Environmental contaminants and the disproportionate prevalence of type-2 diabetes mellitus among Indigenous Cree women in James Bay Quebec, Canada Indigenous populations are disproportionately affected by type 2 diabetes (T2DM) compared to non-Indigenous people. Of importance, the prevalence of T2DM is greater amongst females than males in First Nations communities, in contrast to higher male prevalence reported in non-Indigenous Canadians. Therefore, in this study we extend our previously published work with respect to females, and the potential association between environmental exposures to organochlorine pesticides, such as dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) to explain the greater prevalence of T2DM among Indigenous females compared to males. Using data from the Multi-Community Environment-and-Health Study, Principal Component Analysis (PCA), examined 9-polychlorinated biphenyl congeners, 7-organic pesticides, and 4-metal/metalloids. Modified Poisson regression with robust error variance estimated adjusted prevalence ratios (PR) and corresponding 95% confidence intervals (95% CI), regressing prevalent T2DM on the newly derived principal components (PC), adjusting for a priori covariates, including parity. We further examined the relationship between high detection concentrations of DDT and tertials of categorized DDE exposures on T2DM among Indigenous Cree women. Among 419 female participants, 23% (n = 95) had physician-diagnosed T2DM. PCA analysis show that DDT and Lead (Pb) loaded highly on the second axis (PC-2), although in opposite directions, indicating the different exposure sources. As previously published, T2DM was significantly associated with PC-2 across adjusted models, however, after further adjusting for parity in this analysis, T2DM was no longer significantly associated with increasing PC-2 scores (PR = 0.88, 95% 0.76, 1.03). Furthermore, we found that the highest detectable levels of DDT, and tertiles of DDE were significantly associated with prevalent T2DM in the fully adjusted model (PR = 1.93, 1.17, 3.19), and (PR = 3.58, 1.10, 11.70), respectively. This cross-sectional analysis suggests organochlorines, specifically, detectable high exposure concentrations of DDT and DDE are associated with prevalent type 2 diabetes, signifying a possible important link between parity and environmental organochlorines pesticides among Indigenous Cree women. The International Diabetes Federation1 reports that 463 million adults (20 to 79 years old) worldwide have diabetes, and another 374 million adults have impaired glucose tolerance, a risk factor in developing diabetes. In Canada, it has been estimated that 3.4 million people have diabetes, with another 5.7 million individuals having prediabetes2. Diabetes is caused by an endocrine dysfunction in the homeostatic regulation of blood glucose. Diabetes is classified into the following four general categories. In type 1 diabetes mellitus (T1DM), there is an absolute deficiency in insulin, one of the main hormones responsible for the regulation of blood glucose; however, for type 2 diabetes mellitus (T2DM) there is a relative deficiency in insulin through the progressive loss of insulin secretion from the pancreatic β-cells (i.e., inadequate insulin secretion) and/or increasing insulin peripheral resistance, the bodies inability to respond to insulin3. Gestational diabetes mellitus (GDM) may appear in the second or third trimester of pregnancy, when insulin insensitivity is normally increasing4,5. Diagnosis of GDM is between 24 and 28 weeks of gestation among women not previously found to have diabetes3. Screening for and diagnosis of GDM is accomplished using either a ‘one-step’ (recommended by International Association of Diabetes and Pregnancy Study Groups6 or an older ‘two-step’ (non-fasting) approach recommended by the American College of Obstructions and Gynecologists. Currently, as cited by the American Diabetes Association (2021), the two approaches to diagnosis GDM have yielded inconsistent population-wide outcomes and a uniform approach is yet to be established3. Lastly, there are other specific (less common) types of diabetes, such as, monogenic diabetes syndrome (rare beta cell function genetic defects), exocrine pancreatic diseases (complications of certain diseases), and drug- or chemical-induced diabetes3.Globally, approximately 90% to 95% of all cases of diabetes are T2DM7, and the prevalence of T2DM has been increasing8. The etiology of type 2 diabetes is not known completely, however, the cause of this metabolic disorder characterized by progressive loss of beta-cell function leading to hyperglycemia is multifactorial, including genetics, environmental, and health-related factors. For instance, factors such as genes and family history of diabetes, increasing age, racial and ethnic background disparities, physical inactivity, overweight or obesity (body mass index 25–29.9 kg/m2, or > 30 kg/m2, respectively) leading to inflammation and immune dysregulation, and less defined, the role of environmental pollutants (e.g., organic pollutants or toxic metals). Despite the numerous pathophysiological studies that have contributed to our understanding of diabetes mellitus9, more hypothesis-driven research is needed to determine relationships between environmental factors and differing pathophysiological processes that underlie type 