Environmental Health Science and Research Bureau

Ottawa, Canada

Environmental Health Science and Research Bureau

Ottawa, Canada

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Arbuckle T.E.,Environmental Health Science and Research Bureau
Birth defects research. Part A, Clinical and molecular teratology | Year: 2010

There is growing concern about the potential health effects of exposure to various environmental chemicals during pregnancy and infancy. One of the key limitations of past epidemiologic research in this field has been the potential for exposure misclassification to lead to biases in the health risk estimate. The use of biomarkers in pregnancy cohort or case-control studies has significantly advanced the field; however, this is true only if the biomarker is a true measurement of exposure for the relevant time period of interest. There are a number of theoretical and practical constraints to their use, including difficulty interpreting biomonitoring data, high analytical and collection costs, potential participant selection biases, and ethical challenges in reporting results to study subjects. Identifying a representative sample and collecting biospecimens in the developmental window of interest can be problematic. Various strategies for identifying pregnant women range from the more representative but least efficient sampling of the general population to recruitment through early ultrasound clinics and local advertising. Whereas measurement of xenobiotic chemicals in cord blood, amniotic fluid, or meconium provides unequivocal evidence that the chemical has entered the fetal environment, analysis of maternal blood and urine can be used as a surrogate for fetal exposure. Use of stored midpregnancy serum collected for fetal screening and of large-cohort biobanks offer unique opportunities for biomonitoring data for birth defects studies. Future research is needed to explore less invasive matrices for biomonitoring of infants and to develop less costly analytical methods that require smaller sample volumes. © 2010 Wiley-Liss, Inc.

Abdou H.-S.,Research Center | Atlas E.,Environmental Health Science and Research Bureau | Hache R.J.G.,York University
Endocrinology | Year: 2013

Glucocorticoids promote adipogenesis and contribute to the metabolic syndrome through a number of mechanisms. One of the effectors of glucocorticoid action is the CCAAT/enhancer binding protein β (C/EBPβ). C/EBPβ is a basic leucine-zipper transcription factor involved in diverse processes including differentiation, cellular proliferation, and inflammation. C/EBPβ transcriptional activity is regulated, in part, by its acetylation profile resulting from its dynamic interaction with either acetylases general control nonrepressed protein 5/p300/CBP associated factor (GCN5/PCAF) or deacetylase complexes (mSin3A/histone deacetylase 1 [HDAC1]). Glucocorticoid treatment of preadipocytes promotes C/EBPβ acetylation, leading to mSin3A/HDAC1 dissociation from C/EBPβ and resulting in C/ebpα promoter activation at the onset of adipogenesis, thus increasing the differentiation rate. We recently showed that the regulatory domain 1 (RD1) of C/EBPβ contains four residues (153-156) required for its interaction with HDAC1, therefore supporting RD1 proposed inhibitory role. In an attempt to further elucidate the intrinsic regulatory property of RD1, we sought to characterize the regulatory potential of the N terminus region of RD1 (residues 141-149). In this study, we show that C/EBPβΔ141-149 transcriptional activity was compromised on the C/ebpα, but not on the Pparγ, promoter. Additionally, the ability of C/EBPβΔ141-149 to induce adipogenesis in NIH 3T3 cells was compromised when compared with C/EBPβwt owing to a delayed expression of C/ebpα at the onset of differentiation. Furthermore, the data suggest that the reduced expression of C/ebpα in cells expressing C/EBPβ Δ141-149 was due to a persistent recruitment of HDAC1 to the C/ebpα promoter after glucocorticoid treatment. Together, these results suggest that amino acids 141-149 of C/EBPβ act as a positive regulatory domain required for maximum transcriptional activity. Copyright © 2013 by The Endocrine Society.

