Intranasal administration of tetrabromobisphenol A bis(2-hydroxyethyl ether) induces neurobehavioral changes in neonatal Sprague Dawley rats

Tetrabromobisphenol A (TBBPA) and its derivatives are now being highly concerned due to their emerging environmental occurrence and deleterious effects on non-target organisms. Considering the potential neurotoxicity of TBBPA derivatives which has been demonstrated in vitro, what could happen in vivo is worthy of being studied. Tetrabromobisphenol A bis(2-hydroxyethyl ether) (TBBPA-BHEE), a representative TBBPA derivative, was selected for a 21-day exposure experiment on neonatal Sprague Dawley (SD) rats through intranasal administration. The neurobehavioral, histopathological changes, and differentially expressed genes based on RNA microarray were investigated to evaluate the neurological effects of this chemical. The results indicated that TBBPA-BHEE exposure significantly compromised the motor co-ordination performance and the locomotor activities (p < 0.05). The neurobehavioral phenotype could be attributed to the obvious histopathological changes in both cerebrum and cerebellum, such as neural cell swelling, microglial activation and proliferation. A total of 911 genes were up-regulated, whereas 433 genes were down-regulated. Gene set enrichment analysis showed multiple signaling pathways, including ubiquitin-mediated proteolysis and wingless-int (Wnt) signaling pathway etc. were involved due to TBBPA-BHEE exposure. The gene ontology enrichment analysis showed the basic cellular function and the neurological processes like synaptic transmission were influenced. The toxicological effects of TBBPA-BHEE observed in this study suggested the potential neuronal threaten from unintended exposure, which would be of great value in the biosafety evaluation of TBBPA derivatives.     

Re-evaluation of thyroid hormone signaling antagonism of tetrabromobisphenol A for validating the T3-induced Xenopus metamorphosis assay

We developed the T3-induced Xenopus metamorphosis assay, which is supposed to be able to sensitively detect thyroid hormone(TH) signaling disruption of chemicals. The present study aimed to validate the T3-induced Xenopus metamorphosis assay by re-evaluating the TH signaling antagonism of tetrabromobisphenol A(TBBPA), a known TH signaling disruptor. According to the assay we developed, Xenopus tadpoles at stage 52 were exposed to 10–500 nmol/L TBBPA in the presence of 1 nmol/L T3. After 96 hr of exposure, TBBPA in the range of 10–500 nmol/L was found to significantly inhibit T3-induced morphological changes of Xenopus tadpoles in a concentration-dependent manner in term of body weight and four morphological endpoints including head area(HA), mouth width(MW), unilateral brain width/brain length(ULBW/BL), and hind-limb length/snout-vent length(HLL/SVL).The results show that these endpoints we developed are sensitive for characterizing the antagonistic effects of TBBPA on T3-induced metamorphosis. Following a 24-hr exposure,we found that TBBPA antagonized expression of T3-induced TH-response genes in the tail,which is consistent with previous findings in the intestine. We propose that the tail can be used as an alternative tissue to the intestine for examining molecular endpoints for evaluating TH signaling disruption. In conclusion, our results demonstrate that the T3-induced Xenopus metamorphosis assay we developed is an ideal in vivo assay for detecting TH signaling disruption.     

四溴双酚A的辐照降解研究

研究了甲醇-水溶液中四溴双酚A(TBBPA)的电子束辐照降解.通过测定辐照前后TBBPA的浓度变化来研究吸收剂量、初始浓度、pH、自由基清除剂对辐照降解效果的影响.结果表明,TBBPA在甲醇-水溶液的辐照降解是还原性逐步脱溴降解过程,自由电子在降解过程中起主导作用,降解反应遵循一级动力学方程.在辐照剂量为10 kGy时,20 mg.L-1的TBBPA有91.6%发生脱溴降解,当向辐照体系充入氮气并且加入叔丁醇,可将TBBPA的降解效率提高到100%,或者调节辐照体系溶液的pH值至12,TBBPA的降解效率也可以达到100%.辐照降解是处理TBBPA的一种有效手段.     

Ti/RuO2-IrO2电极电化学方法降解溶液中TBBPA及其降解机理探究

四溴双酚A(TBBPA)是世界上产量和用量最大的溴代阻燃剂之一,在河流、底泥及污水中持久存在,严重威胁环境和人体健康.探讨了阳极为Ti/RuO_2-IrO_2电极的电化学法对溶液中TBBPA的降解效率,并考察了电流密度(5~20 m A·cm~(-2))、初始pH值(3~11)、极板间距(1~3 cm)及电解质浓度(1~40 mmol·L~(-1))对降解速率的影响.研究结果表明,TBBPA的降解遵循一级动力学方程,在溶液初始浓度为5 mg·L~(-1)、电流密度为10 mA·cm~(-2)、电解质浓度为5 mmol·L~(-1)及极板间距为1 cm的条件下,60 min后TBBPA的降解率可达97.2%,且降解速率常数和半衰期分别为0.060 min~(-1)和11.6 min,能量消耗为105.3 k Wh·m~(-3).同时运用HPLC-MS/MS检测出中间产物双酚A(BPA)和2-溴苯酚,并推断其降解途径主要为在羟基自由基(·OH)作用下连续的脱溴过程中,苯环与异丙基之间的C—C键断裂生成BPA和2-溴苯酚.电化学法是一种高效的、有潜力的降解难降解有机污染物的方法,本文将为今后实际废污水中TBBPA的去除提供基础数据和技术参数.     

四溴双酚A对斑马鱼胚胎体内外发育的毒性效应

四溴双酚A(TetrabromobisphenolA,TBBPA)是广泛使用的溴阻燃剂,在环境中普遍存在.采用斑马鱼胚胎体内外微环境模拟实验,研究了TBBPA对斑马鱼(Danio rerio)胚胎体内外发育的影响.结果发现,斑马鱼胚胎直接暴露在TBBPA溶液中,会造成胚胎心包囊水肿、尾部延伸不全等畸形或使胚胎死亡;当TBBPA浓度高于1.6mg·L-1时,处理斑马鱼胚胎的致死率显著升高,与对照组有极显著差异(p<0.01),且致死效应主要发生在24h内.当TBBPA浓度为6.4mg·L-1时,斑马鱼胚胎在48h内全部死亡.在TBBPA浓度大于0.4mg·L-1的各组中,24h内斑马鱼胚胎在20s内的活动频率明显降低;当胚胎直接接触TBBPA48h,表现出的主要毒性效应为胚胎心包囊水肿,但胚胎的心率没观察到异常变化.当斑马鱼胚胎发育到72h时,TBBPA引起斑马鱼胚胎毒性的主要特征是心包囊水肿和脊柱畸形.另外,TBBPA处理后斑马鱼胚胎的孵化率和生存率均显著降低,这表明斑马鱼胚胎直接暴露在TBBPA污染的环境中,会出现明显的发育障碍,主要表现为心脏功能受损和致死效应,这些毒性特征有显著的剂量-效应关系.当成年亲代斑马鱼暴露在TBBPA溶液(1.5mg·L-1)中3～7d后,子代胚胎的发育表现出明显的毒性效应,其胚胎发育到24h和72h时的致死率均呈现一定的时间-效应关系;72h时的死亡率与对照组有极显著差异,子代胚胎的孵化率降低,但没有统计学差异;但子代胚胎的致畸率却显著升高,并呈现显著差异.研究结果表明,水体中残留的TBBPA对体内外斑马鱼胚胎的发育均有直接影响,对于鱼类的生殖和发育具有潜在的危害.     

A screening assay for thyroid hormone signaling disruption based on thyroid hormone-response gene expression analysis in the frog Pelophylax nigromaculatus

