title: Genetic architecture of susceptibility to PCB126-induced developmental cardiotoxicity in zebrafish.
abstract: Variability in risk of developmental defects caused by dioxin-like compounds (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 precise downstream targets influencing this vulnerability. In the present study, zebrafish with divergent genetic backgrounds were screened for susceptibility to developmental cardiotoxicity caused by the prototypical DLC, 3,3',4,4',5-pentachlorobiphenyl (PCB126); a range up to ∼40-fold differences was observed. Differentially sensitive zebrafish were chosen for a genetic cross, and the recombinant generation was used for genome-wide quantitative trait loci (QTL) mapping. Multiple QTLs were identified--several acting alone, one additively, and two others via epistatic interaction. Together, these QTLs account for 24% of the phenotypic variance observed in cardioteratogenicity resulting from PCB126 exposure (logarithm of the odds = 13.55, p = 1.89 × 10⁻¹⁰). Candidate genes in these QTL regions include the following: ahr2, bcor, and capn1 (Chr 22); e2f1 and pdyn (Chr 23); ctnnt2, plcg1, eno3, tgm1, and tgm2 (interacting on Chr 23); and vezf1 (Chr 15). These data demonstrate that DLC-induced cardiac teratogenicity is a multifactorial complex trait influenced by gene × gene and gene × environment interactions. The identified QTLs harbor many DLC-responsive genes critical to cardiovascular development and provide insight into the genetic basis of susceptibility to AHR-mediated developmental toxicity.
authors: Office of Research and Development, National Exposure Research Laboratory, Ecological Exposure Research Division, U.S. Environmental Protection Agency, Cincinnati, Ohio 45268, USA. waits.eric@epa.gov
authors: Eric R
authors: ER
authors: Waits
authors: Daniel W
authors: DW
authors: Nebert
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