Singer T.M.,Environmental Health Science and Research Bureau | Yauk C.L.,Environmental Health Science and Research Bureau
Environmental and Molecular Mutagenesis | Year: 2010

Heritable mutations may result in a wide variety of detrimental outcomes, from embryonic lethality to genetic disease in the offspring. Despite this, today's commonly used test batteries do not include assays for germ cell mutation. Current challenges include a lack of practical assays and concrete evidence for human germline mutagens, and large data gaps that often impede risk assessment. Moreover, most regulatory assessments are based on the assumption that somatic cell mutation assays also protect the germline by default, which has not been adequately confirmed. The field is also faced with new challenges aimed at dramatically reducing animal testing, and attempts to rapidly classify thousands of chemicals using high throughput in vitro assays. These approaches may not adequately capture effects that may be particular to gametes, since many aspects of the germline are unique. In light of these challenges, an urgent need exists to develop new approaches to evaluate the potential of toxicants to cause germline mutation. The application of new technologies will greatly enhance our understanding of mutation in humans exposed to environmental mutagens. However, we must be poised to collect and interpret these data, and facilitate risk translation to regulators and the public. Genetic toxicologists must also become actively involved in the development of high-throughput tools to study germline mutation. Appropriate attention to these areas will result in the development of policies that prioritize the protection of the germline and future generations from DNA sequence mutations. © 2010 Government of Canada.

Vanos J.K.,Environmental Health Science and Research Bureau | Vanos J.K.,Texas Tech University | Hebbern C.,Environmental Health Science and Research Bureau | Cakmak S.,Environmental Health Science and Research Bureau
Environmental Pollution | Year: 2014

Synoptic weather and ambient air quality synergistically influence human health. We report the relative risk of mortality from all non-accidental, respiratory-, and cardiovascular-related causes, associated with exposure to four air pollutants, by weather type and season, in 10 major Canadian cities for 1981 through 1999. We conducted this multi-city time-series study using Poisson generalized linear models stratified by season and each of six distinctive synoptic weather types. Statistically significant relationships of mortality due to short-term exposure to carbon monoxide, nitrogen dioxide, sulphur dioxide, and ozone were found, with significant modifications of risk by weather type, season, and mortality cause. In total, 61% of the respiratory-related mortality relative risk estimates were significantly higher than for cardiovascular- related mortality. The combined effect of weather and air pollution is greatest when tropical-type weather is present in the spring or summer. © 2013 Published by Elsevier Ltd. All rights reserved.

Thomson E.M.,Environmental Health Science and Research Bureau | Williams A.,Environmental Health Science and Research Bureau | Yauk C.L.,Environmental Health Science and Research Bureau | Vincent R.,Environmental Health Science and Research Bureau
American Journal of Pathology | Year: 2012

Increased production of tumor necrosis factor (TNF)-α and matrix metalloproteinases (MMPs) is a feature of inflammatory lung diseases, including emphysema and fibrosis, but the divergent pathological characteristics that result indicate involvement of other processes in disease pathogenesis. Transgenic mice overexpressing TNF-α in type II alveolar epithelial cells under the control of the surfactant protein (SP)-C promoter develop pulmonary inflammation and emphysema but are resistant to induction of fibrosis by administration of bleomycin or transforming growth factor-β. To study the molecular mechanisms underlying the development of this phenotype, we used a microarray approach to characterize the pulmonary transcriptome of SP-C/TNF-α mice and wild-type littermates. Four-month-old SP-C/TNF-α mice displayed pronounced pulmonary inflammation, airspace enlargement, increased MMP-2 and MMP-9 levels, and altered expression of 2332 probes. The functional assessment of genes with increased expression revealed enrichment of inflammatory/immune responses and proteases, whereas genes involved in protease inhibition, angiogenesis, cross-linking of basement membrane proteins, and myofibroblast differentiation were predominantly decreased. Comparison with multiple lung disease models identified a set of genes unique to the SP-C/TNF-α model and revealed that lack of extracellular matrix production distinguished SP-C/TNF-α mice from fibrosis models. Activation of inflammatory and proteolytic pathways and disruption of maintenance and repair processes are central features of emphysema in this TNF-overexpression model. Impairment of myofibroblast differentiation and extracellular matrix production may underlie resistance to induction of fibrosis.