Amphibian metamorphosis provides a wonderful model to study the thyroid hormone (TH) signaling disrupting activity of environmental chemicals, with Xenopus laevis as the most commonly used species. This study aimed to establish a rapid and sensitive screening assay based on TH-response gene expression analysis using Pelophylax nigromaculatus, a native frog species distributed widely in East Asia, especially in China. To achieve this, five candidate TH-response genes that were sensitive to T3 induction were chosen as molecular markers, and T3 induction was determined as 0.2 nmol/L T3 exposure for 48 hr. The developed assay can detect the agonistic activity of T3 with a lowest observed effective concentration of 0.001 nmol/L and EC50 at around 0.118–1.229 nmol/L, exhibiting comparable or higher sensitivity than previously reported assays. We further validated the efficiency of the developed assay by detecting the TH signaling disrupting activity of tetrabromobisphenol A (TBBPA), a known TH signaling disruptor. In accordance with previous reports, we found a weak TH agonistic activity for TBBPA in the absence of T3, whereas a TH antagonistic activity was found for TBBPA at higher concentrations in the presence of T3, showing that the P. nigromaculatus assay is effective for detecting TH signaling disrupting activity. Importantly, we observed non-monotonic dose-dependent disrupting activity of TBBPA in the presence of T3, which is difficult to detect with in vitro reporter gene assays. Overall, the developed P. nigromaculatus assay can be used to screen TH signaling disrupting activity of environmental chemicals with high sensitivity.     

赤子爱胜蚓对不同浓度四溴双酚A代谢的急性与亚急性毒性响应

运用核磁共振一维氢谱研究不同浓度四溴双酚A(TBBPA)急性暴露与亚急性暴露对赤子爱胜蚓(Eisenia fetida)的代谢影响.通过设置不同剂量TBBPA进行急性暴露和亚急性暴露,运用正交偏最小二乘投影分析法(OPLS)比较急性和亚急性暴露下蚯蚓的代谢差异,研究蚯蚓代谢水平与暴露剂量的关系,以找出差异代谢物作为TBBPA毒性效应的代谢标志物.结果表明,急性暴露和亚急性暴露均能很好地区分不同剂量染毒组间的代谢差异,且TBBPA暴露剂量越大,蚯蚓体内代谢与空白组的差异越大.急性暴露和亚急性暴露后,亮氨酸、赖氨酸和甜菜碱等代谢物剂量随TBBPA剂量增加的变化趋势是一致的,亚急性暴露中的变化幅度大于急性暴露.TBBPA暴露剂量为100 mg·kg~(-1)时,赤子爱胜蚓受到毒害作用,体内代谢物变化显著,代谢平衡遭到破坏,差异代谢物对毒性效应的指示作用比较敏感.甜菜碱、亮氨酸和赖氨酸可作为标志性代谢物揭示TBBPA对赤子爱胜蚓在渗透压调节、能量供给以及免疫功能方面的毒性效应,为进一步探索TBBPA毒性机理提供理论基础.     

钴掺杂铁酸铋活化过硫酸盐降解水中四溴双酚A的研究

采用溶胶凝胶法制备了钴掺杂的铁酸铋(xCo-BFO),以此作为多相催化剂,活化过硫酸盐(PMS),产生硫酸根自由基,在水相降解溴代阻燃剂四溴双酚A(TBBPA).研究了钴掺杂量、催化剂用量、PMS初始浓度对降解反应过程的影响.结果表明,在xCo-BFO中Co掺杂量(Co/Fe摩尔比)为0.1,用量为0.5 g.L-1,PMS浓度为2.5 mmol.L-1时,60 min内对40 mg.L-1的TBBPA的去除率可达95%以上.所得催化剂在反应中稳定,反应60 min后Co溶出量仅占总Co的0.27%,经4次重复使用仍具有较高催化活性;具有磁性,回收方便,在污水处理领域具有良好的应用前景.     

四溴双酚A的鲫鱼血清蛋白生物标志物研究

以鲫鱼为供试生物,对四溴双酚A(TBBPA)的急性毒性、血清蛋白潜在生物标志物以及相应的毒性靶器官组织病理进行了研究,结果表明TBBPA对鲫鱼96 h的半致死浓度LC50是3.13 mg/L,TBBPA诱导下鲫鱼血清蛋白可区分为11个组分,各组分随时间和浓度的变化规律存在差异。组分11条带清晰,表达量变化幅度最大,在低浓度TBBPA暴露下表达量先降低后升高,第16天达到最高;高浓度时表达量在第2天达到最高。组分11的分子量为24 kDa,可能为鲫鱼斯坦尼小体(CS)中降血钙因子的解聚物。组织病理切片结果显示,鲫鱼肝脏和肾脏均表现出时间-剂量依赖性,且与组分11的诱导差异性表达呈现相应的病理损伤。因此,鲫鱼血清蛋白组分11对TBBPA的诱导具有浓度和时间响应敏感性,且易于识别和鉴定,可作为TBBPA暴露的鲫鱼血清蛋白潜在生物标志物。     

