Respiratory health and its determinants among Nunavimmiut: results from the Qanuilirpitaa? 2017 Nunavik Health Survey.

OBJECTIVES: Respiratory diseases are the leading cause of hospitalization in Nunavik (northern Québec, Canada) and contribute to disparities in life expectancy with the rest of Canada. As part of Qanuilirpitaa? 2017, a cross-sectional population-based health survey, we sought to describe the prevalence of respiratory health indicators, including the first estimate of airway obstruction based on spirometry in an Inuit population, and explore their associated characteristics. METHODS: We analyzed data from 1296 participants aged 16 years and older, using multivariate logistic regression to assess characteristics associated with spirometry-determined airway obstruction and self-reported respiratory symptoms, i.e., wheezing in the last year and chronic cough during at least 3 months. RESULTS: In this relatively young population (83% aged 16 to 54), the prevalences of wheezing, chronic cough, and airway obstruction were, respectively, 27% (95% CI 24-30), 21% (18-23), and 17% (14-20). These estimates are prone to biases due to the relatively low participation rate (about 37%). The most consistent associations were with smoking (≥ 15 pack-years; odds ratio [OR] 3.13, 3.39, and 2.86 for the three indicators, respectively) and food security (OR 0.55 with wheezing and OR 0.26 with chronic cough), as defined in the Household Food Security Survey Module. Wheezing was also associated with allergic sensitization to dogs (2.60) and obesity (2.18). Chronic cough was associated with respiratory infections during childhood (2.12), housing in need of major repairs (1.72), and housing crowding (1.50), and was negatively associated with participation to traditional activities (0.62) and going on the land (0.64). Airway obstruction was associated with being underweight (3.84) and post-secondary education (0.40). Among young adults and women, wheezing was also associated with any inhalation of solvents for recreational purposes during their lifetime (2.62 and 1.56, respectively), while airway obstruction was associated with regular marijuana use (2.22 and 1.84, respectively). CONCLUSION: Smoking and food insecurity are both highly prevalent and strongly associated with respiratory symptoms in Nunavik. Together with essential smoking prevention and cessation programs, our findings suggest that solving food security and housing crises, improving socioeconomic conditions, and promoting traditional lifestyle may improve respiratory health in Nunavik.

RéSUMé: OBJECTIFS: Les maladies respiratoires sont la première cause d'hospitalisation au Nunavik (Nord-du-Québec, Canada) et contribuent aux écarts d'espérance de vie avec le reste du Canada. Dans le cadre de l'enquête transversale et populationnelle Qanuilirpitaa? 2017, cette étude décrit la prévalence d'indicateurs de santé respiratoire et explore les caractéristiques qui leur sont associées. Elle fournit le premier estimé de la prévalence d'obstruction respiratoire par spirométrie dans la population inuite. MéTHODES: Les données de 1 296 participants âgés de 16 ans et plus ont été analysées par régression logistique multivariée pour évaluer les caractéristiques associées avec le wheezing (dans la dernière année), la toux chronique (durant au moins 3 mois) et l'obstruction bronchique (mesurée par spirométrie). RéSULTATS: Dans cette population relativement jeune (83 % entre 16 et 54 ans), les prévalences de wheezing, de toux chronique et d'obstruction bronchique étaient de 27 % (IC95% 24-30), 21 % (18-23) et 17 % (14-20). Ces estimés pourraient être biaisés puisque le taux de participation à l'enquête était relativement faible (environ 37 %). Les associations les plus fortes et consistantes sont observées avec le tabagisme (≥ 15 paquets-années; RC 3,13, 3,39 et 2,86 pour les trois indicateurs, respectivement) et avec la sécurité alimentaire (RC 0,55 avec le wheezing et 0,26 avec la toux chronique), définie à partir du Module d'enquête sur la sécurité alimentaire des ménages. Le wheezing était notamment associé avec la sensibilisation allergique aux chiens (2,60) et l'obésité (2,18). La toux chronique était associée avec les infections respiratoires sévères dans l'enfance (2,12), un logement ayant besoin de réparations majeures (1,72) et un logement surpeuplé (1,50); tandis que participer aux activités traditionnelles (0,62) et aller souvent dans la nature (0,64) semblaient protecteurs. L'obstruction bronchique était associée avec un faible indice de masse corporelle (3,84) et un niveau de scolarité postsecondaire (0,40). Le wheezing était aussi associé avec le fait d'avoir déjà inhalé des solvants chez les jeunes adultes (2,62) et chez les femmes (1,56), tandis que l'obstruction bronchique était associée avec la consommation régulière de cannabis chez les jeunes adultes (2,22) et chez les femmes (1,84). CONCLUSION: Le tabagisme et l'insécurité alimentaire sont fort prévalents et fortement associés avec des symptômes respiratoires au Nunavik. En plus de rappeler l'importance de la prévention du tabagisme, ces résultats supportent la pertinence des efforts communautaires et gouvernementaux pour résoudre les crises de l'insécurité alimentaire et du logement, améliorer les conditions socioéconomiques et promouvoir la culture inuite afin d'améliorer la santé respiratoire au Nunavik.

