Untargeted metabolic profiling of body fluids in experimental animals and humans exposed to chemicals may reveal early signs of toxicity and indicate toxicity pathways. Avian embryos develop separately from their mothers, which gives unique possibilities to study effects of chemicals during embryo development with minimal confounding factors from the mother. In this study we explored blood plasma and allantoic fluid from chicken embryos as matrices for revealing metabolic changes caused by exposure to chemicals during embryonic development. Embryos were exposed via egg injection on day 7 to the environmental pollutant perfluorooctanoic acid (PFOA), and effects on the metabolic profile on day 12 were compared with those caused by GW7647 and rosiglitazone, which are selective agonists to peroxisome-proliferator activated receptor alpha (PPARalpha) and PPARgamma, respectively. Analysis of the metabolite concentrations from allantoic fluid by Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) showed clear separation between the embryos exposed to GW7647, rosiglitazone, and vehicle control, respectively. In blood plasma only GW7647 caused a significant effect on the metabolic profile. PFOA induced embryo mortality and increased relative liver weight at the highest dose. Sublethal doses of PFOA did not significantly affect the metabolic profile in either matrix, although single metabolites appeared to be altered. Neonatal mortality by PFOA in the mouse has been suggested to be mediated via activation of PPARalpha. However, we found no similarity in the metabolite profile of chicken embryos exposed to PFOA with those of embryos exposed to PPAR agonists. This indicates that PFOA does not activate PPAR pathways in our model at concentrations in eggs and embryos well above those found in wild birds. The present study suggests that allantoic fluid and plasma from chicken embryos are useful and complementary matrices for exploring effects on the metabolic profile resulting from chemical exposure during embryonic development.
来源:Hazardous Substances Data Bank (HSDB)
代谢
全氟辛酸（PFOA）不被代谢，且有证据表明该化合物在肠肝之间循环。
PFOA is not metabolized and there is evidence of enterohepatic circulation of the compound.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
毒性总结
全氟辛酸（PFOA）是一种白色至略带白色的粉末。PFOA主要用于生产其盐类，这些盐类在氟聚合物和氟弹性体的生产中作为必不可少的加工助剂。PFOA还用作防水剂、消防泡沫中的表面活性剂，以及合成氟丙烯酸酯的中间体。它在制造特氟龙和类似化学品（称为氟碳聚合物）的过程中使用，尽管在生产过程中会被烧掉，在最终产品中，包括特氟龙涂层产品中，不会以显著量存在。人类暴露和毒性：一项甲状腺研究结果表明，全氟烷基物质与老年人群中甲状腺激素水平的微妙变化有关，这些关联可能因年龄而异。暴露于PFOA可能会降低生育能力。在明尼苏达州Cottage Grove的一家工厂，那些在可能暴露于PFOA的工作中工作了27年的工人，或者那些有明确PFOA暴露9年的人，死于脑血管疾病的可能性比普通人群高出3.3倍。根据对两个不同3M工厂的工人进行研究，PFOA与血清胆固醇和甘油三酯水平随时间有显著的正相关。有人建议，PFOA水平与ADHD之间存在显著的剂量反应关系。孕早期母体PFOA水平与胎儿腹围和出生长度较小有关。另一项研究中，母体PFOA浓度与儿童普通感冒的发作次数以及PFOA与胃肠炎发作次数之间存在正相关。在一项对男性和女性血清水平的研究中，与同一人群中的女性相比，男性的PFOA浓度更高。在150 uM PFOA暴露的HepG2细胞中，通过同时流式细胞术分析凋亡相关的DNA链断裂，揭示了DNA断裂，这是在核碎片化之前的。流行病学证据不支持PFOA暴露与人类癌症之间有因果关系的假设。然而，根据有限的癌症死亡人数，与不从事PFOA生产相比，从事PFOA暴露工作十年与前列腺癌死亡率增加3.3倍有关。动物研究：动物研究指出，PFOA可引起多种毒性效应，包括肝和脑功能障碍、致癌性以及生殖和发育毒性。在小鼠的皮肤暴露后，PFOA被证明具有免疫毒性。根据另一项针对小鼠的研究，PFOA可以诱导气道炎症并改变气道功能。对小鼠的组织学检查显示，连续14天暴露于PFOA导致严重的肝细胞损伤和明显的炎症细胞浸润。此外，PFOA处理在小鼠肝脏中显著诱导了丙二醛的形成和过氧化氢的生成，这些都是氧化应激的指标。此外，由PFOA暴露引起的肝脏中白细胞介素-6、环氧合酶-2和C反应蛋白的水平，这些炎症反应的标志物显著增加。对小鼠进行围产期暴露于PFOA的研究在成年后代中产生了代谢效应。PFOA诱导的男性生殖障碍可能涉及发育损伤和对小鼠睾丸中NRF2介导的抗氧化反应的抑制。在小鼠和大鼠中，PFOA单独并未引起任何神经毒性症状。然而，在小鼠新生儿暴露后描述了PFOA的发育神经毒性。新生儿暴露于PFOA影响了胆碱能系统，表现为对尼古丁的反应降低，而对照组对尼古丁的反应过度活跃。在Ames试验中，使用四种沙门氏菌typhimurium菌株，在存在或不存在代谢系统的情况下，PFOA并未表现出致突变性。小鼠对PFOA的短期高剂量暴露增强了对脂多糖（LPS）的炎症反应，LPS是一种强大的先天免疫激活剂。生态毒性研究：在罕见的小鱼中发现，PFOA改变了与脂质代谢和运输、激素作用、免疫反应、线粒体功能、脂肪酸生物合成和运输有关的基因。此外，PFOA抑制了负责甲状腺激素生物合成的基因，并显著诱导了雌激素响应基因。对果蝇的研究表明，PFOA在有机体水平上的毒性效应与有机体的发育状况有关，幼虫对这种化学物质最为敏感。
IDENTIFICATION AND USE: Perfluorooctanoic acid (PFOA) is a white to off-white powder. PFOA is used primarily to produce its salts, which are used as essential processing aids in the production of fluoropolymers and fluoroelastomers. PFOA is also used as a water repellent, a surfactant in firefighting foams, and as an intermediate in the synthesis of fluoroacrylic esters. It is used in the process of making Teflon and similar chemicals (known as fluorotelomers), although it is burned off during the process and is not present in significant amounts in the final products, including Teflon-coated products. HUMAN EXPOSURE AND TOXICITY: Results of a thyroid study suggest that perfluoroalkyl substances are associated with subtle alterations in thyroid hormone levels in aging populations, and that these associations are likely to vary by age. Exposure to PFOA may reduce fecundability. At a plant in Cottage Grove, Minnesota, workers with 27 years of exposure in probable PFOA exposed jobs or those with 9 years of definite PFOA exposure were 3.3 times more likely to die of cerebrovascular disease than the general population. Based on workers studied at two different 3M plants, there was a statistically significant positive association between PFOA and serum cholesterol and triglycerides levels over time. It has been suggested that there is a significant dose response relationship between PFOA levels and ADHD. Maternal PFOA levels in early pregnancy were associated with smaller abdominal circumference and birth length. In another study, there was a positive association between the maternal concentrations of PFOA and the number of episodes of common cold for the children, and between PFOA and the number of episodes of gastroenteritis. In a study on blood serum levels of men and women, higher concentrations of PFOA were observed in men in comparison to women from the same populations. Simultaneous flow cytometric analysis of apoptosis-associated DNA strand breaks revealed DNA breaks in HepG2 cells exposed to 150 uM PFOA, prior to nuclear fragmentation. Epidemiologic evidence does not support the hypothesis of a causal association between PFOA exposure and cancer in humans. However, ten years of employment in PFOA exposed jobs was associated with a 3.3-fold increase in prostate cancer mortality compared to no employment in PFOA production, based on limited number of cancer deaths. ANIMAL STUDIES: Animal studies have indicated that PFOA cause a wide array of toxic effects including liver and brain dysfunction, carcinogenicity and reproductive and developmental toxicity. PFOA was demonstrated to be immunotoxic following dermal exposure of mice. Based on another study in mice, PFOA can induce airway inflammation and alter airway function. Histological examination of mice showed that the exposure to PFOA for 14 consecutive days led to serious hepatocellular injury and obvious inflammatory cell infiltration. In addition, malondialdehyde formation and hydrogen peroxide generation, indicators of oxidative stress, were significantly induced by PFOA treatment in the liver of mice. Furthermore, hepatic levels of interleukin-6, cyclooxygenase-2, and C-reactive protein, markers of inflammatory response, were markedly increased by exposure to PFOA. A study with perinatal exposure to PFOA in mice produced metabolic effects in adult offspring. PFOA-induced male reproductive disorders might be involved in developmental impairment and inhibition of NRF2-mediated antioxidant response in the testis of mice. In mice and rats, PFOA alone did not cause any neurotoxic symptoms. However, developmental neurotoxicity of PFOA described after neonatal exposure in mice. Neonatal exposure to PFOA affected the cholinergic system, manifested as a hypoactive response to nicotine, compared to a hyperactive response to nicotine in controls. PFOA was not mutagenic in the Ames test, using four strains of Salmonella typhimurium in the presence or absence of metabolic system. High-dose, short-term exposure of mice to PFOA augments inflammatory responses to lipopolysaccharide (LPS), a potent activator of innate immunity. ECOTOXICITY STUDIES: In rare minnows, PFOA was found to alter genes involved in lipid metabolism and transport, hormone action, immune responses, mitochondrial functions, fatty acid biosynthesis, and transport. In addition, PFOA inhibited genes responsible for thyroid hormone biosynthesis and significantly induced estrogen-responsive genes. A study on fruit flies indicated that the toxic effects of PFOA at the organismal level were associated with the developmental status of the organism, with larvae being most sensitive to this chemical.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
国际癌症研究机构致癌物：全氟辛酸
IARC Carcinogenic Agent:Perfluorooctanoic acid
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构（IARC）致癌物分类：2B组：可能对人类致癌
IARC Carcinogenic Classes:Group 2B: Possibly carcinogenic to humans
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构专著：第110卷：（2017年）某些用作溶剂和聚合物制造的化学品
IARC Monographs:Volume 110: (2017) Some Chemicals Used as Solvents and in Polymer Manufacture
来源:International Agency for Research on Cancer (IARC)