四溴双酚-A污染对颤蚓的氧化胁迫及毒性

在实验室模拟条件下分别采用动、静态生物慢性实验的方法,研究了不同浓度的四溴双酚-A(Tetrabromobisphenol A, TBBPA)对颤蚓(Monopylephorus limosus)体内抗氧化酶系统及相Ⅱ结合酶系统活性的影响以及颤蚓暴露于单一浓度的TBBPA后,其体内抗氧化酶系统的活性随时间的响应.结果表明,暴露 8d 后,颤蚓体内SOD的活性发生显著变化,变化趋势明显分为升高、降低、再升高3阶段,在0.05ms/L时SOD的活性被最大诱导(p<0.01),达到对照组的7.8倍,各浓度组SOD的活性均显著高于对照组,由对照组的1.5倍到对照组的7.8倍;同时, CAT的活性变化则呈升高、降低、再升高、再降低4阶段,0.5mg/L时其活性达到最大值(p<0.01),除0.005mg/L和0.25mg/L浓度组CAT活性受抑制外,其余浓度组CAT的活性均高于对照组,由对照组的1.1倍到1.9倍,染毒浓度为0.25ms/L时, GST的活性达到最大诱导(p<0.01),其活性先缓慢上升后下降,并且各处理组GST的活性均显著高于对照组(p<0.05).在单一浓度TBBPA污染暴露的10d时间内,颤蚓体内SOD的活性变化趋势形成了一个变形的"M" 形曲线,在第3d时其活性达到最大诱导,而CAT活性的变化则表现为一个不规则的"N"形曲线,在第5d,时其活性达到最大诱导,并且SOD的活性比CAT的活性受时间的影响小,相对来说更稳定.可见, SOD与GST的活性变化似乎更能反映出TBBPA对颤蚓的污染效应及其毒性作用,而SOD的活性变化似乎更为灵敏,但是二者能否作为指示TBBPA污染的生物标志物尚需进一步研究.     

Assessment of Bisphenol A (BPA) neurotoxicity in vitro with mouse embryonic stem cells

The adverse effects of environmental pollution on our well-being have been intensively studied with many in vitro and in vivo systems. In our group, we focus on stem cell toxicology due to the multitude of embryonic stem cell (ESC) properties which can be exerted in toxicity assays. In fact, ESCs can differentiate in culture to mimic embryonic development in vivo, or specifically to virtually any kind of somatic cells. Here, we used the toxicant Bisphenol A (BPA), a chemical known as a hazard to infants and children, and showed that our stem cell toxicology system was able to efficiently recapitulate most of the toxic effects of BPA previously detected by in vitro system or animal tests. More precisely, we demonstrated that BPA affected the proper specification of germ layers during our in vitro mimicking of the embryonic development, as well as the establishment of neural ectoderm and neural progenitor cells.     

Molecular toxicity and defense mechanisms induced by silver nanoparticles in Drosophila melanogaster

The widely use of silver nanoparticles (AgNPs) as antimicrobial agents gives rise to potential environmental risks. AgNPs exposure have been reported to cause toxicity in animals. Nevertheless, the known mechanisms of AgNPs toxicity are still limited. In this study, we systematically investigated the toxicity of AgNPs exposure using Drosophila melanogaster. We show here that AgNPs significantly decreased Drosophila fecundity, the third-instar larvae weight and rates of pupation and eclosion in a dose-dependent manner. AgNPs reduced fat body cell viability in MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. AgNPs caused DNA damage in hemocytes and S2 cells. Interestingly, the mRNA levels of the entire metallothionein gene family were increased under AgNPs exposure as determined by RNA-seq analysis and validated by qRT-PCR, indicating that Drosophila responded to the metal toxicity of AgNPs by producing metallothioneins for detoxification. These findings provide a better understanding of the mechanisms of AgNPs toxicity and may provide clues to effect on other organisms, including humans.     

