New insights in the endocrine disrupting effects of three primary metabolites of organophosphate flame retardants.
New insights in the endocrine disrupting effects of three primary metabolites of organophosphate flame retardants.
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DOI：
10.1021/acs.est.9b07874
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发表时间：
2020-03
影响因子：
11.4
通讯作者：
Quan Zhang;Chang Yu;Lili Fu;Sijia Gu;Cui Wang
中科院分区：
文献类型：
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作者：
Quan Zhang;Chang Yu;Lili Fu;Sijia Gu;Cui Wang
尽管有机磷阻燃剂（OPFRs）的代谢产物在生物群中无处不在，内分泌干扰的潜力还没有得到很好的检查。本文选择了OPFR的三种主要代谢产物（BCIPP、BDCIPP和DPHP），通过体外、体内和计算机模拟实验研究其潜在的内分泌干扰作用。三种代谢产物对大鼠雌激素受体α（ERα）具有激动作用，对人盐皮质激素受体（MR）具有拮抗作用。BCIPP具有内分泌干扰作用，而其母体化合物则无内分泌干扰作用。在所测试的化合物中，它也对ERα具有最强的结合能力。BCIPP和BDCIPP均上调H295 R细胞中雌激素合成酶的编码基因，包括17βHSD和CYP 19。所有三种化合物都刺激了CYP 11B 1的转录，而BCIPP和DPHP也触发了CYP 11B 2，编码皮质激素的产生。BDCIPP抑制孕酮合成基因，包括CYP 11 A1、星星和3-βHSD。对斑马鱼胚胎死亡率和孵化率的诱导作用为BCIPP ≥ BDCIPP > DPHP。所有化合物均导致斑马鱼幼体畸形。下丘脑-垂体-肾上腺皮质轴和下丘脑-垂体-性腺轴均被破坏，BCIPP的影响最大。总而言之，数据澄清了OPFR代谢物可能产生与OPFR相当或甚至更高的内分泌干扰作用。
Despite the ubiquity of organophosphate flame retardants (OPFRs) metabolites in the biota, the endocrine disrupting potency has not been well examined. Herein, we chose three primary metabolites of OPFRs (BCIPP, BDCIPP and DPHP) to investigate their potential endocrine disrupting effects by in vitro, in vivo and in silico assays. Three metabolites were agonistic to rat estrogenic receptor alpha (ERα) and antagonists to human mineralocorticoid receptor (MR). BCIPP exerted endocrine disrupting effect contrasting to the negative response of its parental compound. It also poses the strongest binding capacity to ERα among the tested compounds. Both BCIPP and BDCIPP upregulated the genes encoded for oestrogenic synthesis enzymes in H295R cells, including 17βHSD and CYP19. All three compounds stimulated the transcription of CYP11B1, while BCIPP and DPHP also triggered CYP11B2, encoding for corticoid production. BDCIPP inhibits genes for progesterone synthesis including CYP11A1, STAR and 3-βHSD. The induction of mortality and low hatchability of zebrafish embryo were ranked as BCIPP ≥ BDCIPP > DPHP. All compounds lead to malformation of zebrafish larvae. Both of the hypothalamic-pituitary-adrenocortical and hypothalamic-pituitary-gonadal axes were disrupted, with the highest impact by BCIPP. Altogether, the data clarified OPFRs metabolites may produce comparable or even higher endocrine disrupting effects than OPFRs.