Boucher J.G.,Environmental Health Science and Research Bureau | Boudreau A.,Environmental Health Science and Research Bureau | Atlas E.,Environmental Health Science and Research Bureau
Nutrition and Diabetes | Year: 2014

background: Obesity is a major health concern in the developed world, and increasing evidence suggests that exposures to common environmental substances may enhance the risk for the development of this disease. objectiveS: The current study examines the effect of the ubiquitous plastic monomer bisphenol A (BPA) on the differentiation of primary human preadipocytes in vitro and the role of the estrogen and glucocorticoid receptors. mathods: In this study, the mechanism of BPA-induced adipogenesis in preadipocytes from donors with healthy body mass index in the absence of exogenous glucocorticoid was evaluated. The effects of estradiol, the estrogen-receptor (ER) antagonist ICI and the glucocorticoid receptor (GR) antagonist RU486 on BPA-induced adipogenesis were examined. The expression levels of key adipogenic factors were assessed. results: Treatment of preadipocytes with 1-50 mM BPA induced a dose-dependent increase in differentiation and lipid accumulation as determined by lipid staining and triacylglyceride quantification. BPA also induced expression of the adipogenic markers aP2, adipsin, peroxisome proliferator-activated receptor g and the CCAAT-enhancer-binding proteins a and b. Co-treatment of cells with ICI inhibited the BPA-induced increase in aP2 levels, while treatment with ICI or estradiol alone had no effect. Treatment of cells with the GR antagonist RU486 had no effect on BPA-induced differentiation as evaluated by aP2 levels. conclusionS: This study is one of the first to show that BPA induces human adipocyte differentiation in the absence of exogenous glucocorticoid through a non-classical ER pathway rather than through GR activation. These studies add to the growing evidence that endocrine-disrupting chemicals such as BPA have the potential to modulate adipogenesis and impact human biology.© 2014 Macmillan Publishers Limited.

Nguyen K.C.,Environmental Health Science and Research Bureau | Seligy V.L.,Environmental Health Science and Research Bureau | Tayabali A.F.,Environmental Health Science and Research Bureau
Nanotoxicology | Year: 2013

This study examines dose effects of cadmium telluride quantum dots (CdTe-QDs) from two commercial sources on model macrophages (J774A.1) and colonic epithelial cells (HT29). Effects on cellular immune signalling responses were measured following sequential exposure to QDs and Pseudomonas aeruginosa strain PA01. At CdTe-QD concentrations between 10-2 and 10 μg/ml, cells exhibited changes in metabolism and morphology. Confocal imaging revealed QD internalisation and changes in cell-cell contacts, shapes and internal organisations. QD doses below 10-2 μg/ml caused no observed effects. When QD exposures at 10-7 to 10-3 μg/ml preceded PA01 (107 bacteria/ml) challenges, there were elevated cytotoxicity (5-22%, p < 0.05) and reduced levels (two- to fivefold, p < 0.001) of nitric oxide (NO), TNF-α, KC/CXC-1 and IL-8, compared with PA01 exposures alone. These results demonstrate that exposures to sub-toxic levels of CdTe-QDs can depress cell immune-defence functions, which if occurred in vivo would likely interfere with normal neutrophil recruitment for defence against bacteria. © 2013 Informa UK, Ltd.

Boucher J.G.,Environmental Health Science and Research Bureau | Boudreau A.,Environmental Health Science and Research Bureau | Ahmed S.,Environmental Health Science and Research Bureau | Atlas E.,Environmental Health Science and Research Bureau
Environmental Health Perspectives | Year: 2015

BACKGROUND: Exposure to common environmental substances, such as bisphenol A (BPA), has been associated with a number of negative health outcomes. In vivo, BPA is rapidly converted to its predominant metabolite, BPA-glucuronide (BPA-G), which has long been believed to be biologically inactive because it lacks estrogenic activity. However, the effects of BPA-G on cellular metabolism have not been characterized. In the present study we examined the effect of BPA-G on adipogenesis. METHODS: The effect of BPA-G on the differentiation of human and 3T3L1 murine preadipocytes was evaluated in vitro by quantifying lipid accumulation and the expression of adipogenic markers. RESULTS: Treatment of 3T3L1 preadipocytes with 10 μM BPA-G induced a significant increase in lipid accumulation, mRNA expression of the adipogenic markers sterol regulatory element binding factor 1 (SREBF1) and lipoprotein lipase (LPL), and protein levels of LPL, aP2, and adipsin. Treatment of primary human preadipocytes with BPA-G also induced adipogenesis as determined by aP2 levels. Co-treatment of cells with the estrogen receptor (ER) antagonist fulvestrant (ICI) significantly inhibited the BPA-G—induced increase in LPL and aP2 levels, whereas treatment with ICI alone had no effect. Moreover, BPA-G did not display any significant estrogenic activity. CONCLUSIONS: To our knowledge, this study is the first to report that BPA-G induces adipocyte differentiation and is not simply an inactive metabolite. The fact that BPA-G induced adipogenesis and was inhibited by an ER antagonist yet showed no estrogenic activity suggests that it has no classical ER transcriptional activation function and acts through a pathway that remains to be determined. © 2015 Public Health Services, US Dept of Health and Human Services. All rights reserved.