四溴双酚A降解技术的最新研究进展

作为目前产量和使用量最大的溴系阻燃剂,四溴双酚A(Tetrabromobisphenol A,TBBPA)在其生产、使用及处置等环节会被释放到环境中,由于四溴双酚A具有持久性、累积性和生物毒性等特性而对人类健康和生态环境造成威胁。文章在简单介绍四溴双酚A主要性质和毒性的基础上,结合近几年国内外的研究现状,综述了四溴双酚A在光降解、微生物降解和高级氧化等技术的最新研究进展,并对目前存在的问题及未来的研究方向进行了讨论与展望。     

Effects of dissolved organic matter from sewage sludge on sorption of tetrabromobisphenol A by soils

Sorption of tetrabromobisphenol A (TBBPA) by soil influences its fate and transport in the environment. The presence of dissolved organic matter (DOM) may complicate the sorption process in soil. The effects of DOM from sewage sludge on TBBPA sorption by three soils were investigated using batch equilibration experiments in the study. DOM was observed to be sorbed on the soils and the isotherms could be fitted by the Langmuir model. The effects of DOM on TBBPA sorption were dependent on the characteristics ...     

四溴双酚-A和五溴酚对红鲫甲状腺激素和脱碘酶的影响

将红鲫(Carassius auratus)分别暴露于0.5mg·L-1四滇双酚-A(TBBPA)和0.1 mg·L-1五澳酚(PBP)中28 d,采用放射性免疫分析法和化学发光酶联免疫分析法检测红鲫的血清甲状腺激素水平和肝脏脱碘酶活性.结果显示,TBBPA能使红鲫血清TT4和TT3水平降低,rT3水平、肝脏脱碘酶ID2和ID3活性升高.PBP对红鲫甲状腺系统的干扰要小于TBBPA,它对红鲫血清TT3水平和ID2活性几乎没有影响.上述结果表明,TBBPA和PBP能够干扰红鲫体内甲状腺激素的稳态,加速甲状腺激素在肝脏内的转化和代谢;这可能是通过抑制甲状腺激素与运载蛋白的结合来实现的.     

Role of nitric oxide in the genotoxic response to chronic microcystin-LR exposure in human–hamster hybrid cells

Microcystin-LR (MC-LR) is the most abundant and toxic microcystin congener and has been classified as a potential human carcinogen (Group 2B) by the International Agency for Research on Cancer. However, the mechanisms underlying the genotoxic effects of MC-LR during chronic exposure are still poorly understood. In the present study, human–hamster hybrid (A_L) cells were exposed to MC-LR for varying lengths of time to investigate the role of nitrogen radicals in MC-LR-induced genotoxicity. The mutagenic potential at the CD59 locus was more than 2-fold higher (p < 0.01) in A_L cells exposed to a cytotoxic concentration (1 μmol/L) of MC-LR for 30 days than in untreated control cells, which was consistent with the formation of micronucleus. MC-LR caused a dose-dependent increase in nitric oxide (NO) production in treated cells. Moreover, this was blocked by concurrent treatment with the NO synthase inhibitor N^G-methyl-l-arginine (l-NMMA), which suppressed MC-LR-induced mutations as well. The survival of mitochondrial DNA-depleted (ρ⁰) A_L cells was markedly decreased by MC-LR treatment compared to that in A_L cells, while the CD59 mutant fraction was unaltered. These results provided clear evidence that the genotoxicity associated with chronic MC-LR exposure in mammalian cells was mediated by NO and might be considered as a basis for the development of therapeutics that prevent carcinogenesis.     

Assessing microbial and chemical exposure risks of Giardia in indoor swimming pool water disinfected by chlorine

