PUBLICATION
PCB and TCDD derived embryonic cardiac defects result from a novel AhR pathway
- Authors
- Singleman, C., Holtzman, N.G.
- ID
- ZDB-PUB-210305-12
- Date
- 2021
- Source
- Aquatic toxicology (Amsterdam, Netherlands) 233: 105794 (Journal)
- Registered Authors
- Holtzman, Nathalia Glickman
- Keywords
- Aryl hydrocarbon receptor (AhR), Atlantic sturgeon, Embryo, Heart development, PCB 126, SU6656, Src, TCDD, VE-cadherin/Cadherin 5, Zebrafish
- MeSH Terms
-
- Animals
- Drug Synergism
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/drug effects*
- Embryo, Nonmammalian/metabolism
- Embryonic Development/drug effects
- Heart/drug effects*
- Heart/embryology
- Myocardium/metabolism
- Polychlorinated Biphenyls/toxicity*
- Polychlorinated Dibenzodioxins/toxicity*
- Receptors, Aryl Hydrocarbon/metabolism*
- Water Pollutants, Chemical/toxicity*
- Zebrafish/growth & development
- Zebrafish/metabolism*
- PubMed
- 33662880 Full text @ Aquat. Toxicol.
Citation
Singleman, C., Holtzman, N.G. (2021) PCB and TCDD derived embryonic cardiac defects result from a novel AhR pathway. Aquatic toxicology (Amsterdam, Netherlands). 233:105794.
Abstract
Polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are environmental contaminants known to impact cardiac development, a key step in the embryonic development of most animals. To date, little is understood of the molecular mechanism driving the observed cardiac defects in exposed fishes. The literature shows PCB & TCDD derived cardiac defects are concurrent with, but not caused by, expression of cyp1A, due to activation of the aryl hydrocarbon receptor (AhR) gene activation pathway. However, in this study, detailed visualization of fish hearts exposed to PCBs and TCDD show that, in addition to a failure of cardiac looping in early heart development, the inner endocardial lining of the heart fails to maintain proper cell adhesion and tissue integrity. The resulting gap between the endocardium and myocardium in both zebrafish and Atlantic sturgeon suggested functional faults in endothelial adherens junction formation. Thus, we explored the molecular mechanism triggering cardiac defects using immunohistochemistry to identify the location and phosphorylation state of key regulatory and adhesion molecules. We hypothesized that PCB and TCDD activates AhR, phosphorylating Src, which then phosphorylates the endothelial adherens junction protein, VEcadherin. When phosphorylated, VEcadherin dimers, found in the endocardium and vasculature, separate, reducing tissue integrity. In zebrafish, treatment with PCB and TCDD contaminants leads to higher phosphorylation of VEcadherin in cardiac tissue suggesting that these cells have reduced connectivity. Small molecule inhibition of Src phosphorylation prevents contaminant stimulated phosphorylation of VEcadherin and rescues both cardiac function and gross morphology. Atlantic sturgeon hearts show parallels to contaminant exposed zebrafish cardiac phenotype at the tissue level. These data suggest that the mechanism for PCB and TCDD action in the heart is, in part, distinct from the canonical mechanism described in the literature and that cardiac defects are impacted by this nongenomic mechanism.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping