Endocrine-disrupting chemicals and risk of diabetes: an evidence-based review

Endocrine-disrupting chemicals and risk of diabetes: an evidence-based review The purpose of this study was to review the epidemiological and experimental evidence linking background exposure to a selection of environmental endocrine-disrupting chemicals (EDCs) with diabetes and impaired glucose metabolism. The review summarises the literature on both cross-sectional and prospective studies in humans, as well as experimental in vivo and in vitro studies. The findings were subjected to evidence grading according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. We found >40 cross-sectional and seven prospective studies regarding EDCs and risk of diabetes. Taken together, there is moderate evidence for a relationship between exposure to dichlorodiphenyldichloroethylene (p,p′-DDE), a metabolite of the pesticide dichlorodiphenyltrichloroethane, and diabetes development. Regarding polychlorinated biphenyls (PCBs), it is likely that the rodent models used are not appropriate, and therefore the evidence is poorer than for p,p′- DDE. For other EDCs, such as bisphenol A, phthalates and perfluorinated chemicals, the evidence is scarce, since very few prospective studies exist. Brominated flame retardants do not seem to be associated with a disturbed glucose tolerance. Thus, evidence is accumulating that EDCs might be involved in diabetes development. Best evidence exists for p,p′-DDE. For other chemicals, both prospective studies and supporting animal data are still lacking. . . . . . . . . . Keywords Bisphenol A BPA Chemicals DDE DDT Diabetes EDCs Endocrine-disrupting chemicals Pesticides Review Abbreviations PFAS Perfluoroalkyl and polyfluoroalkyl substance BFR Brominated flame retardant PFNA Perfluorononanoic acid BPA Bisphenol A PFOS Perfluorooctane sulfonic acid DDT 1,1,1-Trichloro-2,2-bis (p-chlorophenyl)ethane POP Persistent organic pollutant DEHP Di(2-ethylhexyl) phthalate PPAR Peroxisome proliferator-activated receptor EDC Endocrine-disrupting chemical TCDD 2,3,7,8-Tetrachlorodibenzo-p-dioxin GRADE Grading of Recommendations Assessment, Development and Evaluation p,p′-DDE Dichlorodiphenyldichloroethylene Introduction PCB Polychlorinated biphenyl The prevalence of diabetes is increasing in all countries and the disease is becoming a substantial public health concern world- Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4621-3) contains a slide of the wide. During the last decade, numerous studies have proposed figure for download, which is available to authorised users. links between endocrine-disrupting chemicals (EDCs) and dis- turbances in glucose metabolism. The present review will fo- * Lars Lind cus on a representative selection of groups of environmental lars.lind@medsci.uu.se EDCs and use a well-known system to grade the evidence. We searched PubMed for publications with the search terms con- Occupational and Environmental Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden taminant/pollutant/name of the chemicals included in the re- view [AND] diabetes/glucose/insulin, including both human Cardiovascular Epidemiology, Department of Medical Sciences, Entrance 40, Uppsala University, 751 85 Uppsala, Sweden and experimental studies. 1496 Diabetologia (2018) 61:1495–1502 Overview of EDCs cross-sectional studies are clearly prone to reverse causation and other biases, prospective studies are warranted. An EDC has been defined as ‘an exogenous agent that inter- A meta-analysis of the cross-sectional and prospective feres with synthesis, secretion, transport, metabolism, binding studies, published in 2016, showed that in the cross- action or elimination of natural blood-borne hormones that are sectional setting significant relationships were found between present in the body and are responsible for homeostasis, re- levels of dioxins, PCBs, organochloride pesticides and BPA production and developmental process’ [1]. EDC was origi- and prevalent diabetes, while the relationship for phthalates nally a term devoted to disruption of the reproductive system was of borderline significance [3]. The results of this meta- but has now been broadened to include disturbances in other analysis are summarised in Fig. 1. For the seven prospective hormonal systems. studies included in the meta-analysis, data were only available Some EDCs are lipophilic, such as polychlorinated biphe- for PCBs and organochlorine pesticides but, as seen in the nyls (PCBs), dioxins, organochlorine pesticides and brominated cross-sectional studies, increased levels of these two classes flame retardants (BFRs); they accumulate in the food chain and of contaminants were significantly related to incident diabetes. are ingested by humans. These chemicals are stored in adipose In a 2013 US National Toxicology Program workshop re- tissue and generally have very long half-lives (months to many view of six studies (including two prospective studies) inves- years). Perfluoroalkyl and polyfluoroalkyl substances (PFASs) tigating associations between levels of BFRs and diabetes, no comprise another class of EDCs, the members of which are clear association was found [4]. In a review of four cross- non-lipophilic and are transported bound to albumin and stored sectional studies, no associations were seen between the two in the liver in humans. PFASs also accumulate in the food chain most commonly investigated PFASs, perfluorooctane sulfonic and, depending on the length of their carbon chain, also have acid (PFOS) and perfluorooctanoic acid, and prevalent diabe- very long half-lives (months to years) in humans. Together, tes, although in the only study investigating perfluorononanoic these types of chemicals accumulating in humans are denoted acid (PFNA) a significant association was found [5]. This persistent organic pollutants (POPs). relationship between PFNA and diabetes was confirmed in a However, not all EDCs are persistent and not all accumu- later cross-sectional study [6]. However, in two prospective late to a major degree in humans. Bisphenol A (BPA), a well- studies, PFNA and other PFASs were observed to have no known plastic hardener, has a very short half-life (hours) in effect or even a protective effect [7, 8]. humans but detectable levels are nevertheless found in most Taken together, prospective evidence exists for associa- humans in the industrialised world due to exposure on a more- tions between background exposures to PCBs and organo- or-less daily basis. The phthalates are another huge group of chlorine pesticides and incident diabetes. In addition, cross- EDCs with short half-lives (hours to days) but ubiquitous ex- posure. These chemicals are used as plasticisers and solvents. The present review will focus on selected EDCs—those ab Cross-sectional Prospective able to be analysed in a valid way either in plasma/serum or PCBs (n=13) Pesticides (n=5) in urine, thereby enabling evaluation of the health effects of exposure in epidemiological studies. Please see Table 1 for the groups of EDCs mentioned in Pesticides (n=11) this review. Dioxins (n=6) Epidemiological studies Phthalates (n=4) Some studies have shown that high POP levels are associated with diabetes; the study that induced a major interest in this BPA (n=5) PCBs (n=7) topic was conducted by D.