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Identification and evaluation of candidate genes associated with susceptibility to PCB-126 induced developmental toxicity

Waits, Eric R.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305892257

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Toxicology (Environmental Health).
Dioxin-like compounds (DLCs) are potent teratogens that persist in the environment and pose significant risk to human and ecological health. Variability in risk of congenital heart defects (CHDs) during development 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, 3,3’,4,4’,5-pentachlorobiphenyl (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 (F2-intercross). High-resolution microsatellite molecular markers spanning the entire genome were used to determine association between the phenotype (risk of PCB126-induced cardiac dysregulation) and genotype (chromosomal loci) in the recombinant generation. Multiple QTL were identified–some acting alone, others additively, and others via epistatic interaction. Together, these QTLs account for 23.48% of the phenotypic variance observed in heart defects resulting from PCB126 exposure (LOD score = 13.14; P = 2.52 x 10–7). The transcription factor E2F1 (e2f1) and the tropomyosin 4 (tmp4) genes were identified as potential candidates involved in susceptibility to PCB126-induced developmental cardiotoxicity. The consequences that a loss-of-function of either gene has on the developing zebrafish heart were investigated relative to what is observed following PCB126 exposure. The phenotypes of zebrafish injected with morpholinos targeting E2F1 or TPM4 are highly similar to that of PCB126 cardiotoxicity. Loss of e2f1, tpm4, or exposure to PCB126 diminishes heart function, inhibits valvulogenesis, and results in myocardial hypoplasia.
Daniel Nebert, MD (Committee Chair)
Daniel Prows, PhD (Committee Member)
Thomas Bartman, MD,PhD (Committee Member)
Mary Beth Genter, PhD (Committee Member)
Alvaro Puga, PhD (Committee Member)
133 p.
Genetics
Dioxin; PCB; Genetic Susceptibility; Development; Heart; Zebrafish

Recommended Citations

Citations

  • Waits, E. R. (2011). Identification and evaluation of candidate genes associated with susceptibility to PCB-126 induced developmental toxicity [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305892257

    APA Style (7th edition)

  • Waits, Eric. Identification and evaluation of candidate genes associated with susceptibility to PCB-126 induced developmental toxicity. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305892257.

    MLA Style (8th edition)

  • Waits, Eric. "Identification and evaluation of candidate genes associated with susceptibility to PCB-126 induced developmental toxicity." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305892257

    Chicago Manual of Style (17th edition)

ucin1305892257
526
© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.