Key result
Computational analysis of high-throughput screening data linked endocrine disrupting chemicals to VEGFR signaling perturbation via estrogen and serotonin receptors, proposing a novel adverse outcome pathway for atherosclerosis.
Why the study?
Dysregulation of VEGF and VEGFR contributes to atherosclerosis and CVD, making it a potential target for CVD risk assessment using high-throughput screening data.
This computational toxicology study provides a data-driven adverse outcome pathway linking environmental chemical exposures, such as endocrine disruptors, to atherosclerosis through VEGFR signaling perturbation, offering a framework to reduce animal testing in risk assessment.
No immediate clinical implications for atherosclerosis; leaves open novel adverse outcome pathways for endocrine disruptors in VEGFR signaling.
Dysregulation of vascular endothelial growth factor (VEGF) and its receptor (VEGFR) contributes to atherosclerosis and cardiovascular disease (CVD), making it a potential target for CVD risk assessment. High-throughput screening (HTS) approaches have resulted in large-scale in vitro data, providing mechanistic information that can help assess chemical toxicity and identify molecular initiating events (MIEs) of adverse outcome pathways (AOPs). AOPs represent a logical sequence of biological responses contributing to toxicity and are valuable tools to inform chemical risk assessment. Here, we used HTS data to formulate an AOP relating VEGF signaling perturbation to atherosclerosis. ToxCast, Tox21, and PubChem data were evaluated to obtain bioprofiles of 4165 compounds active in assays targeting VEGFR. Cheminformatics analysis identified 109 enriched structural fingerprints. Applying a subspace clustering approach based on chemical structure bioactivity yielded 12 primary targets, whose relevance to CVD was confirmed by an AI-assisted literature review. An AOP was hypothesized by coupling mechanistic relationships highlighted by HTS data with literature review findings, linking serotonin receptor (HTR), estrogen receptor alpha (ERα), and vasopressin receptor (AVPR) targets with VEGFR activity, angiogenic signaling, and atherosclerosis. Several endocrine disrupting chemicals (EDCs), e.g., bisphenols, triclosan, dichlorodiphenyltrichloroethane (DDT), and polychlorinated biphenyls (PCBs), were identified as relevant chemical stressors. Subspace clustering of these chemicals evaluated potential MIEs and highlighted associations with use case classes. By applying computational methods to profile HTS data and hypothesize a mechanistic AOP, this study proposes a data-driven approach to evaluating environmental cardiotoxicity, which could eventually supplement and reduce the need for animal testing in toxicological assessments. Plain language summaryThis study explores how exposure of humans to chemicals in the environment can contribute to atherosclerosis, the buildup of plaques in arteries that can lead to diseases of the heart and blood vessels. Using existing data on thousands of chemicals from non-animal screening methods, the study links certain chemicals, e.g., bisphenols and DDT, to biological changes related to the signaling receptor VEGFR and the development of atherosclerosis. An adverse outcome pathway (AOP) framework is used to map the sequence of biological events initiated upon exposure to chemicals to the manifestation of adverse health outcomes. This approach helps understand the risks posed by environmental chemicals and protects public health while reducing animal experiments.
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A 2024 study studied Atherosclerosis. Endocrine disrupting chemicals (e.g., bisphenols, DDT, PCBs) vs. Inactive chemicals was evaluated on Derivation of an adverse outcome pathway (AOP) linking VEGFR modulation to atherosclerosis. Computational analysis of high-throughput screening data linked endocrine disrupting chemicals to VEGFR signaling perturbation via estrogen and serotonin receptors, proposing a novel adverse outcome pathway for atherosclerosis.
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