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典型苯甲酮类物质对鱼类的毒性与毒理机制研究
Alternative TitleThe toxicity and mechanism of typical benzophenones to fish
闫赛红
Subtype博士
Thesis Advisor王子健 ; 查金苗
2018-06
Degree Grantor中国科学院生态环境研究中心
Place of Conferral北京
Degree Name理学博士
Degree Discipline环境科学
Keyword苯甲酮类物质,繁殖毒性,遗传毒性,稀有鮈鲫,Rna-seq Benzophenones, Chinese Rare Minnow, Japanese Medaka, Reproduction, Genetic Toxicity, Rna-seq
Abstract

      基于二苯甲酮及其衍生物具有良好的紫外吸收能力,因此被添加到各种个人护理品中,其添加量最高可达总含量的10%,随着使用量的逐渐增加,其在水环境中被频繁的检测到。虽然二苯甲酮类紫外吸收剂对人类接触毒性和健康风险相对较小,但基于其潜在“伪”持久性与生物富集性,因此选择典型二苯甲酮类紫外吸收剂为研究对象,以非靶标生物稀有鮈鲫和青鱂为实验动物,探索其对非靶标水生生物的毒性和毒理机制,为此类物质环境风险管理提供基础数据和技术支撑。基于短期暴露实验和长期暴露实验相结合,取得了以下创新性结果:

      日本青鳉的短期繁殖繁殖实验证实BP,BP-4,BP-12,BZD和2,3,4-triOH-BP显著改变青鳉成鱼的总产卵量,增加后代累计死亡率、畸形率、孵化率; BP、BP-2、BP-3、BP-4、4-OH-BP和2,3,4-triOH-BP暴露显著增加青鳉雄鱼血浆中的VTG含量;BP、BP-1、BP-2、BP-4和BP-12诱导青鳉脑内的fshβ和lhβ基因的mRNA表达显著增加,BP、BZD和4-OHBP诱导雌鱼性腺中的fshr和lhr基因的mRNA表达显著增加;BP、BP-2、BP-4、BP-12、BZD和2,3,4-triOHBP显著增加雄鱼性腺中的lhr基因mRNA表达;BP、BP-1、BP-4和BP-12导致青鳉雌鱼脑内的cyp19β基因的mRNA表达显著增加,而BP、BZD和2,3,4-triOH-BP导致青鳉雄鱼脑内的cyp19β基因的mRNA表达显著增加;组织切片结果显示二苯甲酮类物质导致卵巢中成熟卵母细胞明显减少,未成熟的卵母细胞显著增加,并且出现退化的卵母细胞,雄鱼精巢熟精子比例明显减少。结果表明典型二苯甲酮类物质不仅具有繁殖和发育毒性,同时具有内分泌干扰效应;结果证实二苯甲酮类物质的繁殖毒性与取代基有关,羟基越多,效应越高;一个甲氧基和一个羟基效应相同,没有明显的效应,磺酸基效应升高;与母体化合物相比,代谢产物效应明显升高。

      日本青鳉长期暴露实验结果发现BP、BP-1和BP-4对青鳉具有繁殖毒性,改变后代孵化率,增加死亡率和畸形率;显著增加VTG和E2水平,且改变HPG轴相关基因的表达;性腺组织学证实三种二苯酮类物质抑制雌性腺中成熟卵母细胞和雄性腺中成熟精子的形成,全生命周期结果表明长期低剂量BP、BP-1和BP-4暴露不仅影响繁殖、生长和发育,同时显示更高的类雌激素活性。

      稀有鮈鲫短期暴露实验结果证实转录组水平上BP、BP-1和BP-4改变细胞周期、DNA修复和细胞凋亡等与DNA损伤相关的信号通路。BP、BP-1和BP-4能够引起DNA损伤、激活8-OHdG和诱导caspase酶活与凋亡率的升高;结果BP、BP-1和BP-4具有遗传毒性,其遗传毒性作用机制是BP、BP-1和BP-4引起稀有鮈鲫雄鱼肝脏发生氧化DNA损伤,进一步抑制DNA修复,包括碱基切除修复、核苷酸切除修复和错配修复,引起细胞周期被抑制,从而诱导细胞发生凋亡。

