reflected in more epigenetic changes. Therefore we hypothesise that epigenetic changes have occurred and that the exposure to low background amounts of POPs in the current generation may be more harmful than the exposure to high amounts of POPs was in their parents. In fact, epigenetic alterations have been proposed as one important mechanism in the pathogenesis of type 2 diabetes or atherosclerosis . Although this gene-environment interaction hypothesis goes beyond the data reported in this and our related papers based on the NHANES database, this possibility should be investigated in further studies.
Inuits are among the populations most highly exposed to POPs, mainly through the consumption of seal and beluga fat in the Arctic . The prevalence of diabetes was extremely low in Inuit populations several decades ago, but diabetes, insulin resistance and metabolic syndrome have recently increased to the levels of other Westernised populations in some studies [37, 38]. Even though both genetic susceptibility and rapid change of lifestyle have been named as causes, POPs stored in their adipose tissue may play an important role. Furthermore, epidemics of type 2 diabetes in many Asian countries could also be explained by POPs . Although these chemicals were banned from manufacture and use in many developed countries during the 1970s, a number of them continue to be manufactured, stored, used and traded freely in developing Asian countries . Perhaps it is not coincidental that India, China and Mexico are three of the largest remaining POP producers in the world .
This study has several limitations. First, the cross-sectional study design in NHANES does not allow inferences regarding the causality between POPs and metabolic syndrome. One possibility is that disease-induced changes in body weight could cause bias if POP concentrations were differentially affected by such changes shortly before blood extraction. However, in the NHANES, there were no differences in changes in body weight between participants with and without metabolic syndrome. Thus, adjustment for changes in body weight did not change the results. Second, misclassification bias is possible for participants whose POPs would have been detectable with a higher sample volume. Such misclassification would be non-differential if sample volume is unrelated to metabolic syndrome. Third, inference should be made cautiously in light of the multiple comparisons intrinsic in this investigation, even though consistency of association of POPs with metabolic syndrome components reinforces the findings for metabolic syndrome.
In summary, along with our previous findings on the association of POPs with type 2 diabetes and insulin resistance, our current study suggests that the background exposure to some POPs may be closely related to metabolic syndrome, with different POPs related to different metabolic syndrome traits. Furthermore, the possibility of synergistic effects, where multiple POPs reinforce each other’s toxicity in the general population, should be considered. These data lead to a hypothesis in which various POPs stored in adipose tissue may contribute to clustering of risk factors in metabolic syndrome.