Genetic Architecture of Susceptibility to PCB126-induced Developmental Cardiotoxicity in Zebrafish
- Authors
- Waits, E.R., and Nebert, D.W.
- ID
- ZDB-PUB-110603-22
- Date
- 2011
- Source
- Toxicological sciences : an official journal of the Society of Toxicology 122(2): 466-75 (Journal)
- Registered Authors
- Nebert, Daniel W.
- Keywords
- polychlorinated biphenyls (PCBs), dioxin, heart, development, quantitative traid loci (QTL), genetic susceptibility, aryl hydrocarbon receptor (AHR)
- MeSH Terms
-
- Animals
- Embryo, Nonmammalian/drug effects*
- Epistasis, Genetic
- Genetic Predisposition to Disease*
- Heart Diseases/chemically induced
- Heart Diseases/genetics*
- Phenotype
- Polychlorinated Biphenyls/toxicity*
- Quantitative Trait Loci
- Receptors, Aryl Hydrocarbon/genetics
- Zebrafish/embryology*
- Zebrafish/genetics*
- PubMed
- 21613231 Full text @ Toxicol. Sci.
- CTD
- 21613231
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 cardio-teratogenicity resulting from PCB126 exposure (LOD = 13.55, P = 1.89 × 1010). Candidiate genes in these QTL regions include: ahr2, bcor, and capn1 (Chr 22); e2f1, pdyn, and cyp2j25 (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.