PUBLICATION
Exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP) induces vascular toxicity through Nrf2-VEGF pathway in zebrafish and human umbilical vein endothelial cells
- Authors
- Zhong, X., Qiu, J., Kang, J., Xing, X., Shi, X., Wei, Y.
- ID
- ZDB-PUB-190128-8
- Date
- 2019
- Source
- Environmental pollution (Barking, Essex : 1987) 247: 293-301 (Journal)
- Registered Authors
- Keywords
- Adverse outcome pathway, Developmental toxicity, Nuclear factor erythroid 2-related factor, Tris(1,3-dichloro-2-propyl) phosphate, Vascular endothelial growth factor, Vascular toxicity
- MeSH Terms
-
- Animals
- Flame Retardants/metabolism
- Flame Retardants/toxicity*
- Human Umbilical Vein Endothelial Cells
- Humans
- Larva/metabolism
- NF-E2-Related Factor 2/metabolism
- Organophosphates/metabolism
- Organophosphorus Compounds/toxicity*
- Phosphates/metabolism
- Vascular Endothelial Growth Factor A/metabolism*
- Zebrafish/metabolism
- Zebrafish/physiology*
- PubMed
- 30685670 Full text @ Environ. Pollut.
Citation
Zhong, X., Qiu, J., Kang, J., Xing, X., Shi, X., Wei, Y. (2019) Exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP) induces vascular toxicity through Nrf2-VEGF pathway in zebrafish and human umbilical vein endothelial cells. Environmental pollution (Barking, Essex : 1987). 247:293-301.
Abstract
The growing production and extensive use of organophosphate flame retardants (OPFRs) have led to an increase in their environmental distribution and human exposure. Developmental toxicity is a major concern of OPFRs' adverse health effects. However, the impact of OPFRs exposure on vascular development and the toxicity pathway for developmental defects are poorly understood. In this study, we investigated the effects of exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP), a frequently detected OPFR, on early vascular development, and the possible role of nuclear factor erythroid 2-related factor (Nrf2)-dependent angiogenic pathway in TDCPP's vascular toxicity. TDCPP exposure at 300 and 500 μg/L impeded the growth of intersegmental vessels (ISV), a type of microvessels, as early as 30 hpf. Consistently, a similar pattern of decreased extension and remodeling of common cardinal vein (CCV), a typical macrovessel, was observed in zebrafish at 48 hpf and 72 hpf. Developing vasculature in zebrafish was more sensitive than general developmental parameters to TDCPP exposure. The expression of genes related to VEGF signaling pathway dose-dependently decreased in TDCPP-treated larvae. In in vitro experiments using human umbilical vein endothelial cells (HUVECs), the increased cell proliferation induced by VEGF was suppressed by TDCPP exposure in a dose-dependent fashion. In addition, we found a repression of Nrf2 expression and activity in TDCPP-treated larvae and HUVECs. Strikingly, the application of CDDO-Im, a potent Nrf2 activator, enhanced VEGF and protected against defective vascular development in zebrafish. Our results reveal that vascular impairment is a sensitive index for early exposure to TDCPP, which could be considered in the environmental risk assessment of OPFRs. The identification of Nrf2-mediating VEGF pathway provides new insight into the adverse outcome pathway (AOP) of OPFRs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping