Environmental exposures and T2DM

Over the last 5 years, there has been increasing interest in the potential role of environmental chemicals in the diabetes epidemic. The interest in environmental causes of diabetes has arisen because of evidence of the effects of certain toxicants on relevant biochemical pathways, and because we have been unable to explain all of the rapid and large increases in the prevalence of diabetes from known risk factors. There are many different classes of environmental pollutants.

The chemicals that are currently receiving much attention can be broadly described as endocrine disruptor compounds (EDC). EDCs are chemicals which bind to nuclear receptors such as androgen receptors, peroxisome proliferator-activated receptor (PPAR) α and estrogen receptor (ER) α and β. This binding can interfere with the synthesis, secretion, transport, binding, action, or elimination of a range of hormones that are responsible for normal cell metabolism and maintenance of insulin sensitivity. Several different kinds of chemicals which are very common in the environment can act as EDC. These include bisphenol A, phthalates and persistent organic pollutants (POPs).

Bisphenol A

Bisphenol A (BPA; 4,4’ dihydroxy-2-2 diphenyl propane) is a molecule used in the manufacture of polycarbonate plastic and a base compound used in the manufacture of the resin lining of food and beverage cans in many countries including the USA and Australia.[1] There is mounting evidence for effects of this molecule on adipose tissue and the body’s ability to regulate insulin and glucose levels.[2] BPA has been widely used since the 1950s and is also found in some medical devices, dental sealants and fillings, and thermal paper for cash register receipts. It is also used as an additive in PVC plastic products.[1] Humans mainly become exposed through the use of polycarbonate food and beverage containers. BPA is known to leach out of such containers and the extent to which it leaches out increases with repeated use of such containers especially during heating.[1] There is evidence to suggest that the levels humans are exposed to exceed safe levels recommended by regulatory bodies.[1]

Increasing concerns about BPA led to an expert panel being constituted under the auspices of the National Institute of Health and the US Environmental Protection Agency. The consensus statement issued by this group[3] noted that BPA can be detected in small quantities, current levels of human exposure to BPA already exceed the acceptable safe levels[4] and the unconjugated (bioactive) form of BPA is found in blood in over 95% of people Animal studies have shown that mice exposed long-term to BPA developed hyperinsulinemia, insulin resistance and glucose intolerance[5].

The epidemiological data for BPA and diabetes is less consistent but is growing. There are at least 7 studies, most cross sectional and most of the data come from come from one population, the National Health and Nutrition Examination Survey cohort, across the years 2003-2008[6][7]. Overall the results indicate that risk of diabetes increases as the concentration of urinary BPA increases. Other large cross-sectional studies in China [8][9] provide conflicting data. Prospective data is limited to one study using two populations of women who showed the urinary BPA was associated with incident diabetes in younger cohort of women, but not in the other older cohort[10].

Phthalates

Phthalates represent another class of chemicals which act as EDCs. These chemicals are used in the manufacturing of a variety of products [11] and are often used as plasticizers or solvents in food packaging, cosmetics, perfumes, nail polishes, and other industrial products. For the past 50 years, phthalate production has increased and exposure is nearly ubiquitous with > 75% of the U.S. population having detectable urine concentrations of phthalate metabolites.[11] Studies have suggested that phthalates may disrupt metabolism and adipogenesis.[12] There are a few cross-sectional studies and one prospective studies measuring phthalates and diabetes [13] which have provided some evidence of an prospective association of phthalate metabolites and diabetes, but this study was in women only.[10]

Persistent Organic Pollutants

Persistent organic pollutants (POPs) are organic compounds that, to a varying degree, resist photolytic, biological and chemical degradation. They are characterized by low water solubility and high fat solubility, leading to their bioaccumulation in fatty tissues. POPs include many of the first generation organochlorine insecticides such as dieldrin, DDT, toxaphene and chlordane and several industrial chemical products or byproducts including polychlorinated biphenyls, dioxins and furans[14]. Although some exposure to POPs is occupational or through industrial accidents, human exposure nowadays is from the ingestion of contaminated food as a result of bioaccumulation in the food chain. POPs are ubiquitous in our environment and 80% of populations have detectable levels.[15] In 2001, The Stockholm Convention, an international environmental treaty, developed a list of POPs, the production and use of which was recommended to be minimised and banned, (except in some circumstances) starting in 2004. Despite such regulation, the exposure to chlorinated POPs by the general population continues, mostly through consumption of fatty foods of animal origin[15]. The resistance of POPs to chemical and metabolic degradation means that they become more concentrated as they move up through food webs. Biomagnification can lead to concentrations in humans several orders of magnitude higher than in animals, and in the general environment (air and soil). POPs also accumulate in adipose tissue during life, and are continuously released from adipose tissue over the life-course to the circulation and to vital organs with lipid content[16]. Even though the implementation of the Stockholm Convention has resulted in a decrease in the concentration of banned POPs in the environment, high levels of POPs still exist within humans and the newer POPs e.g. the brominated POPs (which are still widely used and have different exposure patterns to PCBs and dioxins) are not well studied and not necessarily safer[17]. Furthermore, a recent review highlights that the list of toxicants entering the environment from industrial processes is in fact growing[18]. There are many proposed mechanisms which underpin the relationship of POPs exposure to diabetes. POPs act as EDCs, but also act via the binding of TCDD to the aryl hydrocarbon receptor [16].

Some of the earliest data linking POPs to diabetes comes from studies of occupational cohorts exposed to large quantities of POPs, in particular dioxins. An example is the study of Veterans in the Vietnam War (US Veterans exposed to Agent Orange, which was contaminated with TCDD) showing an independent link between POPs exposure and the development of diabetes[19]. However, other occupational studies have provided conflicting results[19]. Data linking POPs and diabetes also arise from populations which are exposed to high levels of POPs through their diet which is high in fish[20].

