Center for Child Environmental Health Risks Research

Seattle, WA, United States

Center for Child Environmental Health Risks Research

Seattle, WA, United States
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Robinson J.F.,University of Washington | Robinson J.F.,Institute for Risk Analysis and Risk Communication | Griffith W.C.,University of Washington | Griffith W.C.,Institute for Risk Analysis and Risk Communication | And 12 more authors.
Reproductive Toxicology | Year: 2010

Methylmercury (MeHg) is a developmental neurotoxicant and teratogen and is hypothesized to perturb a wide range of biological processes, like other metals including arsenic (As) and cadmium (Cd). Common inbred mouse strains including C57 (sensitive) and SWV (resistant) display differences in sensitivity to metals such as As and Cd when exposed during neurulation. In this study, we investigated the impact of MeHg on neurulation, assessing for potential differences in sensitivity and associated toxicogenomic response in C57 and SWV mouse embryos. Parallel with morphological assessments of neural tube closure, we evaluated quantitative differences in MeHg-induced alterations in expression between strains at the gene level and within gene-enriched biological processes. Specifically, we observed differing sensitivities to MeHg-induced impacts on neural tube closure between C57 and SWV embryos in a time-dependent manner. These observations correlated with greater impact on the expression of genes associated with development and environmental stress-related pathways in the C57 compared to the SWV. Additional developmental parameters (e.g. mortality, growth effects) evaluated showed mixed significant effects across the two strains and did not support observations of differential sensitivity to MeHg. This study provides potential insights into MeHg-induced mechanisms of developmental toxicity, alterations associated with increased MeHg sensitivity and common biological processes affected by metals in embryos undergoing neurulation. © 2010 Elsevier Inc.


Robinson J.F.,University of Washington | Yu X.,University of Washington | Yu X.,Institute for Risk Analysis and Risk Communication | Hong S.,University of Washington | And 7 more authors.
Reproductive Toxicology | Year: 2010

Differences in sensitivity are observed between mouse strains, C57 (sensitive) and SWV (resistant) when exposed to cadmium (Cd) during the neurulation period. In this study, we investigated the toxicokinetics of Cd in relation with toxicodynamic responses to identify factors affecting differential Cd-sensitivity in C57 and SWV. Using a level of exposure which induced developmental toxicity and differential effects between strains, we assessed maternal and embryonic Cd uptake and evaluated biomarkers of response previously linked with Cd exposure, specifically metal ion regulators (Mt1, Mt2, DMT1) and markers of cell cycle arrest/apoptosis induction (p53, Cdkn1a, c-Casp3). Greater Cd uptake was observed in C57 embryos compared to SWV and these observations of differential uptake were associated with increased alterations in expression of biomarkers of metal response (e.g. c-Casp3) and strain sensitivity. Using sensitive and resistant mouse strains, we have identified toxicokinetic and dynamic differences which underlie observed differences in Cd embryonic sensitivity and response. © 2010 Elsevier Inc.


Robinson J.F.,University of Washington | Robinson J.F.,Institute for Risk Analysis and Risk Communication | Yu X.,University of Washington | Yu X.,Institute for Risk Analysis and Risk Communication | And 8 more authors.
Toxicology and Applied Pharmacology | Year: 2011

Arsenic (As) and cadmium (Cd) are well-characterized teratogens in animal models inducing embryotoxicity and neural tube defects (NTDs) when exposed during neurulation. Toxicological research is needed to resolve the specific biological processes and associated molecular pathways underlying metal-induced toxicity during this timeframe in gestational development. In this study, we investigated the dose-dependent effects of As and Cd on gene expression in C57BL/6J mouse embryos exposed in utero during neurulation (GD8) to identify significantly altered genes and corresponding biological processes associated with embryotoxicity. We quantitatively examined the toxicogenomic dose-response relationship at the gene level. Our results suggest that As and Cd induce dose-dependent gene expression alterations representing shared (cell cycle, response to UV, glutathione metabolism, RNA processing) and unique (alcohol/sugar metabolism) biological processes, which serve as robust indicators of metal-induced developmental toxicity and indicate underlying embryotoxic effects. Our observations also correlate well with previously identified impacts of As and Cd on specific genes associated with metal-induced toxicity (Cdkn1a, Mt1). In summary, we have identified in a quantitative manner As and Cd induced dose-dependent effects on gene expression in mouse embryos during a peak window of sensitivity to embryotoxicity and NTDs in the sensitive C57BL/6J strain. © 2010 Elsevier Inc.


Robinson J.F.,University of Washington | Robinson J.F.,Institute for Risk Analysis and Risk Communication | Robinson J.F.,Center for Child Environmental Health Risks Research | Guerrette Z.,University of Washington | And 12 more authors.
Birth Defects Research Part B - Developmental and Reproductive Toxicology | Year: 2010

BACKGROUND: Aberrations during neurulation due to genetic and/or environmental factors underlie a variety of adverse developmental outcomes, including neural tube defects (NTDs). Methylmercury (MeHg) is a developmental neurotoxicant and teratogen that perturbs a wide range of biological processes/pathways in animal models, including those involved in early gestation (e.g., cell cycle, cell differentiation). Yet, the relationship between these MeHg-linked effects and changes in gestational development remains unresolved. Specifically, current information lacks mechanistic comparisons across dose or time for MeHg exposure during neurulation. These detailed investigations are crucial for identifying sensitive indicators of toxicity and for risk assessment applications. METHODS: Using a systems-based toxicogenomic approach, we examined dose- and time-dependent effects of MeHg on gene expression in C57BL/6 mouse embryos during cranial neural tube closure, assessing for significantly altered genes and associated Gene Ontology (GO) biological processes. Using the GO-based application GO-Quant, we quantitatively assessed dose- and time-dependent effects on gene expression within enriched GO biological processes impacted by MeHg. RESULTS: We observed MeHg to significantly alter expression of 883 genes, including several genes (e.g., Vangl2, Celsr1, Ptk7, Twist, Tcf7) previously characterized to be crucial for neural tube development. Significantly altered genes were associated with development cell adhesion, cell cycle, and cell differentiation-related GO biological processes. CONCLUSIONS: Our results suggest that MeHg-induced impacts within these biological processes during gestational development may underlie MeHg-induced teratogenic and neurodevelopmental toxicity outcomes. © 2010 Wiley-Liss, Inc.

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