Determinants of iron deficiency and anemia among Nunavimmiut: results from the Qanuilirpitaa? 2017 Nunavik Health Survey.

OBJECTIVE: To estimate the prevalence of iron deficiency (ID) and anemia and study their main distal and proximal protective and risk factors among Nunavimmiut 16 years and older in 2017. METHODS: In a cross-sectional participatory survey of 831 women and 436 men from the Qanuilirpitaa? 2017 Nunavik Inuit Health Survey, venous blood samples were collected to measure various indicators of iron status and anemia as well as biomarkers of nutritional and inflammatory status and contaminant exposures. Sociodemographic, food security status, anthropometric, lifestyle, dietary, and health data were collected using questionnaires, clinical sessions, and a medical chart review. ID and anemia diagnoses were based on serum ferritin (SF) and hemoglobin (Hb), respectively. Multiple regressions were used to assess correlates of anemia and iron status. RESULTS: Prevalence of ID was highest among women of childbearing age (16-49 years old, 33%) and anemia among adults aged 50 years and older (31%). These estimates are prone to biases due to the relatively low participation rate (37%). Serum vitamin D, omega-3 polyunsaturated fatty acid content of erythrocyte membranes, blood selenium, inflammation, higher socioeconomic status (SES), obesity, and alcohol consumption were all positively associated with SF, while Helicobacter pylori infection and a recent pregnancy were negatively associated with Hb among women of childbearing age. Among older adults, food insecurity was associated with lower SF. CONCLUSION: While data reported here provide some indication of an improvement since the previous survey conducted in 2004, additional efforts should be devoted to further increasing the SES and access to country foods and nutritious market foods in this population, the two main protective factors against ID and anemia identified in the present study.

RéSUMé: OBJECTIF: Estimer la prévalence de la carence en fer (CF) et de l'anémie et étudier leurs principaux facteurs de protection et de risque distaux et proximaux chez les Nunavimmiut de 16 ans et plus en 2017. MéTHODOLOGIE: Dans le cadre de l'enquête transversale participative Qanuilirpitaa? menée en 2017 auprès de 831 femmes et 436 hommes, des échantillons de sang furent prélevés pour mesurer divers indicateurs de la CF et de l'anémie ainsi que des biomarqueurs de l'état nutritionnel et inflammatoire et de l'exposition aux contaminants environnementaux. Des données sociodémographiques, anthropométriques, sur la sécurité alimentaire, sur le mode de vie, l'alimentation et la santé ont été recueillies à l'aide de questionnaires, de séances cliniques et d'un examen des dossiers médicaux. Les diagnostics de CF et d'anémie furent basés sur la ferritine sérique (SF) et l'hémoglobine (Hb), respectivement. Des régressions multiples ont été utilisées pour évaluer les déterminants de l'anémie et du statut en fer. RéSULTATS: La prévalence de la CF était la plus élevée chez les femmes en âge de procréer (16 à 49 ans, 33 %) et l'anémie chez les adultes âgés de 50 ans et plus (31 %). Ces estimés pourraient être biaisés puisque le taux de participation à l'enquête était relativement faible (37 %). Chez les femmes en âge de procréer, la vitamine D sérique, la teneur en acides gras polyinsaturés oméga-3 des membranes érythrocytaires, le sélénium sanguin, l'inflammation, un statut socio-économique plus élevé, l'obésité et la consommation d'alcool étaient tous associés positivement à la SF, tandis que l'infection à Helicobacter pylori et une grossesse récente étaient associées négativement à l'Hb. Chez les adultes plus âgés, l'insécurité alimentaire était associée à une diminution de la SF. CONCLUSION: Bien que les données de cette enquête suggèrent une amélioration depuis l'enquête précédente réalisée en 2004, des efforts additionnels sont requis pour améliorer le statut socioéconomique et l'accès aux aliments traditionnels et aux aliments de marché de qualité au Nunavik, les deux principaux facteurs protecteurs de la CF et de l'anémie identifiés dans la présente étude.

Exposure to benzene, toluene and polycyclic aromatic hydrocarbons in Nunavimmiut aged 16 years and over (Nunavik, Canada) - Qanuilirpitaa 2017 survey.