-H. Lee and D. R. Jacobs Jr. and 1 2 3 4 12 34 colleagues in 2006 [2]. In that cross-sectional study, they used OR OR the USA National Health and Nutrition Examination Survey Fig. 1 Summary of a meta-analysis of available cross-sectional (a)and (NHANES) database to show that six different POPs, including prospective (b) studies on the association between environmental con- taminants and diabetes published in 2016 by Song et al [3]. ORs (circles) PCBs, dioxins and organochlorine pesticides, were related to and 95% CI (horizontal bars) are shown and are based on comparisons prevalent diabetes. between the highest and lowest values presented in the different studies Following that landmark study, >40 cross-sectional studies underlying the meta-analysis. The number of studies concerning each of have been published, showing a link between EDC levels and the different chemical classes is shown in parentheses. This figure is available as a downloadable slide prevalent diabetes in different countries. However, since Diabetologia (2018) 61:1495–1502 1497 Table 1 Overview of the groups of EDCs included in this review Group Physical and chemical Example Common route of Use in products Production/regulatory status Toxicity/mechanism of action properties exposure PCBs 209 congeners distinguished by number 3,3′,4,4′,5-Pentachlorobiphenyl High-fat food (dairy, meat, Mixtures have been used in electrical PCB production was banned by the US The chlorination pattern determines the and position of chlorine atoms (PCB-126) fish) equipment, surface coatings, inks, Congress in 1979 and by the Stockholm toxicity. substituted on the biphenyl moiety adhesives, flame retardants and paints Convention on Persistent Organic Mechanisms of action depend on chlorine Resistant to acids, bases and heat Pollutants in 2001 substitution pattern of congener: Most are lipophilic and very persistent Due to their persistence in the oestrogenic, anti-oestrogenic, neurotoxic, environment, there are still concerns dioxin-like Dioxin-like PCBs are ligands to the AH receptor, while many non-dioxin-like PCBs bind to PXR and CAR Organochlorine Insecticidal properties DDT and its main metabolite High-fat food (dairy, meat, DDT was first used during World War II DDT was banned in the USA in 1973 Wide range of toxic effects pesticides Highly lipophilic p,p′-DDE fish) to control lice-borne typhus and also in some other countries but is p,p′-DDE, the most environmentally Many are very persistent Hexachlorobenzene Subsequently, farmers used DDT to still in use in countries with malaria relevant DDT derivative, binds to androgen Several chlordanes control agricultural pests receptor and has anti-androgenic properties Dioxins A diverse range of chemical compounds TCDD Soil, dairy, meat, seafood Not used in products Covered by the Stockholm Convention Wide range of toxic effects, including 419 dioxins and related compounds have Formed during the combustion of wastes on Persistent Organic Pollutants immune toxicity, developmental and been identified or are undesirable byproducts in the neurodevelopmental effects and changes in Lipophilic manufacture of herbicides, disinfectants thyroid and steroid hormones and Some are very persistent and other agents reproductive function Only about 30 dioxins are considered to have significant toxicity, with TCDD being the most toxic Mechanisms of action and toxicity vary depending on the chlorine substitution pattern of the congener: oestrogenic, anti-oestrogenic, neurotoxic, dioxin-like The dioxin-like effect is mediated by activation of the AH receptor BFRs Widely varying chemical properties Main classes are PBDEs, High-fat food (dairy, meat, Used in plastics and textile applications, The use of certain BFRs is banned or Toxic effects, including teratogenicity, At high temperatures, BFRs have an HBCDDs, TBBPA and other fish) electronics, clothes and insulation in restricted in the EU carcinogenicity and neurotoxicity, have been inhibitory effect on combustion phenols, and PBBs buildings and furniture In the USA, the manufacture of PBB observed for some BFR congeners chemistry wasbannedin1976 (especially PBDEs) Some are lipophilic and very persistent Due to the persistence of BFRs in the There is evidence that some BFRs disrupt environment, there are still concerns the thyroid hormone system–most data are available for the PBDE class PFASs Hydrophobic and lipophobic Perfluorocarboxylic acids (e.g. Seafood, drinking water and Used in industry and consumer products Use of PFASs has been largely phased There is evidence that some PFASs disrupt Some are resistant to environmental PFOA, sometimes called C8, food contact material since the 1950s out of food packaging materials the thyroid hormone system. degradation and are extremely persistent and PFNA) and Used in food packaging materials, The European Parliament has approved Some PFASs bind to PPAR-α and to a lesser perfluorosulfonates (e.g. PFOS non-stick cookware, water-resistant an EU directive (2006/122/EU) with degree to PPAR-γ. and PFHxS) clothing, cleaning products, paints, restrictions on marketing and use of varnishes and sealants, firefighting foam PFOS and PFOS-related substances and cosmetics Bisphenols Group of non-persistent chemicals with Bisphenol A (BPA; Ubiquitous Commonly used to produce plastics Controversial issue Initially BPA was designed as a synthetic two phenolic rings joined together by a 4,4′-isopropylidenediphenol) BPA is used mainly in the manufacture BPA is banned in baby bottles oestrogenandhasbeenshowntobindto bridging carbon or other chemical of polycarbonate and is also used in throughout the EU oestrogen receptors (ERα,ERβ, and to the structure. other plastics as a hardener In 2017, 5.4 million tons of BPA was membrane ER) Used in products such as DVDs, dental produced Emerging data shows that BPA interacts materials and lunch boxes with other hormone receptors, including Epoxy plastic can be used in electronics, androgen receptors and the thyroid hormone building materials, in the protective receptor lining in cans and in the relining of water pipes BPA is present in thermal paper 1498 Diabetologia (2018) 61:1495–1502 Table 1 (continued) Group Physical and chemical Example Common route of Use in products Production/regulatory status Toxicity/mechanism of action properties exposure Phthalates Esters of phthalic acid DEHP Ubiquitous Used as plasticisers in the production of Controversial issue MEHP, a metabolite of DEHP, has been Not persistent plastics Some countries have banned their use in found in exposed organisms and interacts Used in cosmetics, perfumes, children’stoys with all three PPARs pharmaceutical tablets, medical tubing, Five million tons of phthalates are nutritional supplements, adhesives, produced annually paints, food containers and wrappers, toys and cleaning materials These EDCs were selected because they can be analysed in a