{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T08:47:05Z","timestamp":1784018825696,"version":"3.55.0"},"reference-count":53,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,26]],"date-time":"2022-11-26T00:00:00Z","timestamp":1669420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["21777093"],"award-info":[{"award-number":["21777093"]}]},{"name":"National Natural Science Foundation of China","award":["21507078"],"award-info":[{"award-number":["21507078"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Environmental estrogens can promote the growth, migration, and invasion of breast cancer. However, few studies evaluate adverse health impacts of environmental estrogens on other organs of breast cancer patients. Therefore, the present study investigated the effects of environmental estrogen bisphenol AF (BPAF) on the main organs of female Balb\/cA nude mice with SK-BR-3 xenograft tumor by detecting the organ development and gene expression of targets associated with G protein-coupled estrogen receptor 1 (GPER1)-mediated phosphatidylinositol 3-kinase\/protein kinase B (PI3K\/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways in hypothalamus, ovary, uterus, liver, and kidney. The results showed that BPAF at 20 mg\/kg bw\/day markedly increased the uterine weight and the uterine coefficient of nude mice compared to SK-BR-3 bearing tumor control, indicating that BPAF promoted the growth of uterus due to its estrogenic activity. Additionally, BPAF significantly up-regulated the mRNA relative expression of most targets related to nuclear estrogen receptor alpha (ER\u03b1) and GPER1-mediated signaling pathways in the hypothalamus, followed by the ovary and uterus, and the least in the liver and kidney, indicating that BPAF activated different estrogen activity related targets in different tissues. In addition, BPAF markedly up-regulated the mRNA expression of GPER1 in all tested tissues, and the molecular docking showed that BPAF could dock into GPER1. Because gene change is an early event of toxicity response, these findings suggested that BPAF might aggravate the condition of breast cancer patients through exerting its estrogenic activity via the GPER1 pathway in various organs.<\/jats:p>","DOI":"10.3390\/ijerph192315743","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T04:58:50Z","timestamp":1669784330000},"page":"15743","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Bisphenol AF Promoted the Growth of Uterus and Activated Estrogen Signaling Related Targets in Various Tissues of Nude Mice with SK-BR-3 Xenograft Tumor"],"prefix":"10.3390","volume":"19","author":[{"given":"Mengjie","family":"Yu","sequence":"first","affiliation":[{"name":"Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Tang","sequence":"additional","affiliation":[{"name":"Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingli","family":"Lei","sequence":"additional","affiliation":[{"name":"Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxin","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanbing","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11436","DOI":"10.1016\/j.envpol.2020.114361","article-title":"Occurrence, mass loads and risks of bisphenol analogues in the Pearl River Delta region, South China: Urban rainfall runoff as a potential source for receiving rivers","volume":"263","author":"Huang","year":"2020","journal-title":"Environ. Pollut."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13136","DOI":"10.1021\/es303960k","article-title":"Distribution and preliminary exposure assessment of bisphenol AF (BPAF) in various environmental matrices around a manufacturing plant in China","volume":"46","author":"Song","year":"2012","journal-title":"Environ. Sci. Technol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.scitotenv.2017.04.167","article-title":"Bioaccumulation and biomagnification of emerging bisphenol analogues in aquatic organisms from Taihu Lake, China","volume":"598","author":"Wang","year":"2017","journal-title":"Sci. Total Environ."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"138164","DOI":"10.1016\/j.scitotenv.2020.138164","article-title":"Biodegradation of bisphenol compounds in the surface water of Taihu Lake and the effect of humic acids","volume":"723","author":"Zhou","year":"2020","journal-title":"Sci. Total Environ."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/j.scitotenv.2017.05.069","article-title":"Occurrence, distribution and sources of bisphenol analogues in a shallow Chinese freshwater lake (Taihu Lake): Implications for ecological and human health risk","volume":"599\u2013600","author":"Liu","year":"2017","journal-title":"Sci. Total Environ."