There are numerous volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) that Inuit may be exposed to from combustion, cooking, heating, vehicle exhaust, active and passive smoking and other local sources of contaminants such as oil spills or open-air burning in landfills. To better assess the levels of exposure to these non-persistent chemicals, we measured a suite of benzene, toluene (two VOCs) and PAHs metabolites in pooled urine samples from youth and adults aged 16 years old and over who participated in the Qanuilirpitaa? 2017 Inuit Health Survey (Q2017), a population health survey conducted in Nunavik. A cost-effective pooling strategy was established and 30 different pools from individual urine samples (n = 1266) were created by grouping individual urine samples by sex, age groups and regions. To assess smoking and exposure to second-hand smoke, cotinine levels were measured in individual urine samples. We found that benzene, toluene, all detected PAHs metabolites and cotinine levels were significantly higher in Q2017 compared to adults in the Canadian Health Measure Survey Cycle 4 (2014-2015) or the general U.S population (2015-2016). Moreover, mean levels of one benzene metabolite, S-phenylmercapturic acid, and several PAHs metabolites, 1-naphthol, 2-and 3-hydroxyfluorene, and 4- and 9-hydroxyphenanthrene, known to be associated with smoking habits, were higher in Q2017 compared to reference values (RV95) established for non-smokers in the general Canadian population. Furthermore, benzene and PAHs metabolites were all correlated with cotinine levels. Our results suggest that the high smoking prevalence in Nunavik is an important contributor to the elevated benzene and PAHs exposure. Other local sources may add to that exposure, although we were not able to account for their contribution. These data highlight the importance of regional and community efforts for reducing smoking and to encourage smoke-free homes in Nunavik, while continuing to investigate and reduce other possible local sources of exposure to benzene, toluene and PAHs.

Variation in biomarker levels of metals, persistent organic pollutants, and omega-3 fatty acids in association with genetic polymorphisms among Inuit in Nunavik, Canada.

BACKGROUND: Biomarker measures of contaminant exposure and nutrient status can help increase understanding of the risks and benefits associated with the consumption of traditional foods by Inuit. While gene-environment and gene-nutrient interactions may help explain variations in biomarker measures, the role of genetic polymorphisms is largely understudied especially for vulnerable sub-populations. OBJECTIVE: The aim of this study was to characterize the relationship between single nucleotide polymorphisms (SNPs) in key genes and blood concentrations of environmental chemicals and nutrients among Inuit. METHODS: Blood samples from 665 individuals who participated in the Qanuippitaa Survey (Nunavik, Canada) in 2004 were analyzed for toxicants and nutrients. DNA was extracted and 140 SNPs in classes relevant to the toxicokinetics and/or toxicodynamics of the target contaminants and nutrients, and/or are involved in cardiovascular health and lipid metabolism were genotyped using the Sequenom iPLEX Gold platform. RESULTS: Geometric means (µg/L) of mercury (Hg), cadmium (Cd), lead (Pb), DDE, PCB-153, and selenium (Se) were 11.1, 2.8, 39.9, 2.9, 1.1 and 301.2, respectively. Red blood cell membrane levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were 5.1%/total fatty acid (TFA) and 1.3%/TFA respectively. Out of 106 SNPs which met our inclusion criteria, biomarker levels for Hg, Cd, Pb, DDE, PCB-153, DHA, and EPA differed (p < 0.05) by genotype for 20, 13, 12, 19, 21, 9 and 8 SNPs, respectively. Following Bonferroni correction (p < 0.0005), only 9 SNPs remained significant (rs2274976 in MTHFR, rs174602 in FADS2, rs7115739 and rs74771917 in FADS3, rs713041 in GPX4, rs2306283 and rs4149056 in SLCO1B1, rs1885301 in ABCC2/MRP2, and rs4244285 in CYP2C19; 5 associated with Hg, 2 with Pb, 2 with DDE, 4 with PCB-153, 1 with DHA). CONCLUSIONS: The findings suggest that polymorphisms in environmentally-responsive genes can influence biomarker levels of key toxicants and nutrients. While there are no immediate clinical or public health implications of these findings, we believe that such gene-environment and gene-nutrient studies provide a foundation that will inform and provide direction to future studies.

Organophosphate pesticides exposure during fetal development and IQ scores in 3 and 4-year old Canadian children.

