Bisphenol A and Di(2-Ethylhexyl) Phthalate promote pulmonary carcinoma in female rats via estrogen receptor beta: In vivo and in silico analysis

• Published in: Ecotoxicology and environmental safety 2023-01, Vol.250, p.114496-114496, Article 114496
• Main Authors: Xiao, Mingyang, Zhang, Yating, Zhang, Xuan, Zhang, Guopei, Jin, Cuihong, Yang, Jinghua, Wu, Shengwen, Lu, Xiaobo
• Format: Article
• Language: English
• Subjects: Animals; Benzhydryl Compounds - toxicity; BPA; Carcinoma, Non-Small-Cell Lung - chemically induced; Carcinoma, Non-Small-Cell Lung - genetics; Combined effect; DEHP; Diethylhexyl Phthalate - toxicity; Endocrine Disruptors - toxicity; ESR2; Estrogen Receptor beta; Estrogens; Female; Lung Neoplasms - chemically induced; Lung Neoplasms - genetics; Pulmonary carcinoma; Rats
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2022.114496

The prevalence of lung cancer in women currently merits our attentions. However, cigarette exposure alone does not tell the whole story that lung cancer is more prevalent among non-smoking women. Since female lung cancer is closely linked to estrogen levels, many of endocrine disrupting chemicals (EDCs), as the substances similar to estrogen, affect hormone levels and become a potential risk of female lung cancer. Additionally, the combined toxicity of EDCs in daily environment has only been discussed on a limited scale. Consequently, this study explored the cancer-promoting effect of two representative substances of EDCs namely Bisphenol A (BPA) and Di(2-Ethylhexyl) Phthalate (DEHP) after their exposure alone or in combination, using a rat pulmonary tumor model published previously, combining bioinformatics analysis based on The Comparative Toxicogenomics Database (CTD) and The Cancer Genome Atlas (TCGA) databases. It demonstrated that BPA and DEHP enhanced the promotion of pulmonary tumor in female rats, either alone or in combination. Mechanistically, BPA and DEHP mainly directly bound and activated ESR2 protein, phosphorylated CREB protein, activated HDAC6 transcriptionally, induced the production of the proto-oncogene c-MYC, and accelerated the formation of pulmonary tumor in female rats. Remarkably, BPA, rather than DEHP, exhibited a much more critical effect in female lung cancer. Additionally, the transcription factor ESR2 was most affected in carcinogenesis, causing genetic disruption. Furthermore, the TCGA database revealed that ESR2 could enhance the promotion and progression of non-small cell lung cancer in females via activating the WNT/β-catenin pathway. Finally, our findings demonstrated that BPA and DEHP could enhance the promotion of pulmonary carcinoma via ESR2 in female rats and provide a potential and valuable insight into the causes and prevention of lung cancer in non-smoking women due to EDCs exposure. •Combined exposure to BPA and DEHP promotes pulmonary carcinoma in female rats.•BPA and DEHP can directly bind and activate ESR2 in vivo and in silico.•Genetic perturbations induced by BPA and DEHP are mainly caused by ESR2, not ESR1.•BPA is the main effect in the combined exposure to BPA and DEHP.•ESR2 is related to multiple lung cancer pathways in female lung cancer.