Other Abstract

      Based on the good ability of UV absorption, benzophenone-type UV filters (BPs) have been added to various personal care products and the maximum amount of benzophenones added in personal care products can be up to 10%. BPs have been detected frequently in water environments due to their increased consumption. Although BPs have relatively low risks and toxicity on human health, they are potential pseudo-pseudopersistence and bioconcentration. Therefore, BPs were selected to be the research object. In order to study their toxic and toxicological mechanisms to fish, the non-target organisms, Japanese medaka (Oryzias latipes) and Chinese rare minnow (Gobiocypris rarus) were used to carry out the experiment, providing basic data and technical support for the management on environmental risks of BPs. Based on the combination of short-term and long-term exposure experiments, the following innovative results were obtained:

      The results of short-term reproduction and reproduction of Japanese medaka showed that BP, BP-4, BP-12, BZD, and 2,3,4-triOH-BP significantly changed total oviposition of medaka. In the clean water experiment, BPs increased the cumulative mortality and malformation rate of offspring (p<0.05), and in the continued exposure experiment, BPs significantly decreased the hatching rate, increased the mortality rate and the total deformity rate (p<0.05). BP, BP-2, BP-3, BP-4, 4-OH-BP, and 2,3,4-triOH-BP significantly increased levels of VTG in the plasma of males (p<0.05); BP, BP-1, BP-2, BP-4, and BP-12 significantly increased the mRNA expression of fshβ and lhβ in the brain of medaka (p<0.05). BP, BZD and 4-OHBP significantly increased the mRNA expression of fshr and lhr in the gonads of females (p<0.05). BP, BP-2, BP-4, BP-12, BZD, and 2,3,4-triOHBP significantly increased the levels of lhr gene in gonads of males. BP, BP-1, BP-4, and BP-12 caused a significant increase in cyp19β mRNA expression in the brains of females (p<0.05), while BP, BZD, and 2,3,4-triOH-BP increased the mRNA expression ofcyp19β in male fish brain (p<0.05), The results of the histological analysis showed that mature oocytes had significantly reduced, while immature oocytes were increased significantly, and degenerating oocytes appeared. The proportion of mature sperm in testes were also significant decreased. The results show that BPs not only have reproductive and developmental toxicity, but also have endocrine disrupting effects;The results confirmed that the reproductive activity of BPs is related to the substituents. The more hydroxyl groups, the higher the effect; one methoxy group has the same effect as one hydroxyl group; the sulfonic acid group increases the effect; the metabolite effect is obviously increased compared with the parent compound.

      The long-term exposure experiments of medaka show that BP, BP-1, and BP-4 have reproductive toxicity, changed the hatching rate of offspring, increased mortality and deformity rate, significant increase the levels of VTG and E2, and changed mRNA expression of HPG axis-related genes. Histological analysis confirmed that the three benzophenones inhibit the formation of mature sperm in the male glands and mature oocytes in female glands. According to the above endpoints, the long-term low-dose BP, BP-1 and BP-4 exposures not only affect reproduction, growth and development, but also show highter estrogen-like activity.

      The short-term test of Chinese rare minnow confirmed that BP, BP-1, and BP-4 at the transcriptome level altered DNA damage-related signaling pathways such as cell cycle, DNA repair, and apoptosis. BP, BP-1 and BP-4 can induce DNA damage, activate and 8-OHdG, and increase the caspase activity and apoptosis rate. These results suggest that BP, BP-1 and BP-4 have genotoxicity. Their genotoxicity mechanism was that BP, BP-1 and BP-4 caused oxidative DNA damage in the livers of males, further inhibited DNA repair, causing cell cycle arrest, and lead to apoptosis.

Pages151
Language中文
Document Type学位论文
Identifierhttp://ir.rcees.ac.cn/handle/311016/41562
Collection环境水质学国家重点实验室
Recommended Citation
GB/T 7714
闫赛红. 典型苯甲酮类物质对鱼类的毒性与毒理机制研究[D]. 北京. 中国科学院生态环境研究中心,2018.
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