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Identification and evaluation of candidate genes associated with susceptibility to PCB-126 induced developmental toxicity: a genome-wide analysis
Citation:
WAITS, E. R., T. Bartman, AND D. W. Nebert. Identification and evaluation of candidate genes associated with susceptibility to PCB-126 induced developmental toxicity: a genome-wide analysis. Presented at SETAC North America 31st Annual Meeting, Portland, OR, November 07 - 11, 2010.
Impact/Purpose:
The objective of this task is to develop molecular indicators to evaluate the integrity and sustainability of aquatic fish, invertebrate, and plant communities. Specifically, this subtask aims to evaluate methods for the measurement of: fish and invertebrate community composition, especially for morphologically indistinct (cryptic) species population genetic structure of aquatic indicator species and its relationship to landscape determinants of population structure (to aid in defining natural assessment units and to allow correlation of population substructure with regional stressor coverages) genetic diversity within populations of aquatic indicator species, as an indicator of vulnerability to further exposure and as an indicator of cumulative exposure patterns of temporal change in genetic diversity of aquatic indicator species, as a monitoring tool for establishing long-term population trends.
Description:
Dioxin-like compounds (DLCs) are potent teratogens that persist in the environment and pose significant risk to ecological health. Variability in risk of developmental cardiotoxicity caused by DLCs has been demonstrated within and among several vertebrate species. Beyond our knowledge of the aryl hydrocarbon receptor (AHR) and its role in mediating toxicity for this class of compounds, little else is known concerning the precise downstream targets influencing this vulnerability. In the present study, six lines of zebrafish (Danio rerio) with divergent genetic backgrounds were screened for susceptibility to developmental cardiotoxicity caused by the prototypical DLC, PCB126; a range of up to 40-fold differences was observed. The most susceptible and the most resistant strains were then chosen for quantitative trait loci (QTL) analysis. High-resolution molecular markers spanning the entire genome were used to determine association between the phenotype and genotype in the recombinant generation. We identified multiple QTL--some acting alone, others additively, and others via epistatic interaction. Together, these QTL account for 23.48% of the phenotypic variance observed in heart defects resulting from PCB126 exposure. Transcription factor E2F1 (E2F1) and tropomyosin 4 (tmp4) were identified as potential candidate genes involved in susceptibility to PCB126-induced developmental cardiotoxicity. We investigated the consequences that loss-of-function of either gene has on the developing zebrafish heart relative to what is observed following PCB126 exposure. The phenotypes of zebrafish injected with moprpholinos targeting E2F1 or tpm4 are reminiscent of PCB126 cardiotoxicity. Loss of E2F1, tpm4, or exposure to PCB126 diminishes heart function, inhibits valvulogenesis, and results in myocardial hypoplasia. Knowledge of the genetic basis of susceptibility can inform estimates of individual or population-level responses to environmental contaminants.