Cross-sectional human and prospective data from general population studies in developed countries indicates strong associations between POPs and diabetes, however the evidence is conflicting, and the magnitude of risk is very uncertain. The prospective data exploring POPs exposure and diabetes is limited by several factors: extremely small numbers of diabetes cases, inadequate control of confounders, limited age groups, limited ethnicity, self-reported diabetes data and the lack of data exploring possible interactions with obesity reviewed in[16],[21].

While the Stockholm Convention has resulted in lower serum levels of dioxins and PCBs in some countries, levels of the more modern POPs such as PBDEs are high, particularly so in children[22]. Further, not all countries who have signed the Stockholm Convention are meeting their obligations and in particular, developing countries are at risk of introducing new sources of POPs through uncontrolled dumping of waste. Such countries are some of the most vulnerable in terms of the escalating diabetes epidemic.

Conclusion

There are accumulating data linking environmental toxicants/pollutants to the development of diabetes. Certainly, while the evidence is mounting, the relationship between these pollutants and diabetes is yet to be fully conclusive and is generally stronger for POPs than it is for BPA and phthalates. Despite increasing public pressure and vocal opposition to current government practice, in the absence of further comprehensive prospective data, the controversy is only set to continue. The industrial revolution has provided us with the means to live a more modern life which undoubtedly has made life easier and indeed more enjoyable. We all benefit from the advancement of the industries which produce these chemicals, however, what is the price of we are willing to pay? As described by Neel and colleagues[23], " this paradox of progress" now mandates us as individuals to re-examine our lifestyles, and for and governments to devise effective strategies to limit the significant individual and societal toll of these pollutants.

References

  1. ^ Talsness CE, et al. Components of plastic: experimental studies in animals and relevance for human health. Philos Trans R Soc Lond B Biol Sci 2009;364:2079-96.

  2. ^ Richter CA, et al. In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol 2007;24:199-224.

  3. ^ vom Saal FS, et al. Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol 2007;24:131-8.

  4. ^ Taylor JA, et al. Similarity of bisphenol A pharmacokinetics in rhesus monkeys and mice: relevance for human exposure. Environmental health perspectives 2011;119:422-30.

  5. ^ Alonso-Magdalena P, et al. The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance. Environmental health perspectives 2006;114:106-12.

  6. ^ Shankar A, et al. Relationship between urinary bisphenol A levels and diabetes mellitus. The Journal of clinical endocrinology and metabolism 2011;96:3822-6.

  7. ^ Melzer D, et al. Bisphenol A and adult disease: making sense of fragmentary data and competing inferences. Annals of internal medicine 2011;155:392-4.

  8. ^ Wang T, et al. Urinary bisphenol A (BPA) concentration associates with obesity and insulin resistance. The Journal of clinical endocrinology and metabolism 2012;97:E223-7.

  9. ^ Ning G, et al. Relationship of urinary bisphenol A concentration to risk for prevalent type 2 diabetes in Chinese adults: a cross-sectional analysis. Annals of internal medicine 2011;155:368-74.

  10. ^ Sun Q, et al. Association of Urinary Concentrations of Bisphenol A and Phthalate Metabolites with Risk of Type 2 Diabetes: A Prospective Investigation in the Nurses' Health Study (NHS) and NHSII Cohorts. Environmental health perspectives 2014.

  11. ^ Hauser R, et al. Phthalates and human health. Occupational and environmental medicine 2005;62:806-18.

  12. ^ Desvergne B, et al. PPAR-mediated activity of phthalates: A link to the obesity epidemic? Molecular and cellular endocrinology 2009;304:43-8.

  13. ^ Kuo CC, et al. Environmental chemicals and type 2 diabetes: an updated systematic review of the epidemiologic evidence. Current diabetes reports 2013;13:831-49.

  14. ^ Lee DH, et al. Low dose of some persistent organic pollutants predicts type 2 diabetes: a nested case-control study. Environmental health perspectives 2010;118:1235-42.

  15. ^ Lee DH, et al. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes: results from the National Health and Examination Survey 1999-2002. Diabetes care 2006;29:1638-44.

  16. ^ Lee DH, et al. Chlorinated Persistent Organic Pollutants, Obesity, and Type 2 Diabetes. Endocrine reviews 2014:er20131084.

  17. ^ Taylor KW, et al. Evaluation of the association between persistent organic pollutants (POPs) and diabetes in epidemiological studies: a national toxicology program workshop review. Environmental health perspectives 2013;121:774-83.

  18. ^ Grandjean P, et al. Neurobehavioural effects of developmental toxicity. Lancet neurology 2014;13:330-8.

  19. ^ Remillard RB, et al. Linking dioxins to diabetes: epidemiology and biologic plausibility. Environmental health perspectives 2002;110:853-8.

  20. ^ Rignell-Hydbom A, et al. Exposure to persistent organochlorine pollutants and type 2 diabetes mellitus. Hum Exp Toxicol 2007;26:447-52.

  21. ^ Magliano DJ, et al. Persistent organic pollutants and diabetes: a review of the epidemiological evidence. Diabetes & metabolism 2014;40:1-14.

  22. ^ Toms LM, et al. Serum polybrominated diphenyl ether (PBDE) levels are higher in children (2-5 years of age) than in infants and adults. Environmental health perspectives 2009;117:1461-5.

  23. ^ Neel BA, et al. The paradox of progress: environmental disruption of metabolism and the diabetes epidemic. Diabetes 2011;60:1838-48.

Comments

Nobody has commented on this article

Commenting is only available for registered Diapedia users. Please log in or register first.