Cakmak S.,Environmental Health Science and Research Bureau | Dales R.E.,University of Ottawa | Coates F.,Aerobiology Research Laboratories
Journal of Allergy and Clinical Immunology | Year: 2012

Background: Clinical experiments demonstrate that the asthmatic response to an aeroallergen can be enhanced by prior exposure to an air pollutant. Objective: We sought to compare the effects of ambient aeroallergens on hospitalization for asthma between high and low air pollution days in 11 large Canadian cities. Methods: Daily time-series analysis was used, and results were adjusted for day of the week, temperature, barometric pressure, and relative humidity. Results: The relative risk of admission for an interquartile increase in tree pollen levels was 1.124 (95% CI, 1.101-1.147) on days of lower values of fine particulate matter with a median aerodynamic diameter less than or equal to 2.5 μm (PM 2.5) compared with 1.179 (95% CI, 1.149-1.21) on days of higher PM 2.5 values. Significant (P ≤.05) differences in the relative risks of admission between lower versus higher values of particulate matter with a median aerodynamic diameter less than or equal to 10 μm in diameter were 1.149 (95% CI, 1.118-1.181) versus 1.210 (95% CI, 1.161-1.261) for ascomycetes, 1.112 (95% CI, 1.085-1.14) versus 1.302 (95% CI, 1.242-1.364) for basidiomycetes, 1.159 (95% CI, 1.125-1.195) versus 1.149 (95% CI, 1.129-1.169) for deuteromycetes, and 1.061 (95% CI, 1.016-1.107) versus 1.117 (95% CI, 1.092-1.143) for weeds. Conclusion: We identified an association between aeroallergens and hospitalizations for asthma, which was enhanced on days of higher air pollution. Minimizing exposure to air pollution might reduce allergic exacerbations of asthma. © 2011 American Academy of Allergy, Asthma & Immunology.

Stieb D.M.,Environmental Health Science and Research Bureau | Stieb D.M.,University of Ottawa | Chen L.,Environmental Health Science and Research Bureau | Eshoul M.,University of Ottawa | Judek S.,Environmental Health Science and Research Bureau
Environmental Research | Year: 2012

Low birth weight and preterm birth have a substantial public health impact. Studies examining their association with outdoor air pollution were identified using searches of bibliographic databases and reference lists of relevant papers. Pooled estimates of effect were calculated, heterogeneity was quantified, meta-regression was conducted and publication bias was examined. Sixty-two studies met the inclusion criteria. The majority of studies reported reduced birth weight and increased odds of low birth weight in relation to exposure to carbon monoxide (CO), nitrogen dioxide (NO 2) and particulate matter less than 10 and 2.5 microns (PM 10 and PM 2.5). Effect estimates based on entire pregnancy exposure were generally largest. Pooled estimates of decrease in birth weight ranged from 11.4g (95% confidence interval -6.9-29.7) per 1ppm CO to 28.1g (11.5-44.8) per 20ppb NO 2, and pooled odds ratios for low birth weight ranged from 1.05 (0.99-1.12) per 10μg/m 3 PM 2.5 to 1.10 (1.05-1.15) per 20μg/m 3 PM 10 based on entire pregnancy exposure. Fewer effect estimates were available for preterm birth and results were mixed. Pooled odds ratios based on 3rd trimester exposures were generally most precise, ranging from 1.04 (1.02-1.06) per 1ppm CO to 1.06 (1.03-1.11) per 20μg/m 3 PM 10. Results were less consistent for ozone and sulfur dioxide for all outcomes. Heterogeneity between studies varied widely between pollutants and outcomes, and meta-regression suggested that heterogeneity could be partially explained by methodological differences between studies. While there is a large evidence base which is indicative of associations between CO, NO 2, PM and pregnancy outcome, variation in effects by exposure period and sources of heterogeneity between studies should be further explored. © 2012.

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