BACKGROUND: Organophosphate pesticides are widely used in agriculture and for other purposes, leading to ubiquitous exposure in human populations. Some studies reported cognitive deficits in children exposed prenatally to organophosphate pesticides, but findings from recent studies were inconsistent. Furthermore, recent biomonitoring studies suggest exposure levels have decreased. Hence, the risks from current prenatal exposure to organophosphate pesticides for child neurodevelopment are uncertain. Furthermore, sex-differences also remain to be better documented in relation to potential neurodevelopmental effects. OBJECTIVE: To examine the association between prenatal exposure to organophosphate pesticides and IQ scores among boys and girls living in several major Canadian cities. METHODS: We used data from the MIREC cohort (Maternal-Infant Research on Environmental Chemicals). Women were recruited in 2008-2011 from 10 Canadian cities during their first trimester of pregnancy, and urine spot samples were collected for measurement of three dimethyl alkyl phosphate (DMAP) and three diethyl alkyl phosphate (DEAP) metabolites. When children were 3-4 years of age, we used the Wechsler Preschool and Primary Scales of Intelligence-III (WPPSI-III) to assess cognitive ability of children from 6 out of the 10 cities (Halifax, Hamilton, Kingston, Montreal, Toronto, and Vancouver). We analysed the association between maternal exposure to organophosphate pesticides (DMAP and DEAP urinary metabolites) and children's IQ scores with generalized estimating equations (GEEs) to take into account the clustered-data resulting from the six study sites. All analyses were sex-stratified (n = 296 boys and 311 girls). RESULTS: The participants were predominantly well-educated, white women, with a relatively high household income. Children had a mean age of 3.4 years at the moment of IQ assessment (range, 3.0-4.1 years). In girls, there was no association between IQ scores and DEAPs or DMAPs. Higher concentrations of DEAPs were significantly associated with poorer Verbal IQ scores (for a 10-fold increase in concentrations, -6.28; 95% CIs, -12.13, -0.43) in boys. The association for Performance IQ in boys also indicated poorer scores with higher DEAP concentrations, but the confidence intervals included the null value (-4.05; 95% CIs, -10.19, 2.10). The relation between DMAPs and IQ scores in boys was also negative, but association estimates were small and not significant. CONCLUSION: Urinary metabolites of organophosphate pesticides were not associated with IQ in girls, but we observed that higher maternal urinary DEAPs were associated with poorer Verbal IQ in boys. However, exposure misclassification may be an issue as only one urine sample per woman was analysed. The present study contributes to the accumulating evidence linking exposure to organophosphate pesticides during fetal development with poorer cognitive function in children, bringing data on the risks in a context of low exposure levels encountered in primarily urban populations from Canada.

Anemia, iron status, and associated protective and risk factors among children and adolescents aged 3 to 19 years old from four First Nations communities in Quebec.

OBJECTIVES: Anemia and iron deficiency (ID) are frequent among Indigenous children of Canada, but few data are available in Quebec. The present study aimed to characterize anemia and ID prevalence and associated protective and risk factors among First Nations youth in Quebec. METHODS: The 2015 First Nations (JES!-YEH!) pilot study was conducted among children and adolescents (3 to 19 years; n = 198) from four First Nations communities in Quebec. Blood and urine samples and anthropometric measurements were collected. Hemoglobin (Hb), serum ferritin (SF), plasma hs-CRP, and urinary cotinine levels were measured. Factors associated with anemia and ID (including traditional and market food consumption) were assessed using an interview-administered food frequency questionnaire, based on which nutritional intakes were calculated. Structural equation models were used to test associations. RESULTS: The prevalence of anemia and ID was elevated (16.8% and 20.5% respectively). Traditional meat, fruit, and fruit juice (natural and powdered)-via their positive association with vitamin C intake-were the only food variables positively associated with SF (coefficient [95% CI] 0.017 [0.000, 0.114]; 0.090 [0.027, 0.161]; and 0.237 [0.060, 0.411]). Male sex was also associated with higher SF (0.295 [0.093, 0.502]). Inflammation status (hs-CRP > 5 mg/L) was inversely associated with Hb (- 0.015 [- 0.025, - 0.005]), whereas SF was positively associated with Hb (0.066 [0.040, 0.096]). Fruit and juice consumption was also positively associated with Hb, via vitamin C intake and SF (0.004 [0.001, 0.010]; 0.008 [0.003, 0.017]). CONCLUSIONS: Interventions fostering healthier food environments as well as higher consumption of traditional meats and foods naturally rich in vitamin C, which is known to enhance iron absorption, and fighting inflammation could contribute to decrease the high prevalence of anemia and ID in this young Indigenous population.

Persistent Organic Pollutants and Breast Cancer: A Systematic Review and Critical Appraisal of the Literature.

Persistent organic pollutants (POPs) bioaccumulate in the food chain and have been detected in human blood and adipose tissue. Experimental studies demonstrated that POPs can cause and promote growth of breast cancer. However, inconsistent results from epidemiological studies do not support a causal relationship between POPs and breast cancer in women. To identify individual POPs that are repeatedly found to be associated with both breast cancer incidence and progression, and to demystify the observed inconsistencies between epidemiological studies, we conducted a systematic review of 95 studies retrieved from three main electronic databases. While no clear pattern of associations between blood POPs and breast cancer incidence could be drawn, POPs measured in breast adipose tissue were more clearly associated with higher breast cancer incidence. POPs were more consistently associated with worse breast cancer prognosis whether measured in blood or breast adipose tissue. In contrast, POPs measured in adipose tissue other than breast were inversely associated with both breast cancer incidence and prognosis. Differences in biological tissues used for POPs measurement and methodological biases explain the discrepancies between studies results. Some individual compounds associated with both breast cancer incidence and progression, deserve further investigation.