valid way either in plasma/serum or in the urine, thereby enabling the evaluation of the health effects of exposure in epidemiological studies Congeners: congeners are related chemical substances, related to each other by origin, structure, or function AH, aryl hydrocarbon; CAR, constitutive androstane receptor; EU, European Union; HBCDD, hexabromocyclodecane; MEHP, mono-ethyl-hexyl-phthalate; PBB, polybrominated bisphenol; PBDE, polybrominated diphenyl ether; PFHxS, perfluorohexasulfonate; PFOA, perfluorooctanoic acid; PXR, pregnane X receptor; TBBPA, tetrabromobisphenol A Diabetologia (2018) 61:1495–1502 1499 sectional evidence exists for relationships between dioxins contaminants early in life would have the greatest impact on and BPA and prevalent diabetes, while there is no convincing future weight gain. evidence for relationships between phthalates, BFRs or A recent meta-analysis of seven mother–child cohorts showed PFASs and diabetes. a positive relationship between prenatal exposure to DDT/ dichlorodiphenyldichloroethylene (p,p′-DDE) and future weight gain in the children [17]. Thesedataaresupportedbyanexper- Experimental studies imental study showing that prenatal exposure of mice to this pesticide induced reduced energy expenditure and a transient Several studies indicate that Vietnam veterans exposed to Agent weight gain [12]. When given a high-fat diet, the mice developed Orange contaminated with dioxins have an increased risk of impaired glucose tolerance. incident diabetes (see [4] for review) but animal studies have In a review from 2011, no convincing association was generally shown a hypoglycaemic response to the potent dioxin found between exposure to other types of lipophilic POP 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [9]. Neither could and future weight gain in mother–child cohorts [18]. any consistent hyperglycaemic responses be seen in rodent stud- In a recent review of more short-lived, less lipophilic EDCs, ies exploring the effect of PCB exposure [10], except in one prenatal exposure to phthalates and BPA, as well as childhood study in which dioxin-like PCBs impaired glucose tolerance in exposure to these plastic-associated chemicals, was not consis- lean but not fat mice [11]. tently associated with increased future body weight. In contrast, Regarding organochlorine pesticides, perinatal exposure to most studies of PFASs in this context have shown a relationship 1,1,1-trichloro-2,2-bis (p-chlorophenyl)ethane (DDT) induced between prenatal exposure to PFASs and impaired weight gain impaired glucose tolerance later in life in mice [12]. In addition, [19]. adult rodents exposed to DDT later in life showed impaired Taken together, the best evidence for EDCs inducing obe- glucose tolerance and reduced insulin secretion [13]. sity that might cause diabetes is present for the pesticide DDT. Nadal and co-workers showed that mice exposed in utero to BPA displayed impaired glucose tolerance and reduced insulin secretion later in life [14]. In addition, long-term exposure of Mechanistic studies BPA later in life induced impaired glucose tolerance in mice [15]. Taken together, in vivo animal studies do not support the Insulin secretion and insulin sensitivity are the two main charac- epidemiological evidence of a diabetogenic response to dioxins teristics determining glucose tolerance. In a recent study, the early or PCBs, while evidence in rodents supports an effect for DDT and late insulin response was modelled using data obtained at a and BPA. 2 h OGTT [20]. Both the dynamic first-phase and the static second-phase insulin response were impaired in non-diabetic in- dividuals with high levels of organochlorine pesticides, while the Potential obesogenic role of contaminants association with PCBs was weaker. When the proinsulin-to- insulin ratio was used as a proxy for a disturbed beta cell func- Based on the experimental finding that the organotin substance tion, high levels of some phthalates and some PFASs were asso- tributyltin induced weight gain in mice and that this effect was ciated with this ratio [6, 21]. mediated by peroxisome proliferator-activated receptor In experimental studies, the potent dioxin TCDD has been (PPAR)-γ and involved reprogramming of mesenchymal stem shown to influence insulin secretioninaratinsulin-secretingbeta cells towards the adipocyte lineage [16], it has been proposed cell line and in isolated rat pancreatic cells [22]. TCDD has also that certain environmental contaminants could contribute to been reported to induce pancreatic cell death by auto- the obesity epidemic seen worldwide, acting as so-called phagy in the beta cell line INS-1E [23]. In insulin-sensitive ‘obesogens’. Since obesity is the major risk factor for future tissues such as liver, skeletal muscle and adipose tissue from type 2 diabetes, it is of interest to investigate whether the the guinea pig, TCDD induced insulin resistance [24], possibly contaminants found to be related to diabetes might also induce by downregulation of glucose transporters [25]. The insecticides obesity. malathion and diazinon have been reported to influence insulin- The lipophilic POPs, such as dioxins, PCBs and organochlo- secreting beta cells [26, 27], partly by downregulation of musca- rine pesticides, accumulate in adipose tissue to a major degree. rinic receptors. Prenatal exposure of rats to di(2-ethylhexyl) The degree of fat mass influences their circulating levels, making phthalate (DEHP) has been shown to induce hyperglycaemia, it difficult to study the relationships between these compounds hyperinsulinaemia and a reduced beta cell mass [28]. In vitro, and obesity in adults. However, mother–child cohorts, with mea- organochloride pesticides reduced insulin secretion in pancreatic surements in the pregnant mothers and follow-up of the weight INS-1E beta cells [20]. gain of the children, may provide evidence for the ‘obesogen’ Using the HOMA index of insulin sensitivity in humans, a hypothesis, since it has been suggested that exposure to prospective study showed insulin sensitivity to be impaired in 1500 Diabetologia (2018) 61:1495–1502 middle-aged individuals who 20 years earlier showed high measure EDCs in <100 μl of plasma at a reasonable cost will levels of organochlorine pesticides [29]. Other cross-sectional biobanked plasma from large cohorts be used for this purpose. studies have linked levels of PCBs and, especially, organochlo- Although analytical chemistry has improved over the years re- rine pesticides to insulin sensitivity [20]. Although some garding the volumes needed for proper analyses, the advance- phthalates and PFASs have been linked to impaired insulin ment of the field is heavily dependent on further developments. sensitivity in humans, some studies have failed to reproduce Another area in need of improvement is the study of mixture the link between PFASs and insulin resistance [6, 7, 21, 30]. effects. Nowadays, the relationships between EDCs and diseases, Experimental prenatal exposure to PFOS, as well as to DDT, such as diabetes, are usually studied either by the sum of con- phthalates