Environmental impact on vascular development predicted by high-throughput screening - PubMed (original) (raw)
Environmental impact on vascular development predicted by high-throughput screening
Nicole C Kleinstreuer et al. Environ Health Perspect. 2011 Nov.
Abstract
Background: Understanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of > 1,000 unique compounds across > 500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease.
Objective: We mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling.
Methods: ToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles.
Results: Targets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U.S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns for chemicals with effects in rabbits versus rats, despite derivation of in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here.
Conclusions: We predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways.
Conflict of interest statement
The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.
A.V.S. is employed by Syngenta. The other authors declare they have no actual or potential competing financial interests.
Figures
Figure 1
Work flow to identify pVDCs among 309 environmental chemicals. Assays critical to vascular development were identified by VT-KB, chemicals were ranked by their VBS against these vascular targets, and the ToxPi tool was used to filter/visualize the chemical library. Multivariate algorithms produced predictive signatures of species-specific vascular disruption, correlated with ToxRefDB in vivo end points in prenatal guideline studies. The chemical library was tested against additional reference in vitro assays, and reference antiangiogenic compounds (thalidomide and 5HPP-33) were tested against the pVDC signature.
Figure 2
ToxPi visualization for top 50 pVDCs ranked by VBS across six in vitro targets: CCL2 down-regulation, CXCL10 up-regulation, uPAR up- and down-regulation, PAI‑1 up- and down-regulation, VEGFR2 down-regulation, and TIE2 binding.
Figure 3
Vascular developmental signaling pathways identified by pVDC signature and hypothesized species-specific target sites. Rabbit-specific developmental toxicants potentially target the PAS (e.g., PAI‑1, uPAR), and rat-specific developmental toxicants potentially target inflammatory chemokine signaling (e.g., CXCL10, CCL2). The VEGF and ANG/TIE2 pathways are critical pathways associated with developmental toxicity across species. Abbreviations: ANG, angiopoietin; Elk‑1, ETS-like transcription factor 1; GPI, glycosylphosphatidylinositol; JAK/STAT, Janus kinase/signal transducer and activator of transcription; MMP, matrix metalloproteinase; NFKB, nuclear factor kappa B; PLC/IP3, phospholipase C/inositol triphosphate; P13K/AKT, phosphatidylinositol 3-kinase/protein kinase B; SHC/RAS/MAPK/ERK 1&2, Src homology 2 domain containing proteins/RAt sarcoma family/mitogen-activated protein kinases/extracellular-signal-regulated kinases 1 and 2; SRC/FAK, sarcoma tyrosine kinase/focal adhesion kinase.
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