WITHDRAWN: Corrigendum to "Biomarkers of cadmium, lead and mercury exposure in relation with early biomarkers of renal dysfunction and diabetes: Results from a pilot study among aging Canadian" [Toxicol. Lett. 312 (2019) 148-156].

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.toxlet.2019.05.020. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Exposure to polychlorinated biphenyls and organochlorine pesticides and risk of dementia, Alzheimer's disease and cognitive decline in an older population: a prospective analysis from the Canadian Study of Health and Aging.

BACKGROUND: Little attention has been paid to neurotoxicants on the risk of dementia. Exposure to known neurotoxicants such as polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides is suspected to have adverse cognitive effects in older populations. OBJECTIVE: To assess whether plasma concentrations of PCBs and OC pesticides are associated with the risk of cognitive decline, Alzheimer's disease (AD) and of all-cause dementia in the Canadian older population. METHODS: Analyses were based on data from the Canadian Study of Health and Aging, a 3-phase, 10-year population-based study of individuals aged 65+ years. Analyses included 669 clinically assessed subjects, of which 156 developed dementia including 108 incident cases of AD. Subjects were screened at each phase with the 100-point Modified Mini-Mental State Examination (3MS), a measurement of global cognitive function. Statistical analyses included Cox proportional hazards model when the outcome was dementia or AD, and a repeated-measure mixed model when the outcome was the 3MS score. RESULTS: No association of PCB and OC pesticides with the risk of dementia and AD was observed. Elevated concentrations of PCB congeners nos 118, 153, 156, 163, and OC pesticides 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (p,p'-DDT) and its metabolite 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) were significantly associated with cognitive decline as assessed with the 3MS. A posteriori analyses suggested that only p,p'-DDE was significantly related to a higher cognitive decline in time based on the 3MS among incident cases of dementia compared to subjects remaining nondemented. CONCLUSION: PCB and OC pesticide plasma concentrations were not related to the incident diagnosis of neither dementia, nor AD. Using the 3MS scores as the outcome, higher concentrations of four PCB congeners and two OC pesticides were associated with lower cognitive performances in subjects. The association of p,p'-DDE with cognitive decline in time in incident cases of dementia merits further investigation.

Biomarkers of cadmium, lead and mercury exposure in relation with early biomarkers of renal dysfunction and diabetes: Results from a pilot study among aging Canadians.

Cadmium (Cd), lead (Pb) and mercury (Hg) are known nephrotoxicants that have been associated with the risk of developing type-2 diabetes (T2D). The aim of this pilot study was to explore relations between biomarkers of Cd, Pb and Hg exposure, early urinary biomarkers of renal dysfunction (kidney-injured molecule-1 (KIM-1), N-acetylglucosaminidase and retinol-binding protein (RBP)) and plasma biomarkers deemed predictive of the risk of developing T2D (adiponectin, leptin, branched-chain and aromatic amino acids), among 70 participants (age range: (46-87 yrs)) from the Canadian Longitudinal Study on Aging (CLSA) with normal glycemic control (glycated haemoglobin ≤ 6.5%) in all but four of them. Significant (p < 0.05) Spearman correlation coefficients were obtained between: plasma adiponectin and RBP (r = 0.42), urinary Cd (r = 0.32), blood Cd (r = 0.36); KIM-1 and CdU (r = 0.33) as well as HgU (r = 0.37); RBP and isoleucine (r = -0.28), leucine (r = -0.33), tyrosine (r = -0.3) and valine (r = -0.44); CdU and isoleucine and valine (r = -0.27 for both). Multiple linear regression analyses showed that some T2D-related biomarkers are confounders of associations between RBP and Hg or Cd biomarkers. Path analyses support a mediating effect of adiponectin on the relation between urinary Cd and RBP. Concluding, this pilot study originally investigated a comprehensive set of biomarkers on complex interactions between toxic metal exposure, renal function and T2D in a group of aging Canadians. Its findings warrant further investigation of longitudinal data in a greater number of participants.

Temporal trends of legacy and emerging persistent organic pollutants in inuit preschoolers from Northern Quebec (Canada).

In this study, we report the temporal trends of persistent organic pollutants (POPs) in 181 preschool Inuit children from Nunavik and the influence of confounding factors on blood contaminant levels. From 2006 to 2010, no significant trends were detected in Σpolychlorinated biphenyls (ΣPCBs), Σorganochlorine pesticides (ΣOPs), Σtoxaphene, and Σper- and polyfluoroalkyl substances (ΣPFASs). On the contrary, significant downward trends ranging from 9.3% to 14.3% per year were found for polybrominated diphenyl ethers (PBDEs). Breastfeeding was significantly associated with increased levels of POPs. Age was positively and significantly related to ΣPCBs, ΣOPs and Σtoxaphene. Compared with girls, boys had significantly higher concentrations of ΣPBDEs, but lower concentrations of ΣPFASs. Weight-for-height or body mass index z-scores were negatively and significantly related to ΣPCBs and ΣOPs. Passive smoking was positively and significantly associated with ΣOPs and Σtoxaphene. In conclusion, continued efforts to reduce contaminant exposure are needed to protect children's health and development.

Maternal smoking and high BMI disrupt thyroid gland development.

BACKGROUND: Maternal lifestyle factors, including smoking and increased body weight, increase risks of adult diseases such as metabolic syndrome and infertility. The fetal thyroid gland is essential for the control of fetal metabolic rate, cardiac output, and brain development. Altered fetal thyroid function may contribute to increased disease onset later in life. Here, we investigated the impact of maternal smoking and high maternal weight on human fetal thyroid function during the second trimester. METHODS: Thyroid glands and plasma were collected from fetuses electively terminated in the second trimester (normally progressing pregnancies). Plasma total triiodothyronine (T3) and total thyroxine (T4) were measured by solid-phase extraction-liquid chromatography-tandem mass spectrometry. Fetal plasma thyroid-stimulating hormone (TSH) levels were measured using a multiplex assay for human pituitary hormones. Histology and immunolocalization of thyroid developmental markers were examined in thyroid sections. Transcript levels of developmental, functional, apoptotic, and detoxification markers were measured by real-time PCR. Statistical analyses were performed using multivariate linear regression models with fetal age, sex, and maternal smoking or maternal body mass index (BMI) as covariates. RESULTS: Maternal smoking was associated with significant changes in fetal plasma T4 and TSH levels during the second trimester. Smoke-exposed thyroids had reduced thyroid GATA6 and NKX2-1 transcript levels and altered developmental trajectories for ESR2 and AHR transcript levels. Maternal BMI > 25 was associated with increased fetal thyroid weight, increased plasma TSH levels, and abnormal thyroid histology in female fetuses. Normal developmental changes in AHR and ESR1 transcript expression were also abolished in fetal thyroids from mothers with BMI > 25. CONCLUSIONS: For the first time, we show that maternal smoking and high maternal BMI are associated with disturbed fetal thyroid gland development and endocrine function in a sex-specific manner during the second trimester. These findings suggest that predisposition to post-natal disease is mediated, in part, by altered fetal thyroid gland development.

Nickel and associated metals in New Caledonia: Exposure levels and their determinants.

The ultramafic massifs of the New Caledonian archipelago contain about 10% of the world's nickel reserves, which also contain significant but lower amounts of cobalt, chromium, and manganese. Natural erosion of these massifs and mining activities may contribute to the exposure of local populations to these metals through contamination of air, food, and water resources. We conducted a biomonitoring survey to evaluate exposure to these four metals and its main determinants by constructing a stratified sample of 732 adults and children (>3 years old) from visitors to 22 health centers across the archipelago. Urine was collected and analyzed by inductively-coupled plasma mass spectrometry to determine metal concentrations. A face-to-face interview was conducted to document sociodemographic characteristics, lifestyle and dietary habits, and residence-mine distance. Environmental samples (soil, house dust, water, and foodstuffs) were collected from two areas (one with and one without mining activity) to delineate determinants of exposure in more detail. Nickel and chromium were metals with the highest concentrations found in urine, especially in children, at levels exceeding reference values derived from representative national surveys elsewhere throughout the world (for children: 4.7 µg/g creatinine for nickel and 0.50 µg/g creatinine for chromium): 13% of children exceeded the reference value for nickel and 90% for chromium. Large variations were observed by region, age, and sex. In this geological setting, urinary and environmental nickel concentrations appear to be driven mainly by soil content. This is the first archipelago-wide survey of metal exposure in New Caledonia. The potential health consequences of this chronic high exposure need to be assessed.

Genetic polymorphisms are associated with exposure biomarkers for metals and persistent organic pollutants among Inuit from the Inuvialuit Settlement Region, Canada.

BACKGROUND: Inuit are exposed to some of the highest levels of contaminants worldwide. Studies suggest that several genes that mediate the metabolism of these contaminants are polymorphic. We hypothesize that single nucleotide polymorphisms (SNPs) in such genes may underline differences in biomarker concentrations and/or modify exposure-biomarker associations. METHODS: Members from the Inuvialuit Settlement Region (Canada) were recruited. Blood concentrations of mercury (Hg), cadmium (Cd), lead (Pb), dichlorodiphenyldichloroethylene (DDE), and polychlorinated biphenyl (PCB-153) were measured. SNPs from pathways such as glutathione, metallothionein, oxidative stress, and xenobiotic transport were genotyped in 281 participants, and data from 112 SNPs were included in the analyses. Surveys were administered to obtain information on demographics, and key sources of Hg (diet) and Cd (smoking) exposure. ANOVA and linear regressions were used for data analyses. RESULTS: Geometric mean concentrations of metals were 4.6µg/L for Hg, 1.3µg/L for Cd, and 32.2µg/L for Pb. Concentrations of organic pollutants were 2.0µg/L for DDE and 0.6µg/L for PCB-153. Biomarker levels for Hg, Cd, Pb, DDE, and PCB-153 differed (p<0.05) by genotype for 4, 3, 4, 3, and 3 SNPs, respectively. In multivariable analyses (for Pb, DDE, PCB-153) adjusting age, sex and body mass index (BMI), only 2 associations (one for Pb and one for DDE) remained significant. In multivariable analyses accounting for sources of Hg or Cd exposure, 24 SNPs (9 for Hg, 15 for Cd with 4 overlapping) had significant (p<0.05) main effects on biomarker levels and/or modified exposure-biomarker associations. CONCLUSION: The findings suggest that polymorphisms in key environmentally responsive genes can influence biomarker levels and/or modify exposure-biomarker associations for contaminants of concern to Arctic populations. Consideration of such gene-environment results may help improve the ability to conduct exposure (and ultimately risk) assessments of country foods and Inuit health.