and BPA, resulted in impaired insulin sensitivity and centration of the chemicals in a certain class or by simply glucose intolerance [12, 14, 31]. In addition, exposure to a mix- analysing the contaminants one by one. One exception to this ture of PCBs, or a mixture of 23 lipid-soluble POPs, induced rule is the use of toxic equivalents, based on binding to the aryl glucose disturbances and insulinresistanceinvivoinmice[32, hydrocarbon receptor, but this ‘pharmacological approach’ is 33]. The effect of a mixture of POPs has also be observed in vitro only applicable to dioxins and other dioxin-like chemicals. In in cultured adipocytes [33]. other instances, sophisticated statistical methods are needed to Taken together, many of the EDCs investigated have been study mixture effects and some examples of using those methods shown to impair insulin secretion and sensitivity in both hu- to study mixture effects have been published [34, 35]. It is also man and experimental studies. possible to use less sophisticated methods to estimate the effects of multiple EDCs once they have been identified one by one, as exemplified by our recent estimation in the Prospective Discussion and future perspectives Investigation of the Vasculature in Uppsala Seniors (PIVUS) study that the population attributable risk for diabetes for the Ideally, large prospective studies are needed to investigate wheth- combination of 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB-153), er fetal and prenatal exposure to EDCs induces obesity and later p,p′-DDE, monoethylphthalate and PFNA was 13%. The impact type 2 diabetes. Unfortunately, those studies are not likely to be of these contaminants was estimated to be related to a yearly conducted for practical reasons. Since an ideal study would take healthcare cost of diabetes in Europe of €4.51 billion [36]. This 60–70 years to accomplish, most of the chemicals used at the is in line with the findings of an expert panel, based on several initiation of the study would probably not be in use at the time published studies, who concluded that the cost of obesity and when the results became available. Thus, in practice, we do have diabetes caused by EDCs was €18 billion a year [37]. to rely on results from studies not covering the whole lifespan. Since it is impossible to obtain the highest degree of evidence Currently, results of a moderate number of prospective studies by performing randomised clinical trials with environmental con- taminants, it is essential to support epidemiological findings with involving PCBs and organochlorine pesticides are available. It is reassuring that the results of a meta-analysis of these studies are animal data to establish causality. Therefore, use of relevant in line with results from a much larger number of cross-sectional models using animals having similar sensitivity to the different studies on the same EDCs. Firm experimental data also exist to chemicals as humans is critical to increase the level of confidence support a causal relationship between DDT/p,p′-DDE exposure in human findings. and diabetes development. According to the well-established At first glance it seems contradictory that aryl hydrocarbon Grading of Recommendations Assessment, Development and receptor activation (dioxins), androgen receptor antagonism Evaluation (GRADE) criteria used for reviewing evidence (p,p′-DDE) and PPAR-γ binding (phthalates and PFASs) all (http://www.gradeworkinggroup.org), moderate evidence exists could lead to disturbed glucose metabolism but it must be re- of a true relationship between DDT/p,p′-DDE exposure and membered that a number of pharmaceutical drugs with different diabetes development. To achieve a high degree of evidence, modes of action can also impair glucose tolerance (e.g. β- randomised trials are needed but will never be accomplished in blockers, thiazide diuretics and neuroleptic drugs). Several down- the field of EDC research. Regarding dioxins and PCBs, it is stream effects of the agonistic/antagonistic actions on the recep- likely that the rodent models used are not appropriate due to the tors described above, such as mitochondrial dysfunction [38], large discrepancy in sensitivity of the aryl hydrocarbon receptor inflammation [39], oxidative stress [40] and alterations in thyroid between humans and rodents and therefore there is less evidence and cortisol pathways [41], comprise possible mediating path- than for DDT/p,p′-DDE. For other EDCs, the evidence is low, ways linking different EDCs to glucose disturbances. since we do not have enough prospective data. In conclusion, several epidemiological studies have pointed to A very important future aim is to gain prospective data in an association between EDCs and diabetes. According to the population-based studies with a high number of incident out- principle of REACH, a European Union regulation of chemicals comes. The major hurdle in achieving that goal is not the lack (no. 1907/2006) designed to ensure a high level of protection of of such cohorts but rather that the volume of blood/urine needed human health and the environment, this might be enough for for analysis of EDCs is still too large. Only when it is possible to regulatory authorities to regard this problem as serious. The best Diabetologia (2018) 61:1495–1502 1501 C57BL/6 mice and mitigate beneficial effects of weight loss on evidence for an association between EDCs and diabetes, graded glucose homeostasis in obese mice. Environ Health Perspect 121: as moderate, is found for DDT/p,p′-DDE. A lower grade of 105–110 evidence is found for PCBs, since supporting experimental data 12. La Merrill M, Karey E, Moshier E et al (2014) Perinatal exposure of are lacking. For other EDCs, prospective studies are needed to mice to the pesticide DDT impairs energy expenditure and metabo- lism in adult female offspring. PLoS One 9:e103337 support the findings of existing cross-sectional studies. 13. Yau DT, Mennear JH (1977) The inhibitory effect of DDT on insu- lin secretion in mice. Toxicol Appl Pharmacol 39:81–88 Duality of interest The authors declare that there is no duality of interest 14. Garcia-Arevalo M, Alonso-Magdalena P, Rebelo Dos Santos J, associated with this manuscript. 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Lind L, Salihovic S, Lampa E, Lind PM (2017) Mixture effects of 41. Abliz A, Chen C, Deng W, Wang W, Sun R (2016) NADPH oxi- 30 environmental contaminants on incident metabolic syndrome— dase inhibitor apocynin attenuates PCB153-induced thyroid injury a prospective study. Environ Int 107:8–15 in rats. Int J Endocrinol 2016:8354745 36. Trasande L, Lampa E, Lind L, Lind PM (2017) Population attribut- able risks and costs of diabetogenic chemical exposures in the elderly. J Epidemiol Community Health 71:111–114 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diabetologia Springer Journals

Endocrine-disrupting chemicals and risk of diabetes: an evidence-based review

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Copyright © 2018 by The Author(s)