Swimming pools adopt chlorination to ensure microbial safety. Giardia has attracted attention in swimming pool water because of its occurrence, pathogenicity, and chlorine resistance. To control Giardia concentrations in pool water and reduce the microbial risk, higher chlorine doses are required during disinfection. Unfortunately, this process produces carcinogenic disinfection byproducts that increase the risk of chemical exposure. Therefore, quantitatively evaluating the comparative microbial vs. chemical exposure risks that stem from chlorination inactivation of Giardia in swimming pool water is an issue that demands attention. We simulated an indoor swimming pool disinfection scenario that followed common real-world disinfection practices. A quantitative microbial risk assessment coupled with a chemical exposure risk assessment was employed to compare the Giardia microbial exposure risk (MER) and the trihalomethane chemical exposure risk (CER) to humans. The results demonstrated a 22% decrease in MER- and CER-induced health exposure risk, from 8.45E-5 at 8:00 to 6.60E-5 at 19:00. Both the MER and CER decreased gradually, dropping to 3.26E-5 and 3.35E-5 at 19:00, respectively. However, the CER exceeded the MER after 18:30 and became the dominant factor affecting the total exposure risk. Past the 18 hr mark, the contribution of trihalomethane CER far exceeded the risk aversion from microbial inactivation, leading to a net increase in total exposure risk despite the declining MER. Swimmers may consider swimming after 19:00, when the total exposure risk is the lowest. Lowering water temperature and/or pH were identified as the most sensitive factors to minimize the overall health exposure risk.     

四溴双酚A在鲫鱼不同器官中的分布、富集及病理研究

研究了将鲫鱼(Carassius auratus)长期暴露于不同浓度的四溴双酚A(TBBPA)后的器官组织分布和浓缩富集系数,同时对不同暴露时间的鲫鱼不同器官病理切片进行了观察.结果显示,各浓度组鲫鱼肝脏和肾脏的TBBPA含量都表现出先升高后下降的趋势,鳃和肌肉中TBBPA含量只有在高浓度时呈现相同的趋势.病理切片显示鲫鱼肝脏、肾脏和鳃等器官组织均表现出时间-剂量依赖性的病理损伤,在相同暴露浓度下,雄鱼的性腺损伤程度高于雌鱼.     

4种典型溴代阻燃剂对离体条件下罗非鱼肝脏抗氧化系统影响的研究

以罗非鱼(Mossambica tilapia)为实验生物,研究了离体条件下其肝脏抗氧化系统中谷胱甘肽(GSH)含量、谷胱甘肽硫转移酶(GST)和超氧化物歧化酶(SOD)活性对4种溴代阻燃剂(Brominated flame retardants,BFRs)——四溴联苯醚(BDE-47)、十溴联苯醚(BDE-209)、六溴环十二烷(HBCD)和四溴双酚A(TBBPA)的响应.研究结果表明:离体暴露于4种BFRs 1 h后,罗非鱼肝脏上清液中GSH含量和SOD活性随暴露剂量升高均呈现先升高后回落的趋势,但总体均高于对照组水平;GST活性则被抑制.上述3种抗氧化参数中,同一参数对4种BFRs响应均呈现一致的变化趋势,其中GST和SOD活性响应更为灵敏.GST活性对BDE-47、BDE-209和HBCD的最低响应浓度均低于1 ng·L-1,且与TBBPA和BDE-209在一定浓度范围内存在较好的剂量-效应关系;SOD活性对4种BFRs暴露较为敏感,最低响应浓度均低于10 ng·L-1,并且与除BDE-209外的上述3种污染物在一定的浓度范围内具有良好的剂量-效应关系.因此,GST和SOD活性指标是值得进一步研究的溴代阻燃剂污染候选生物标志物.     

四溴双酚A和镉复合污染对不同生物体的安全阈值

以赤子爱胜蚓（Eisenia fetida）、斑马鱼（Zebrafish）作为受试生物,进行急性毒性试验,死亡率、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）为效应指标,采用基准剂量（BMD）法推导四溴双酚A （TBBPA）和镉（Cd）单一及联合暴露对不同生物体的安全阈值.结果表明,在本研究的试验剂量范围内,蚯蚓、斑马鱼TBBPA、Cd暴露剂量与死亡率、SOD、CAT活性效应指标存在明显剂量-效应关系.单一暴露下,CAT、SOD活性指标最敏感,蚯蚓和斑马鱼的TBBPA安全阈值分别为0.95,0.44mg/L,Cd安全阈值分别为71.17,0.42mg/L.联合暴露下安全阈值小于单一暴露.蚯蚓、斑马鱼TBBPA安全阈值分别为0.33,0.024mg/L,Cd为6.45,0.176mg/L.