Risk of gestational diabetes mellitus in relation to plasma concentrations of amino acids and acylcarnitines: A nested case-control study.

AIMS: Gestational diabetes mellitus (GDM) affects between 5 and 10% of all pregnancies in Canada and can lead to adverse health outcomes in both the mother and fetus. Amino acids (AA) and acylcarnitines (AC) have been identified as early biomarkers of type 2 diabetes but their usefulness in screening for GDM has yet to be demonstrated. METHODS: We conducted a nested case-control study involving 50 controls and 50 GDM cases diagnosed between the 24th and 28th week of gestation. Heparinized plasma samples were obtained during the first and early second trimester of pregnancy. Case and controls were matched according to date of recruitment, maternal age, gestational age at blood sampling as well as pre-pregnancy body mass index. Eight AA and eight AC were quantified using an ultra-high pressure liquid-chromatography quadrupole time-of-flight mass spectrometry platform. Conditional regression analyses adjusted for matching factors and smoking habits during pregnancy were performed to identify plasma metabolites associated with GDM risk. RESULTS: Odds ratio (OR) and 95% confidence interval (CI) for the prediction of GDM per one standard deviation increase of AA or AC in plasma levels were 0.25 (0.08-0.79) for butyrylcarnitine, 0.31 (0.12-0.79) for glutamic acid, 2.5 (1.2-5.3) for acetylcarnitine, 2.9 (1.3-6.8) for isobutyrylcarnitine and 5.3 (1.7-17.0) for leucine. These five metabolites were selected by stepwise conditional logistic regression to create a predictive model with an OR of 2.7 (1.5-4.9). CONCLUSION: Whether the identified metabolites can predict the risk of developing GDM requires additional studies in a larger sample of pregnant women.

Estradiol metabolites as biomarkers of endometrial cancer prognosis after surgery.

Endometrial cancer (EC) is the most common gynecologic malignancy prevailing after menopause. Defining steroid profiles may help predict the risk of recurrence after hysterectomy, which remains limited due to the lack of reliable markers. Adrenal precursors, androgens, parent estrogens and catechol estrogen metabolites were measured by mass spectrometry (MS) in preoperative serums and those collected one month after hysterectomy from 246 newly diagnosed postmenopausal EC cases. We also examined the associations between steroid hormones and EC status by including 110 healthy postmenopausal women. Steroid concentrations were analyzed in relation to clinicopathological features, recurrence and overall survival (OS). The mean follow-up time was 65.5 months and 26 patients experienced relapse after surgery for a recurrence incidence of 10.6% (6.4% Type I and 29.5% Type II). Recurrence and OS were related to a more aggressive disease but not linked to body mass index. Preoperative levels of estriol (E3) and estrone-sulfate (E1-S) were inversely associated with recurrence in a multivariate logistic regression analysis (Hazard ratios (HRs) of 0.31, P=0.039 and 3.01, P=0.024; respectively). All circulating steroids declined considerably after surgery almost reaching those of healthy women, except 4-methoxy-E2 (4MeO-E2) for which postoperative levels increased by 35% and were associated to a 68% decreased risk of recurrence (HR=0.32, P=0.015). Women diagnosed with both histological types of EC present significantly higher levels of steroids, in support of their mitogenic effects. The estrogen precursor E1-S, the anticancer metabolite 4MeO-E2, and E3 that exert mixed antagonist and agonist estrogenic activities and immunological effects, are potential independent prognostic factors.

Health effects associated with measured levels of contaminants in the Arctic.

The Human Health Assessment Group has over the past decade recommended that effect studies be conducted in the circumpolar area. Such studies examine the association between contaminant exposure in the Arctic populations and health effects. Because foetuses and young children are the most vulnerable, effect studies are often prospective child cohort studies. The emphasis in this article is on a description of the effects associated with contaminant exposure in the Arctic. The main topics addressed are neurobehavioural, immunological, reproductive, cardiovascular, endocrine and carcinogenic effect. For each topic, the association between exposure and effects is described, and some results are reported for similar studies outside the Arctic.