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Medicine & Public Health; Internal Medicine; Metabolic Diseases; Human Physiology
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0012-186X
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10.1007/s00125-018-4621-3
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Abstract

The purpose of this study was to review the epidemiological and experimental evidence linking background exposure to a selection of environmental endocrine-disrupting chemicals (EDCs) with diabetes and impaired glucose metabolism. The review summarises the literature on both cross-sectional and prospective studies in humans, as well as experimental in vivo and in vitro studies. The findings were subjected to evidence grading according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. We found >40 cross-sectional and seven prospective studies regarding EDCs and risk of diabetes. Taken together, there is moderate evidence for a relationship between exposure to dichlorodiphenyldichloroethylene (p,p′-DDE), a metabolite of the pesticide dichlorodiphenyltrichloroethane, and diabetes development. Regarding polychlorinated biphenyls (PCBs), it is likely that the rodent models used are not appropriate, and therefore the evidence is poorer than for p,p′- DDE. For other EDCs, such as bisphenol A, phthalates and perfluorinated chemicals, the evidence is scarce, since very few prospective studies exist. Brominated flame retardants do not seem to be associated with a disturbed glucose tolerance. Thus, evidence is accumulating that EDCs might be involved in diabetes development. Best evidence exists for p,p′-DDE. For other chemicals, both prospective studies and supporting animal data are still lacking. . . . . . . . . . Keywords Bisphenol A BPA Chemicals DDE DDT Diabetes EDCs Endocrine-disrupting chemicals Pesticides Review Abbreviations PFAS Perfluoroalkyl and polyfluoroalkyl substance BFR Brominated flame retardant PFNA Perfluorononanoic acid BPA Bisphenol A PFOS Perfluorooctane sulfonic acid DDT 1,1,1-Trichloro-2,2-bis (p-chlorophenyl)ethane POP Persistent organic pollutant DEHP Di(2-ethylhexyl) phthalate PPAR Peroxisome proliferator-activated receptor EDC Endocrine-disrupting chemical TCDD 2,3,7,8-Tetrachlorodibenzo-p-dioxin GRADE Grading of Recommendations Assessment, Development and Evaluation p,p′-DDE Dichlorodiphenyldichloroethylene Introduction PCB Polychlorinated biphenyl The prevalence of diabetes is increasing in all countries and the disease is becoming a substantial public health concern world- Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4621-3) contains a slide of the wide. During the last decade, numerous studies have proposed figure for download, which is available to authorised users. links between endocrine-disrupting chemicals (EDCs) and dis- turbances in glucose metabolism. The present review will fo- * Lars Lind cus on a representative selection of groups of environmental lars.lind@medsci.uu.se EDCs and use a well-known system to grade the evidence. We searched PubMed for publications with the search terms con- Occupational and Environmental Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden taminant/pollutant/name of the chemicals included in the re- view [AND] diabetes/glucose/insulin, including both human Cardiovascular Epidemiology, Department of Medical Sciences, Entrance 40, Uppsala University, 751 85 Uppsala, Sweden and experimental studies. 1496 Diabetologia (2018) 61:1495–1502 Overview of EDCs cross-sectional studies are clearly prone to reverse causation and other biases, prospective studies are warranted. An EDC has been defined as ‘an exogenous agent that inter- A meta-analysis of the cross-sectional and prospective feres with synthesis, secretion, transport, metabolism, binding studies, published in 2016, showed that in the cross- action or elimination of natural blood-borne hormones that are sectional setting significant relationships were found between present in the body and are responsible for homeostasis, re- levels of dioxins, PCBs, organochloride pesticides and BPA production and developmental process’ [1]. EDC was origi- and prevalent diabetes, while the relationship for phthalates nally a term devoted to disruption of the reproductive system was of borderline significance [3]. The results of this meta- but has now been broadened to include disturbances in other analysis are summarised in Fig. 1. For the seven prospective hormonal systems. studies included in the meta-analysis, data were only available Some EDCs are lipophilic, such as polychlorinated biphe- for PCBs and organochlorine pesticides but, as seen in the nyls (PCBs), dioxins, organochlorine pesticides and brominated cross-sectional studies, increased levels of these two classes flame retardants (BFRs); they accumulate in the food chain and of contaminants were significantly related to incident diabetes. are ingested by humans. These chemicals are stored in adipose In a 2013 US National Toxicology Program workshop re- tissue and generally have very long half-lives (months to many view of six studies (including two prospective studies) inves- years). Perfluoroalkyl and polyfluoroalkyl substances (PFASs) tigating associations between levels of BFRs and diabetes, no comprise another class of EDCs, the members of which are clear association was found [4]. In a review of four cross- non-lipophilic and are transported bound to albumin and stored sectional studies, no associations were seen between the two in the liver in humans. PFASs also accumulate in the food chain most commonly investigated PFASs, perfluorooctane sulfonic and, depending on the length of their carbon chain, also have acid (PFOS) and perfluorooctanoic acid, and prevalent diabe- very long half-lives (months to years) in humans. Together, tes, although in the only study investigating perfluorononanoic these types of chemicals accumulating in humans are denoted acid (PFNA) a significant association was found [5]. This persistent organic pollutants (POPs). relationship between PFNA and diabetes was confirmed in a However, not all EDCs are persistent and not all accumu- later cross-sectional study [6]. However, in two prospective late to a major degree in humans. Bisphenol A (BPA), a well- studies, PFNA and other PFASs were observed to have no known plastic hardener, has a very short half-life (hours) in effect or even a protective effect [7, 8]. humans but detectable levels are nevertheless found in most Taken together, prospective evidence exists for associa- humans in the industrialised world due to exposure on a more- tions between background exposures to PCBs and organo- or-less daily basis. The phthalates are another huge group of chlorine pesticides and incident diabetes. In addition, cross- EDCs with short half-lives (hours to days) but ubiquitous ex- posure. These chemicals are used as plasticisers and solvents. The present review will focus on selected EDCs—those ab Cross-sectional Prospective able to be analysed in a valid way either in plasma/serum or PCBs (n=13) Pesticides (n=5) in urine, thereby enabling evaluation of the health effects of exposure in epidemiological studies. Please see Table 1 for the groups of EDCs mentioned in Pesticides (n=11) this review. Dioxins (n=6) Epidemiological studies Phthalates (n=4) Some studies have shown that high POP levels are associated with diabetes; the study that induced a major interest in this BPA (n=5) PCBs (n=7) topic was conducted by D.