Construction of an adverse outcome pathway for the cardiac toxicity of bisphenol a by using bioinformatics analysis

Bisphenol A (BPA), a common endocrine disruptor, has shown cardiovascular toxicity in several epidemiological studies, as well as in vivo and in vitro experimental studies. However, the related adverse outcome pathway (AOP) of BPA toxicity remains unraveled. This study aimed to develop an AOP for the cardiac toxicity of BPA through bioinformatics analysis. The interactions among BPA, genes, phenotypes, and cardiac toxicity were retrieved from several databases, including the Comparative Toxicogenomics Database, Computational Toxicology, DisGeNet, and MalaCards. The target genes and part of target phenotypes were obtained by Venn analysis and literature screening. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed for target genes by using the DAVID online analysis tool to obtain other target phenotypes. AOP hypotheses from BPA exposure to heart disease were established and evaluated comprehensively by a quantitative weight of evidence (QWOE) method. The target genes included ESR2, MAPK1, TGFB1, and ESR1, and the target phenotypes included heart contraction, cardiac muscle contraction, cellular Ca²⁺ homeostasis, cellular metabolic process, heart development, etc. Overall, the AOP of BPA cardiac toxicity was deduced to be as follows. Initially, BPA bound with ERα/β and then activated the MAPK, AKT, and IL-17 signaling pathways, leading to Ca²⁺ homeostasis disorder and increased inflammatory response. Subsequently, cardiac function was impaired, causing coronary heart disease, arrhythmia, cardiac dysplasia, and other heart diseases. According to the Bradford-Hill causal considerations, the score of AOP by QWOE was 69, demonstrating a moderate confidence and providing clues on cardiotoxicity-assessment procedure and further studies on BPA.