2 diabetes10.Worldwide, the age-standardized prevalence of T2DM has been reported to be several times higher in Indigenous populations than their non-Indigenous counterparts11,12. In Canada, Indigenous peoples (i.e. First Nations, Metis, and Inuit as defined by the Canadian Constitution Act 1982) are disproportionately living with higher rates of T2DM, but there is a relative paucity of information related to Metis and Inuit peoples compared to First Nations people13,14. On-reserve First Nations residents have the highest age-adjusted prevalence for T2DM being more than threefold higher than Canadian non-Indigenous population, 17.2% compared to 5%, respectively13,14. In addition, Canadian Indigenous peoples bear a disproportionate burden of the complications associated with T2DM compared to non-Indigenous Canadians, being hospitalized more often with diabetes-related conditions, and die more often from these complications than their non-Indigenous Canadian counterparts13,14,15,16.In 2014, estimated worldwide age-adjusted prevalence for T2DM was 9.0% for men and 7.9% for women17; this difference was also noted in 1980 (8.3% men and 7.5% women)18. American Diabetes Association5 lists being male as a risk factor in their Diabetes Risk Test. Of importance to the present study, the prevalence of T2DM in First Nations communities is greater in females than males, sharply contrasting observations in non-Indigenous Canadian population13,16. Age-standardized T2DM prevalence rates are reported to be higher for First Nations women (over 20%), than, in contrast to the ~ 16% for First Nations men15. In the James Bay Cree First Nations of northern Quebec, Canada, the crude prevalence were found to be higher in women than men for data collected in 198919. More recently, for the same population Dannenbaum et al.20 reported that more Cree women are living with diabetes than men, 62.2% compared to 37.8%, respectively. The reason behind why Cree women are disproportionally affected by diabetes is yet to be elucidated, however, Dannenbaum et al.20 suggested the cause could be multifactorial with factors, such as physical activity and obesity, including excessive weight gain during pregnancy being of importance. Crowshoe et al.21 and Halseth et al.22 suggests that the disproportionate burden of T2DM affecting First Nations women may be related to the higher prevalence of GDM in First Nations women compared to non-Indigenous women. Indeed, Indigenous women in Canada experience GDM rates 2 to 3 times higher than non-Indigenous women15.We agree with Dannenbaum et al.20 that the issue whereby First Nation women have greater prevalence of T2DM than their male counterparts is multifactorial—and like Crowshoe et al.21 and Halseth22, GDM is critical to the development of T2DM—but we also hypothesize that lipophilic contaminants may be playing a role. Local sources and long-range transport of contaminants have been identified as sources of contaminants for First Nations people in Canada, through direct exposure and/or indirect exposure through consumption of wild game and fish23,24.In reviews of contaminants and their association with T2DM by Taylor et al.25 and Kuo et al.26, it was reported that results were suggestive that relationships existed between persistent organic pollutants (e.g. dichloro-diphenyl-dichloroethylene, DDE) and T2DM. Further, in a study by Pal et al.27 of two First Nations in northern Ontario, Canada, evidence was presented that persistent organic pollutants (e.g. DDE) were higher in T2DM individuals compared to non-T2DM people. In Canada, Indigenous people are disproportionately affected by obesity28. The environmental obesogens hypothesis has been proposed as contributing to obesity through endocrine hormone mimicry29,30; however, in a cross-sectional study among Indigenous First Nation adults, Akbar et al.31 show no obesogenic association between persistent organic pollutants (i.e., polychlorinated biphenyls and organochlorine pesticides) and measures of morphometry, including body mass index. And, although DDT and its DDE metabolite may have endocrine disruption actions (e.g., androgen receptor antagonist), the specific mechanism by which these contaminants function have yet to be elucidated32—especially as it relates to T2DM.Recently, Zuk et al.33 examined the association of complex environmental contaminant mixtures and T2DM in First Nation Cree community members of northern Quebec, Canada, using Principal Component Analysis to reduce the dimensionality of the concentration data for 20 contaminants to orthogonal principal component axes and found an association between DDT and T2DM33. In the present study, we will extend the work of Zuk et al.33 with respect to only females, and the potential association between DDT and DDE with T2DM.The Cree First Nation (Indigenous) communities of the Eeyou Istchee territory are located on the eastern side of the James Bay in Quebec, Canada (Fig. 1). The Nituuchischaayihtitaau Aschii: Multi-Community Environment and-Health Study was conducted in seven communities from 2005 to 2009, with two communities having been studied previously (2002). The aim of the Nituuchischaayihtitaau Aschii study was to provide health assessment and investigate the effect of lifestyle, environmental contaminant exposure, and diet among the participants from the Eeyou Istchee territory. Participants