-H. Lee and D. R. Jacobs Jr. and 1 2 3 4 12 34 colleagues in 2006 [2]. In that cross-sectional study, they used OR OR the USA National Health and Nutrition Examination Survey Fig. 1 Summary of a meta-analysis of available cross-sectional (a)and (NHANES) database to show that six different POPs, including prospective (b) studies on the association between environmental con- taminants and diabetes published in 2016 by Song et al [3]. ORs (circles) PCBs, dioxins and organochlorine pesticides, were related to and 95% CI (horizontal bars) are shown and are based on comparisons prevalent diabetes. between the highest and lowest values presented in the different studies Following that landmark study, >40 cross-sectional studies underlying the meta-analysis. The number of studies concerning each of have been published, showing a link between EDC levels and the different chemical classes is shown in parentheses. This figure is available as a downloadable slide prevalent diabetes in different countries. However, since Diabetologia (2018) 61:1495–1502 1497 Table 1 Overview of the groups of EDCs included in this review Group Physical and chemical Example Common route of Use in products Production/regulatory status Toxicity/mechanism of action properties exposure PCBs 209 congeners distinguished by number 3,3′,4,4′,5-Pentachlorobiphenyl High-fat food (dairy, meat, Mixtures have been used in electrical PCB production was banned by the US The chlorination pattern determines the and position of chlorine atoms (PCB-126) fish) equipment, surface coatings, inks, Congress in 1979 and by the Stockholm toxicity. substituted on the biphenyl moiety adhesives, flame retardants and paints Convention on Persistent Organic Mechanisms of action depend on chlorine Resistant to acids, bases and heat Pollutants in 2001 substitution pattern of congener: Most are lipophilic and very persistent Due to their persistence in the oestrogenic, anti-oestrogenic, neurotoxic, environment, there are still concerns dioxin-like Dioxin-like PCBs are ligands to the AH receptor, while many non-dioxin-like PCBs bind to PXR and CAR Organochlorine Insecticidal properties DDT and its main metabolite High-fat food (dairy, meat, DDT was first used during World War II DDT was banned in the USA in 1973 Wide range of toxic effects pesticides Highly lipophilic p,p′-DDE fish) to control lice-borne typhus and also in some other countries but is p,p′-DDE, the most environmentally Many are very persistent Hexachlorobenzene Subsequently, farmers used DDT to still in use in countries with malaria relevant DDT derivative, binds to androgen Several chlordanes control agricultural pests receptor and has anti-androgenic properties Dioxins A diverse range of chemical compounds TCDD Soil, dairy, meat, seafood Not used in products Covered by the Stockholm Convention Wide range of toxic effects, including 419 dioxins and related compounds have Formed during the combustion of wastes on Persistent Organic Pollutants immune toxicity, developmental and been identified or are undesirable byproducts in the neurodevelopmental effects and changes in Lipophilic manufacture of herbicides, disinfectants thyroid and steroid hormones and Some are very persistent and other agents reproductive function Only about 30 dioxins are considered to have significant toxicity, with TCDD being the most toxic Mechanisms of action and toxicity vary depending on the chlorine substitution pattern of the congener: oestrogenic, anti-oestrogenic, neurotoxic, dioxin-like The dioxin-like effect is mediated by activation of the AH receptor BFRs Widely varying chemical properties Main classes are PBDEs, High-fat food (dairy, meat, Used in plastics and textile applications, The use of certain BFRs is banned or Toxic effects, including teratogenicity, At high temperatures, BFRs have an HBCDDs, TBBPA and other fish) electronics, clothes and insulation in restricted in the EU carcinogenicity and neurotoxicity, have been inhibitory effect on combustion phenols, and PBBs buildings and furniture In the USA, the manufacture of PBB observed for some BFR congeners chemistry wasbannedin1976 (especially PBDEs) Some are lipophilic and very persistent Due to the persistence of BFRs in the There is evidence that some BFRs disrupt environment, there are still concerns the thyroid hormone system–most data are available for the PBDE class PFASs Hydrophobic and lipophobic Perfluorocarboxylic acids (e.g. Seafood, drinking water and Used in industry and consumer products Use of PFASs has been largely phased There is evidence that some PFASs disrupt Some are resistant to environmental PFOA, sometimes called C8, food contact material since the 1950s out of food packaging materials the thyroid hormone system. degradation and are extremely persistent and PFNA) and Used in food packaging materials, The European Parliament has approved Some PFASs bind to PPAR-α and to a lesser perfluorosulfonates (e.g. PFOS non-stick cookware, water-resistant an EU directive (2006/122/EU) with degree to PPAR-γ. and PFHxS) clothing, cleaning products, paints, restrictions on marketing and use of varnishes and sealants, firefighting foam PFOS and PFOS-related substances and cosmetics Bisphenols Group of non-persistent chemicals with Bisphenol A (BPA; Ubiquitous Commonly used to produce plastics Controversial issue Initially BPA was designed as a synthetic two phenolic rings joined together by a 4,4′-isopropylidenediphenol) BPA is used mainly in the manufacture BPA is banned in baby bottles oestrogenandhasbeenshowntobindto bridging carbon or other chemical of polycarbonate and is also used in throughout the EU oestrogen receptors (ERα,ERβ, and to the structure. other plastics as a hardener In 2017, 5.4 million tons of BPA was membrane ER) Used in products such as DVDs, dental produced Emerging data shows that BPA interacts materials and lunch boxes with other hormone receptors, including Epoxy plastic can be used in electronics, androgen receptors and the thyroid hormone building materials, in the protective receptor lining in cans and in the relining of water pipes BPA is present in thermal paper 1498 Diabetologia (2018) 61:1495–1502 Table 1 (continued) Group Physical and chemical Example Common route of Use in products Production/regulatory status Toxicity/mechanism of action properties exposure Phthalates Esters of phthalic acid DEHP Ubiquitous Used as plasticisers in the production of Controversial issue MEHP, a metabolite of DEHP, has been Not persistent plastics Some countries have banned their use in found in exposed organisms and interacts Used in cosmetics, perfumes, children’stoys with all three PPARs pharmaceutical tablets, medical tubing, Five million tons of phthalates are nutritional supplements, adhesives, produced annually