Evaluation of exposure to organophosphate, carbamate, phenoxy acid, and chlorophenol pesticides in pregnant women from 10 Caribbean countries.

Pesticides are commonly used in tropical regions such as the Caribbean for both household and agricultural purposes. Of particular concern is exposure during pregnancy, as these compounds can cross the placental barrier and interfere with fetal development. The objective of this study was to evaluate exposure of pregnant women residing in 10 Caribbean countries to the following commonly used classes of pesticides in the Caribbean: organophosphates (OPs), carbamates, phenoxy acids, and chlorophenols. Out of 438 urine samples collected, 15 samples were randomly selected from each Caribbean country giving a total of 150 samples. Samples were analyzed for the following metabolites: six OP dialkylphosphate metabolites [dimethylphosphate (DMP), dimethylthiophosphate (DMTP), dimethyldithiophosphate (DMDTP), diethylphosphate (DEP), diethylthiophosphate (DETP) and diethyldithiophosphate (DEDTP)]; two carbamate metabolites [2-isopropoxyphenol (2-IPP) and carbofuranphenol]; one phenoxy acid 2,4-dichlorophenoxyacetic acid (2,4-D); and five chlorophenols [2,4-dichlorophenol (DCP), 2,5-dichlorophenol (2,5-DCP), 2,4,5-trichlorophenol (TCP), 2,4,6-trichlorophenol (2,4,6-TCP), and pentachlorophenol (PCP)]. OP metabolites were consistently detected in ≥60% of the samples from Antigua and Barbuda, Bermuda, and Jamaica. Of the carbamate metabolites, 2-IPP was detected in seven of the 10 Caribbean countries with a detection frequency around 30%, whereas carbofuranphenol was detected in only one sample. The detection frequency for the phenoxy acid 2,4-D ranged from 20% in Grenada to a maximum of 67% in Belize. Evidence of exposure to chlorophenol pesticides was also established with 2,4-DCP by geometric means ranging from 0.52 µg L(-1) in St Lucia to a maximum of 1.68 µg L(-1) in Bermuda. Several extreme concentrations of 2,5-DCP were detected in four Caribbean countries-Belize (1100 µg L(-1)), Bermuda (870 µg L(-1)), Jamaica (1300 µg L(-1)), and St Kitts and Nevis (1400 µg L(-1)). 2,4,5-TCP, 2,4,6-TCP, and pentachlorophenol were rarely detected. This biomonitoring study underscores the need for Caribbean public health authorities to encourage their populations, and in particular pregnant women, to become more aware of the potential routes of exposure to pesticides and to utilize these chemicals more cautiously given the possible adverse effects such exposures can have on their unborn children and infants.

Kinetics of Diol and Hydroxybenzo[a]pyrene Metabolites in Relation to DNA Adduct Formation and Gene Expression in Rats.

Benzo[a]pyrene (BaP) is a human carcinogen, but there are no validated biomarkers of exposure and the relationship of carcinogenesis with early biological alterations is not fully documented. This study aimed at better documenting the toxicokinetics of diolBaP and hydroxyBaP metabolites as potential biomarkers of exposure to BaP in relation to DNA adduct formation and gene expression. Rats were intravenously (iv) injected with 40 µmol/kg BaP. BaP and several metabolites were measured in blood, tissues, and excreta collected at frequent intervals over 72 h posttreatment. BaP diol epoxide (BaPDE)-DNA adduct formation and gene expression were assessed in lungs. 3-HydroxyBaP (3-OHBaP) and 4,5-diolBaP were the most abundant measured metabolites, and differences in time courses were apparent between the two metabolites. Over the 0-72 h period, mean proportions of BaP dose recovered in urine as 3-OHBaP and 4,5-diolBaP (±SD) were 0.017 ± 0.003% and 0.1 ± 0.03%. Corresponding values in feces were 1.5 ± 0.5% and 0.42 ± 0.052%. BaPDE-DNA adducts were significantly increased in lungs and a correlation was observed with urinary 3-OHBaP and 4,5-diolBaP. Analysis of gene expression showed a modulation of expression of metabolic genes (Cyp1a1, Cyp1b1, Nqo1, Ahr) and oxidative stress and repair genes (Nrf2, Rad51). However, BaPDE adducts formation did not exhibit any significant correlation with expression of genes, except a negative correlation with Rad51 expression. Similarly, there was no significant correlation between urinary excretion of OHBaP and diolBaP and expression of genes, except for urinary 7-OHBaP excretion, which was negatively correlated with Rad51 expression. Results indicate that concomitant measurements of diolBaP and OHBaP may serve to better assess the extent of exposure as compared to single metabolite measurements, given kinetic differences between metabolites. Further, although some urinary metabolites were correlated with BaPDE adducts, links with gene expression need to be further investigated.