Mode of action exploration of reproductive toxicity induced by bisphenol S using human normal ovarian epithelial cells through ERß-MAPK signaling pathway.

BACKGROUND: In the plastics production sector, bisphenol S (BPS) has gained popularity as a replacement for bisphenol A (BPA). However, the mode of action (MOA) of female reproductive toxicity caused by BPS remains unclear and the safety of BPS is controversial. METHODS: Human normal ovarian epithelial cell line, IOSE80, were exposed to BPS at human-relevant levels for short-term exposure at 24 h or 48 h, or for long-term exposure at 28 days, either alone or together with five signaling pathway inhibitors: ICI 18,2780 (estrogen receptor [ER] antagonist), G15 (GPR30 specific inhibitor), U0126 (extracellular regulated protein kinase [ERK] 1/2 inhibitor), SP600125 (c-Jun N-terminal kinase [JNK] inhibitor) or SB203580 (p38 mitogen­activated protein kinase [p38MAPK] inhibitor). MOA through ERß-MAPK signaling pathway interruption was explored, and potential thresholds were estimated by the benchmark dose method. RESULTS: For short-term exposure, BPS exposure at human-relevant levels elevated the ESR2 and MAPK8 mRNA levels, along with the percentage of the G0/G1 phase. For long-term exposure, BPS raised the MAPK1 and EGFR mRNA levels, the ERß, p-ERK, and p-JNK protein levels, and the percentage of the G0/G1 phase, which was partly suppressed by U0126. The benchmark dose lower confidence limit (BMDL) of the percentage of the S phase after 24 h exposure was the lowest among all the BMDLs of a good fit, with BMDL5 of 9.55 µM. CONCLUSIONS: The MOA of female reproductive toxicity caused by BPS at human-relevant levels might involve: molecular initiating event (MIE)-BPS binding to ERß receptor, key event (KE)1-the interrupted expression of GnRH, KE2-the activation of JNK (for short-term exposure) and ERK pathway (for long-term exposure), KE3-cell cycle arrest (the increased percentage of the G0/G1 phase), and KE4-interruption of cell proliferation (only for short-term exposure). The BMDL of the percentage of the S phase after 24 h exposure was the lowest among all the BMDLs of a good fit, with BMDL5 of 9.55 µM.

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/ß 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.