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"136100","DOI":"10.1016\/j.scitotenv.2019.136100","article-title":"Serum concentration of bisphenol analogues in pregnant women in China","volume":"707","author":"Li","year":"2020","journal-title":"Sci. Total Environ."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lucarini, F., Krasniqi, T., Bailat Rosset, G., Roth, N., Hopf, N.B., Broillet, M.C., and Staedler, D. (2020). Exposure to new emerging bisphenols among young children in Switzerland. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17134793"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11379","DOI":"10.1016\/j.envpol.2019.113779","article-title":"Bisphenol analogue concentrations in human breast milk and their associations with postnatal infant growth","volume":"259","author":"Jin","year":"2020","journal-title":"Environ. Pollut."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"113980","DOI":"10.1016\/j.envpol.2020.113980","article-title":"Evaluation of the effects of low concentrations of bisphenol AF on gonadal development using the Xenopus laevis model: A finding of testicular differentiation inhibition coupled with feminization","volume":"260","author":"Cai","year":"2020","journal-title":"Environ. Pollut."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"115274","DOI":"10.1016\/j.bmc.2019.115274","article-title":"Bisphenol AF: Halogen bonding effect is a major driving force for the dual ERalpha-agonist and ERbeta-antagonist activities","volume":"28","author":"Liu","year":"2020","journal-title":"Bioorg. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"114709","DOI":"10.1016\/j.taap.2019.114709","article-title":"Differential activity of BPA, BPAF and BPC on zebrafish estrogen receptors in vitro and in vivo","volume":"380","author":"Pinto","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"230","DOI":"10.2174\/1874467212666190306164507","article-title":"The endocrine disruptor bisphenol A (BPA) exerts a wide range of effects in carcinogenesis and response to therapy","volume":"12","author":"Hafezi","year":"2019","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_13","first-page":"6417","article-title":"Trichostatin A alleviates the process of breast carcinoma by downregulating LPAR5","volume":"24","author":"Zheng","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_14","first-page":"19","article-title":"Endocrine disruptors from the environment affecting breast cancer (Review)","volume":"20","author":"Calaf","year":"2020","journal-title":"Oncol. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.canlet.2014.04.018","article-title":"Estrogen metabolism and breast cancer","volume":"356","author":"Samavat","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Terry, M.B., Michels, K.B., Brody, J.G., Byrne, C., Chen, S., Jerry, D.J., Malecki, K.M.C., Martin, M.B., Miller, R.L., and Neuhausen, S.L. (2019). Environmental exposures during windows of susceptibility for breast cancer: A framework for prevention research. Breast Cancer Res., 21.","DOI":"10.1186\/s13058-019-1168-2"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1002\/tox.23417","article-title":"Low concentrations of 17\u03b2-estradiol exacerbate tamoxifen resistance in breast cancer treatment through membrane estrogen receptor-mediated signaling pathways","volume":"37","author":"Xu","year":"2022","journal-title":"Environ. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s12282-015-0609-8","article-title":"Molecular epidemiology, and possible real-world applications in breast cancer","volume":"23","author":"Ito","year":"2016","journal-title":"Breast Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.jsbmb.2017.03.021","article-title":"Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives","volume":"176","author":"Barton","year":"2018","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1093\/toxsci\/kfx101","article-title":"Editor\u2019s highlight: Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells","volume":"158","author":"Mesnage","year":"2017","journal-title":"Toxicol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e14652","DOI":"10.1200\/JCO.2019.37.15_suppl.e14652","article-title":"Effect on tumor growth by TGF-\u03b21\/COX-2 siRNA combination product (STP705) in a human cholangiocarcinoma (HuCCT-1) xenograft tumor model in nude mice","volume":"37","author":"Molyneaux","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"358","DOI":"10.7555\/JBR.31.20160162","article-title":"Effects of bisphenol compounds on the growth and epithelial mesenchymal transition of MCF-7 CV human breast cancer cells","volume":"31","author":"Kim","year":"2017","journal-title":"J. Biomed. