A Systems-Based Approach to Investigate Dose- and Time-Dependent Methylmercury-Induced Gene Expression Response in C57BL/6 Mouse Embryos Undergoing Neurulation

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. Birth Defects Res (Part B) 89:188-200, 2010. (C) 2010 Wiley-Liss, Inc.