underwent physical examinations, completed health surveys, and provided blood samples, among other tissues, for analysis. The data and sample collection was conducted by experienced field research nurses who also conducted a medical chart review to verify the self-reported survey information related to disease status.Figure 1Map of the study region in northern Quebec, Canada.Study populationOf the initial 1750 recruited participants, we assessed adult females over the age of 20 years old who had medical-chart verified T2DM diagnoses, complete environmental contaminant body burden profiles, underwent physical examination, completed the health survey, and provided blood for analyses. We excluded those who had T1DM diagnoses. In total, 419 women representing seven of nine communities from the Eeyou Istchee territory were carried forward for analyses.Environmental contaminant analysesWe have previously published the analytical methods, including the limits of detection, for both organic and metal and metalloid contaminants33,34,35. Briefly, organic contaminants were assessed in blood plasma post solid-phase extraction and florisil column cleaning prior to measurement on an Agilent high resolution gas chromatography-mass spectrometry (HRGC-MS; Agilent 6890 and Agilent 5973) unit. The analytes of organic contaminants in blood plasma included polychlorinated biphenyl (PCBs) congeners (CBs 99, 187, 183, 180, 170, 153, 128, 118, and 105) and organic pesticides (cis-Nonachlor, Dichlorodiphenyltrichloroethane [p,p′-DDT], Dichlorodiphenyldichloroethylene [p,p′-DDE], Hexachlorobenzene [HCB], Mirex, oxy-chlordane, trans-Nonachlor. Whole blood samples were assessed for Lead (Pb), total mercury (Hg), cadmium (Cd), and selenium (Se) using a Perkin Elmer Sciex Elan 6000 inductively coupled plasma-mass spectrometer (ICP-MS). All environmental contaminant analyses were conducted at the Institut National de Santé Publique du Québec (INSPQ), the reference laboratory for the Arctic Monitoring and Assessment Program.Risk factor covariatesDemographic information such as sex and age, and behavioral risk factors such as smoking status, were obtained from the self-reported surveys. As previously described33, age was transformed into three categories as follows: 20–39, 40–59, and ≥ 60 years of age. Self-reported education was categorized as: completed less than high school, completed high school, and completed some or more post-secondary schooling. Smoking status was defined as current or former and never smoker. Fasting blood samples were drawn by clinical field nurses who also took anthropometric measures such as standing height (cm), weight (kg) for body mass index (BMI). Total lipids were determined as described by Rylander et al.36. Parity was determined by developing a composite variable of the two questions: ‘How many children did you give birth to?’ and ‘How many pregnancies did you have that resulted in a miscarriage?’.Statistical methodsWe performed a scaled and centered principal component analysis (PCA) to reduce the 21 contaminant variables into a smaller subset of uncorrelated (orthogonal) predictor variables37,38. The derived principal components scores (PCs) with eigenvalues exceeding 1.0 were used as independent predictors in the regression analysis of T2DM. Prior to PCA, the contaminant concentrations were log10 (variate + 1) transformed in order to improve the distribution of these variables. Component loadings that had absolute scores of 0.5 or greater were considered important for the given principal component axis.Descriptive statistics of the variables were stratified by T2DM status and are reported as means ± standard deviation, or frequencies and percentages, were appropriate. Modified Poisson regression with robust error variance was used to calculate adjusted prevalence ratios (PR) and their corresponding 95% confidence intervals (95% CI) using SAS PROC GENMOD39,40. Multivariable models were used to assess the association between T2DM and principal components, while adjusting for the following a priori covariates: age, lipid concentrations, BMI, smoking status, education, and parity.Based on the significant associations obtained from the regression of PCA axes on prevalent T2DM, we further explored the role of p,p′-DDT and p,p′-DDE using a subsequent sensitivity analysis. Owing to the low numbers of DDT exposed participants, we categorized this variable into two levels; the top 10% of exposures and compared them to those that were below the limit of detection (90%). We also categorized DDE exposures into tertials (< 25% [reference group], 25–75%, and ≥ 75% of concentrations. Both DDT and DDE models were adjusted for age, lipids, BMI, smoking status, education, and parity. As above, a modified Poisson regression with robust error variance was used to calculate adjusted prevalence ratios (PR) and their corresponding 95% confidence intervals (95% CI).All statistical analyses were conducted using SAS v9.4 (SAS Institute, Inc., Cary, NC) and the geographic map and PCA loadings figures were generated using R (version 3.5.3, Vienna, Austria).Ethics approval and consent to participateThe Nituuchischaayihtitaau Aschii—Multi-Community
https://www.nature.com/articles/s41598-021-03065-6
Environmental contaminants and the disproportionate prevalence of type-2 diabetes mellitus among Indigenous Cree women in James Bay Quebec, Canada