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.fct.2017.08.037","article-title":"Inhibitory effects of 3,3\u2019-diindolylmethane on epithelial-mesenchymal transition induced by endocrine disrupting chemicals in cellular and xenograft mouse models of breast cancer","volume":"109","author":"Lee","year":"2017","journal-title":"Food Chem. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"145814","DOI":"10.1016\/j.scitotenv.2021.145814","article-title":"Molecular mechanism study of BPAF-induced proliferation of ERalpha-negative SKBR-3 human breast cancer cells in vitro\/in vivo","volume":"775","author":"Lei","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.toxlet.2012.03.802","article-title":"Bisphenol AF may cause testosterone reduction by directly affecting testis function in adult male rats","volume":"211","author":"Feng","year":"2012","journal-title":"Toxicol. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.cbpc.2013.11.001","article-title":"Long-term exposure investigating the estrogenic potency of estriol in Japanese medaka (Oryzias latipes)","volume":"160","author":"Lei","year":"2014","journal-title":"Comp. Biochem. Physiol. C Toxicol. Pharmacol."},{"key":"ref_27","first-page":"914","article-title":"Inhibition of GPR30 by estriol prevents growth stimulation of triple-negative breast cancer cells by 17\u03b2-estradiol","volume":"134","author":"Girgert","year":"2014","journal-title":"BMC Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.toxlet.2021.09.004","article-title":"Uterotrophic and in vitro screening for (anti)estrogenic activity of dipyrone","volume":"352","author":"Passoni","year":"2021","journal-title":"Toxicol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"115815","DOI":"10.1016\/j.taap.2021.115815","article-title":"Comparative study of estrogenic activities of phytoestrogens using OECD in vitro and in vivo testing methods","volume":"434","author":"Sim","year":"2022","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.reprotox.2007.07.006","article-title":"Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract","volume":"24","author":"Newbold","year":"2007","journal-title":"Reprod. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.reprotox.2010.07.008","article-title":"Neonatal exposure to bisphenol A reduces the pool of primordial follicles in the rat ovary","volume":"30","author":"Santambrosio","year":"2010","journal-title":"Reprod. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.mce.2017.02.045","article-title":"Recent advances on bisphenol-A and endocrine effects on human prostate cancer","volume":"457","author":"Cernera","year":"2017","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.tox.2018.12.001","article-title":"Profiling of bisphenol A and eight its analogues on transcriptional activity via human nuclear receptors","volume":"413","author":"Kojima","year":"2019","journal-title":"Toxicology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.chemosphere.2018.11.018","article-title":"Persistent endocrine-disrupting chemicals found in human follicular fluid stimulate the proliferation of granulosa tumor spheroids via GPR30 and IGF1R but not via the classic estrogen receptors","volume":"217","author":"Gogola","year":"2019","journal-title":"Chemosphere"},{"key":"ref_35","first-page":"51","article-title":"Leydig cell tumorigenesis\u2014Implication of G-protein coupled membrane estrogen receptor, peroxisome proliferator-activated receptor and xenoestrogen exposure","volume":"61","author":"Duliban","year":"2019","journal-title":"In vivo and in vitro appraisal. Tissue. Cell."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1007\/s12032-015-0558-2","article-title":"G protein-coupled estrogen receptor (GPER) mediates NSCLC progression induced by 17beta-estradiol (E2) and selective agonist G1","volume":"32","author":"Liu","year":"2015","journal-title":"Med. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1016\/j.envpol.2017.09.069","article-title":"Bisphenol A induces proliferative effects on both breast cancer cells and vascular endothelial cells through a shared GPER-dependent pathway in hypoxia","volume":"231","author":"Xu","year":"2017","journal-title":"Environ. Pollut."