paints, food containers and wrappers, toys and cleaning materials These EDCs were selected because they can be analysed in a valid way either in plasma/serum or in the urine, thereby enabling the evaluation of the health effects of exposure in epidemiological studies Congeners: congeners are related chemical substances, related to each other by origin, structure, or function AH, aryl hydrocarbon; CAR, constitutive androstane receptor; EU, European Union; HBCDD, hexabromocyclodecane; MEHP, mono-ethyl-hexyl-phthalate; PBB, polybrominated bisphenol; PBDE, polybrominated diphenyl ether; PFHxS, perfluorohexasulfonate; PFOA, perfluorooctanoic acid; PXR, pregnane X receptor; TBBPA, tetrabromobisphenol A Diabetologia (2018) 61:1495–1502 1499 sectional evidence exists for relationships between dioxins contaminants early in life would have the greatest impact on and BPA and prevalent diabetes, while there is no convincing future weight gain. evidence for relationships between phthalates, BFRs or A recent meta-analysis of seven mother–child cohorts showed PFASs and diabetes. a positive relationship between prenatal exposure to DDT/ dichlorodiphenyldichloroethylene (p,p′-DDE) and future weight gain in the children [17]. Thesedataaresupportedbyanexper- Experimental studies imental study showing that prenatal exposure of mice to this pesticide induced reduced energy expenditure and a transient Several studies indicate that Vietnam veterans exposed to Agent weight gain [12]. When given a high-fat diet, the mice developed Orange contaminated with dioxins have an increased risk of impaired glucose tolerance. incident diabetes (see [4] for review) but animal studies have In a review from 2011, no convincing association was generally shown a hypoglycaemic response to the potent dioxin found between exposure to other types of lipophilic POP 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [9]. Neither could and future weight gain in mother–child cohorts [18]. any consistent hyperglycaemic responses be seen in rodent stud- In a recent review of more short-lived, less lipophilic EDCs, ies exploring the effect of PCB exposure [10], except in one prenatal exposure to phthalates and BPA, as well as childhood study in which dioxin-like PCBs impaired glucose tolerance in exposure to these plastic-associated chemicals, was not consis- lean but not fat mice [11]. tently associated with increased future body weight. In contrast, Regarding organochlorine pesticides, perinatal exposure to most studies of PFASs in this context have shown a relationship 1,1,1-trichloro-2,2-bis (p-chlorophenyl)ethane (DDT) induced between prenatal exposure to PFASs and impaired weight gain impaired glucose tolerance later in life in mice [12]. In addition, [19]. adult rodents exposed to DDT later in life showed impaired Taken together, the best evidence for EDCs inducing obe- glucose tolerance and reduced insulin secretion [13]. sity that might cause diabetes is present for the pesticide DDT. Nadal and co-workers showed that mice exposed in utero to BPA displayed impaired glucose tolerance and reduced insulin secretion later in life [14]. In addition, long-term exposure of Mechanistic studies BPA later in life induced impaired glucose tolerance in mice [15]. Taken together, in vivo animal studies do not support the Insulin secretion and insulin sensitivity are the two main charac- epidemiological evidence of a diabetogenic response to dioxins teristics determining glucose tolerance. In a recent study, the early or PCBs, while evidence in rodents supports an effect for DDT and late insulin response was modelled using data obtained at a and BPA. 2 h OGTT [20]. Both the dynamic first-phase and the static second-phase insulin response were impaired in non-diabetic in- dividuals with high levels of organochlorine pesticides, while the Potential obesogenic role of contaminants association with PCBs was weaker. When the proinsulin-to- insulin ratio was used as a proxy for a disturbed beta cell func- Based on the experimental finding that the organotin substance tion, high levels of some phthalates and some PFASs were asso- tributyltin induced weight gain in mice and that this effect was ciated with this ratio [6, 21]. mediated by peroxisome proliferator-activated receptor In experimental studies, the potent dioxin TCDD has been (PPAR)-γ and involved reprogramming of mesenchymal stem shown to influence insulin secretioninaratinsulin-secretingbeta cells towards the adipocyte lineage [16], it has been proposed cell line and in isolated rat pancreatic cells [22]. TCDD has also that certain environmental contaminants could contribute to been reported to induce pancreatic cell death by auto- the obesity epidemic seen worldwide, acting as so-called phagy in the beta cell line INS-1E [23]. In insulin-sensitive ‘obesogens’. Since obesity is the major risk factor for future tissues such as liver, skeletal muscle and adipose tissue from type 2 diabetes, it is of interest to investigate whether the the guinea pig, TCDD induced insulin resistance [24], possibly contaminants found to be related to diabetes might also induce by downregulation of glucose transporters [25]. The insecticides obesity. malathion and diazinon have been reported to influence insulin- The lipophilic POPs, such as dioxins, PCBs and organochlo- secreting beta cells [26, 27], partly by downregulation of musca- rine pesticides, accumulate in adipose tissue to a major degree. rinic receptors. Prenatal exposure of rats to di(2-ethylhexyl) The degree of fat mass influences their circulating levels, making phthalate (DEHP) has been shown to induce hyperglycaemia, it difficult to study the relationships between these compounds hyperinsulinaemia and a reduced beta cell mass [28]. In vitro, and obesity in adults. However, mother–child cohorts, with mea- organochloride pesticides reduced insulin secretion in pancreatic surements in the pregnant mothers and follow-up of the weight INS-1E beta cells [20]. gain of the children, may provide evidence for the ‘obesogen’ Using the HOMA index of insulin sensitivity in humans, a hypothesis, since it has been suggested that exposure to prospective study showed insulin sensitivity to be impaired in 1500 Diabetologia (2018) 61:1495–1502 middle-aged individuals who 20 years earlier showed high measure EDCs in <100 μl of plasma at a reasonable cost will levels of organochlorine pesticides [29]. Other cross-sectional biobanked plasma from large cohorts be used for this purpose. studies have linked levels of PCBs and, especially, organochlo- Although analytical chemistry has improved over the years re- rine pesticides to insulin sensitivity [20]. Although some garding the volumes needed for proper analyses, the advance- phthalates and PFASs have been linked to impaired insulin ment of the field is heavily dependent on further developments. sensitivity in humans, some studies have failed to reproduce Another area in need of improvement is the study of mixture the link between PFASs and insulin resistance [6, 7, 21, 30]. effects. Nowadays, the relationships between EDCs and