Bisphenol A analogues induce a feed-forward estrogenic response in zebrafish.
Bisphenol A analogues induce a feed-forward estrogenic response in zebrafish.
复制标题
DOI：
10.1016/j.taap.2022.116263
复制
发表时间：
2022-10
影响因子：
3.8
通讯作者：
Silvia Karim;Ruixin Hao;C. Pinto;J. Gustafsson;Marina Grimaldi;P. Balaguer;M. Bondesson
中科院分区：
文献类型：
--
作者：
Silvia Karim;Ruixin Hao;C. Pinto;J. Gustafsson;Marina Grimaldi;P. Balaguer;M. Bondesson
由于暴露于双酚A（BPA）与人类和野生动物的健康问题有关，因此合成了BPA类似物，被认为是替代分子。本文采用斑马鱼体内和体外实验相结合的方法，研究了BPA及其五种类似物BPAF、BPE、BPC、BPC-Cl和BPS的雌激素活性。我们使用转基因雌激素报告基因（5xERE：GFP）鱼研究双酚的激动作用。暴露于BPA，BPAF，BPE，和BPC，诱导GFP表达的雌激素报告鱼在低暴露浓度的心脏瓣膜和在较高浓度的肝脏，而BPC-Cl激活GFP表达主要在肝脏，和BPS微弱的心脏。使用表达斑马鱼雌激素受体的报告细胞，将体内反应与双酚暴露的体外雌激素活性进行比较，该报告细胞驱动雌激素反应元件（ERE）-荧光素酶报告基因的表达。在这些细胞中，BPA、BPAF、BPC、BPE和BPS优先激活Esr 1，而BPC-C1优先激活Esr 2a。定量PCR结果显示，BPAF诱导经典的雌激素靶基因vtg 1、esr 1和cyp 19 a1的表达呈浓度效应，但最具效应的靶基因是f13 a1 a。暴露于BPC-Cl导致vtg 1和f13 a1 a的不同表达模式，在低浓度下激活，随后在高浓度下表达下降。由于13 a1 a的表达被所有测试的化合物强烈激活，我们建议将此mRNA作为仔鱼雌激素活性的生物标志物。我们进一步表明，暴露于BPAF和BPC-Cl增加了斑马鱼幼虫的E2水平，表明双酚暴露导致前馈反应，可以进一步增强这些化合物的雌激素活性。
Because exposure to bisphenol A (BPA) has been linked to health problems in humans and wildlife, BPA analogues have been synthesized to be considered as replacement molecules. We here have examined estrogenic activity of BPA and five of its analogues, BPAF, BPE, BPC, BPC-Cl, and BPS by a combination of zebrafish-basedin vivoandin vitroassays. We used transgenic estrogen reporter (5xERE:GFP) fish to study agonistic effects of bisphenols. Exposures to BPA, BPAF, BPE, and BPC, induced GFP expression in estrogen reporter fish at low exposure concentrations in the heart valves and at higher concentrations in the liver, whereas BPC-Cl activated GFP expression mainly in the liver, and BPS faintly in the heart only. Thein vivoresponse was compared toin vitroestrogenicity of bisphenol exposure using reporter cells that express the zebrafish estrogen receptors driving expression of an estrogen response element (ERE)-luciferase reporter. In these cells, BPA, BPAF, BPC, BPE and BPS preferentially activated Esr1, whereas BPC-Cl preferentially activated Esr2a. By quantitative PCR we found that exposure to BPAF induced expression of the classical estrogen target genesvtg1, esr1,andcyp19a1bin a concentration response manner, but the most responsive target gene wasf13a1a. Exposure to BPC-Cl resulted in a different expression pattern ofvtg1andf13a1awith an activation at low concentrations, followed by a declining expression at higher concentrations. Because expression off13a1awas strongly activated by all compounds tested, we suggest including this mRNA as a biomarker for estrogenicity in larval fish. We further showed that exposure to BPAF and BPC-Cl increased E2 levels in zebrafish larvae, indicating that bisphenol exposures result in a feed-forward response that can further augment the estrogenic activity of these compounds.