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1111\/jog.13972","article-title":"Bisphenol A promotes the proliferation of leiomyoma cells by GPR30-EGFR signaling pathway","volume":"45","author":"Li","year":"2019","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1053\/j.gastro.2019.01.010","article-title":"Estrogen activation of G-protein-coupled estrogen receptor 1 regulates phosphoinositide 3-kinase and mTOR signaling to promote liver growth in zebrafish and proliferation of human hepatocytes","volume":"156","author":"Chaturantabut","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.jep.2011.02.011","article-title":"The effects of BuYang HuanWu Decoction and its effective components on proliferation-related factors and ERK1\/2 signal transduction pathway in cultured vascular smooth muscle cells","volume":"135","author":"Chen","year":"2011","journal-title":"J. Rthnopharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1080\/01635581.2016.1158292","article-title":"Aqueous extracts of Toona sinensis leaves inhibit renal carcinoma cell growth and migration through JAK2\/stat 3, Akt, MEK\/ERK, and mTOR\/HIF-2a pathways","volume":"68","author":"Chen","year":"2016","journal-title":"Nutr. Canc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3108","DOI":"10.1111\/jcmm.13588","article-title":"MICAL1 facilitates breast cancer cell proliferation via ROS-sensitive ERK\/cyclin D pathway","volume":"22","author":"Deng","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.mce.2016.12.007","article-title":"GPER\/ERK&AKT\/NF-kappaB pathway is involved in cadmium-induced proliferation, invasion and migration of GPER-positive thyroid cancer cells","volume":"442","author":"Zhu","year":"2017","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.fct.2019.04.033","article-title":"Cyanidin-3-O-glucoside protects against cadmium-induced dysfunction of sex hormone secretion via the regulation of hypothalamus-pituitary-gonadal axis in male pubertal mice","volume":"129","author":"Li","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"113974","DOI":"10.1016\/j.ygcen.2021.113974","article-title":"Distribution of kisspeptin system and its relation with gonadotropin-releasing hormone in the hypothalamus of the South American plains vizcacha, Lagostomus maximus","volume":"317","author":"Schmidt","year":"2022","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"110712","DOI":"10.1016\/j.ecoenv.2020.110712","article-title":"Manganese exposure caused reproductive toxicity of male mice involving activation of GnRH secretion in the hypothalamus by prostaglandin E2 receptors EP1 and EP2","volume":"201","author":"Wu","year":"2020","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"110698","DOI":"10.1016\/j.ecoenv.2020.110698","article-title":"In utero exposure to DBP stimulates release of GnRH by increasing the secretion of PGE2 in the astrocytes of the hypothalamus in the offspring mice","volume":"198","author":"Xia","year":"2020","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"111225","DOI":"10.1016\/j.envres.2021.111225","article-title":"Inflammatory cytokines as key players of apoptosis induced by environmental estrogens in the ovary","volume":"198","author":"Zhang","year":"2021","journal-title":"Environ. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.livres.2019.03.001","article-title":"Emerging role of the orphan nuclear receptor estrogen-related receptor gamma in liver metabolic diseases","volume":"3","author":"Kim","year":"2019","journal-title":"Liver Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/S0006-291X(03)00311-5","article-title":"Estrogenic activity of an environmental pollutant, 2-nitrofluorene, after metabolic activation by rat liver microsomes","volume":"303","author":"Fujimoto","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"147669","DOI":"10.1016\/j.scitotenv.2021.147669","article-title":"Evidence of increased estrogenicity upon metabolism of Bisphenol F- elucidation of the key metabolites","volume":"787","author":"Shao","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"114662","DOI":"10.1016\/j.bcp.2021.114662","article-title":"Sex-specific expression mechanism of hepatic estrogen inactivating enzyme and transporters in diabetic women","volume":"190","author":"Fashe","year":"2021","journal-title":"Biochem. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"113069","DOI":"10.1016\/j.ecoenv.2021.113069","article-title":"Comparison of the mechanisms of estrogen disrupting effects between triphenyl phosphate (TPhP) and tris (1,3-dichloro-2-propyl phosphate (TDCIPP)","volume":"229","author":"Ji","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/23\/15743\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:27:19Z","timestamp":1760146039000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/23\/15743"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,26]]},"references-count":53,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijerph192315743"],"URL":"https:\/\/doi.org\/10.3390\/ijerph192315743","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,26]]}}}