diseases, Experimental prenatal exposure to PFOS, as well as to DDT, such as diabetes, are usually studied either by the sum of con- phthalates and BPA, resulted in impaired insulin sensitivity and centration of the chemicals in a certain class or by simply glucose intolerance [12, 14, 31]. In addition, exposure to a mix- analysing the contaminants one by one. One exception to this ture of PCBs, or a mixture of 23 lipid-soluble POPs, induced rule is the use of toxic equivalents, based on binding to the aryl glucose disturbances and insulinresistanceinvivoinmice[32, hydrocarbon receptor, but this ‘pharmacological approach’ is 33]. The effect of a mixture of POPs has also be observed in vitro only applicable to dioxins and other dioxin-like chemicals. In in cultured adipocytes [33]. other instances, sophisticated statistical methods are needed to Taken together, many of the EDCs investigated have been study mixture effects and some examples of using those methods shown to impair insulin secretion and sensitivity in both hu- to study mixture effects have been published [34, 35]. It is also man and experimental studies. possible to use less sophisticated methods to estimate the effects of multiple EDCs once they have been identified one by one, as exemplified by our recent estimation in the Prospective Discussion and future perspectives Investigation of the Vasculature in Uppsala Seniors (PIVUS) study that the population attributable risk for diabetes for the Ideally, large prospective studies are needed to investigate wheth- combination of 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB-153), er fetal and prenatal exposure to EDCs induces obesity and later p,p′-DDE, monoethylphthalate and PFNA was 13%. The impact type 2 diabetes. Unfortunately, those studies are not likely to be of these contaminants was estimated to be related to a yearly conducted for practical reasons. Since an ideal study would take healthcare cost of diabetes in Europe of €4.51 billion [36]. This 60–70 years to accomplish, most of the chemicals used at the is in line with the findings of an expert panel, based on several initiation of the study would probably not be in use at the time published studies, who concluded that the cost of obesity and when the results became available. Thus, in practice, we do have diabetes caused by EDCs was €18 billion a year [37]. to rely on results from studies not covering the whole lifespan. Since it is impossible to obtain the highest degree of evidence Currently, results of a moderate number of prospective studies by performing randomised clinical trials with environmental con- taminants, it is essential to support epidemiological findings with involving PCBs and organochlorine pesticides are available. It is reassuring that the results of a meta-analysis of these studies are animal data to establish causality. Therefore, use of relevant in line with results from a much larger number of cross-sectional models using animals having similar sensitivity to the different studies on the same EDCs. Firm experimental data also exist to chemicals as humans is critical to increase the level of confidence support a causal relationship between DDT/p,p′-DDE exposure in human findings. and diabetes development. According to the well-established At first glance it seems contradictory that aryl hydrocarbon Grading of Recommendations Assessment, Development and receptor activation (dioxins), androgen receptor antagonism Evaluation (GRADE) criteria used for reviewing evidence (p,p′-DDE) and PPAR-γ binding (phthalates and PFASs) all (http://www.gradeworkinggroup.org), moderate evidence exists could lead to disturbed glucose metabolism but it must be re- of a true relationship between DDT/p,p′-DDE exposure and membered that a number of pharmaceutical drugs with different diabetes development. To achieve a high degree of evidence, modes of action can also impair glucose tolerance (e.g. β- randomised trials are needed but will never be accomplished in blockers, thiazide diuretics and neuroleptic drugs). Several down- the field of EDC research. Regarding dioxins and PCBs, it is stream effects of the agonistic/antagonistic actions on the recep- likely that the rodent models used are not appropriate due to the tors described above, such as mitochondrial dysfunction [38], large discrepancy in sensitivity of the aryl hydrocarbon receptor inflammation [39], oxidative stress [40] and alterations in thyroid between humans and rodents and therefore there is less evidence and cortisol pathways [41], comprise possible mediating path- than for DDT/p,p′-DDE. For other EDCs, the evidence is low, ways linking different EDCs to glucose disturbances. since we do not have enough prospective data. In conclusion, several epidemiological studies have pointed to A very important future aim is to gain prospective data in an association between EDCs and diabetes. According to the population-based studies with a high number of incident out- principle of REACH, a European Union regulation of chemicals comes. The major hurdle in achieving that goal is not the lack (no. 1907/2006) designed to ensure a high level of protection of of such cohorts but rather that the volume of blood/urine needed human health and the environment, this might be enough for for analysis of EDCs is still too large. Only when it is possible to regulatory authorities to regard this problem as serious. The best Diabetologia (2018) 61:1495–1502 1501 C57BL/6 mice and mitigate beneficial effects of weight loss on evidence for an association between EDCs and diabetes, graded glucose homeostasis in obese mice. Environ Health Perspect 121: as moderate, is found for DDT/p,p′-DDE. A lower grade of 105–110 evidence is found for PCBs, since supporting experimental data 12. La Merrill M, Karey E, Moshier E et al (2014) Perinatal exposure of are lacking. For other EDCs, prospective studies are needed to mice to the pesticide DDT impairs energy expenditure and metabo- lism in adult female offspring. PLoS One 9:e103337 support the findings of existing cross-sectional studies. 13. Yau DT, Mennear JH (1977) The inhibitory effect of DDT on insu- lin secretion in mice. Toxicol Appl Pharmacol 39:81–88 Duality of interest The authors declare that there is no duality of interest 14. Garcia-Arevalo M, Alonso-Magdalena P, Rebelo Dos Santos J, associated with this manuscript. Quesada I, Carneiro EM, Nadal A (2014) Exposure to bisphenol- A during pregnancy partially mimics the effects of a high-fat Contribution statement Both authors were responsible for drafting the article diet altering glucose homeostasis and gene expression in adult male and revising it critically for important intellectual content. Both authors ap- mice. PLoS One 9:e100214 proved the version to be published. 15. Moon MK, Jeong IK, Jung Oh T et al (2015) Long-term oral expo- sure to bisphenol A induces glucose intolerance and insulin resis- tance. J Endocrinol 226:35–42 16. 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Journal

DiabetologiaSpringer Journals

Published: May 9, 2018

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