Rainbow trout (Oncorhynchus mykiss) confined to respirometer-metabolism chambers were dosed with perfluorooctanoate (PFOA) by intra-arterial (i.a.) injection and sampled to obtain concentration time-course data for plasma, urine, and expired water. The data were then analyzed by compartmental modeling to estimate rates of renal and branchial clearance. Averaged across all animals, the renal clearance rate (1.35 mL/hr/kg) was more than ten times greater than the branchial clearance rate (0.12 mL/hr/kg). The average whole-body elimination half-life was 12.6 d, which is somewhat longer than values obtained in previous studies with smaller trout. The tissue distribution of PFOA was assessed by collecting tissues at the end of chambered exposures and in a separate tissue time-course experiment. From the time-course study it appeared that an internal steady-state was established within 24 hr of i.a. injection. Consistent with previous studies, the rank order of PFOA concentration in tissues at steady state was: plasma>liver>kidney>muscle. In a second set of chambered experiments, fish were exposed to PFOA in water to determine the rate of branchial uptake. Branchial uptake rates were too low to assess directly by measuring PFOA concentrations in inspired and expired water. Uptake rate constants (mean 0.19 L/d/kg; 0.1% uptake efficiency) were therefore estimated by compartmental modeling using plasma concentration time-course data and model parameters derived from the elimination experiments. It is clear from this effort that elimination of PFOA by trout occurs primarily via the renal route. This finding is consistent with numerous studies of mammals and suggests that trout possess membrane transporters that facilitate the movement of PFOA from plasma to urine.
Determination of the chemical clearance rate from human blood is a critical component of toxicokinetic exposure assessment. Analysis of temporal biomonitoring data without consideration of ongoing exposure results in calculation of apparent elimination half-life values that are longer than the intrinsic value. The intrinsic elimination half-life is solely a function of the rate of elimination while the apparent elimination half-life reflects the processes of both elimination and ongoing exposure. Confusion between intrinsic and apparent half-life values can lead to misinterpretation of biomonitoring data and can result in exaggerated predictions in subsequent modeling efforts. This work provides a review of the first-order equations that have been developed to calculate intrinsic and apparent half-life values and the potential bias that can result from confusing these two values. Published human biomonitoring data forperfluorooctanoic acid (PFOA) are analyzed using these equations to provide examples of low, medium and high bias in determination of the intrinsic elimination half-life from plasma or serum, the components of blood typically analyzed for PFOA. An approach is also provided to estimate the extent of exposure reduction that is indicated by declining longitudinal or cross-sectional biomonitoring data. Based on the evaluation methodology presented in this work, the intrinsic elimination half-life of PFOA in humans is 2.4 years, representing the average of independent estimates of 2.5 years (95% CI, 2.4-2.7) and 2.3 years (95% CI, 2.1-2.4). The declining concentration of PFOA in blood of the general USA adult population represents an estimated exposure reduction of 20-30% over the period 1999-2008.
Perfluorinated alkyl acids (PFAAs) have been detected in serum at low concentrations in background populations. Higher concentrations have been observed in adult males compared to females, with a possible explanation that menstruation offers females an additional elimination route. In this study, we examined the significance of blood loss as an elimination route of PFAAs. Pooled serum samples were collected from individuals undergoing a medical procedure involving ongoing blood withdrawal called venesection. Concentrations from male venesection patients were approximately 40% lower than males in the general population for perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). A simple pharmacokinetic model was used to test the hypothesis that blood loss could explain why adult males have higher concentrations of PFAAs than females, and why males undergoing venesections had lower concentrations compared to males in the general population. The model application generally supported these hypotheses showing that venesection might reduce blood serum concentrations by 37% (PFOA) and 53% (PFOS) compared to the observed difference of 44% and 37%. Menstruation was modeled to show a 22% reduction in PFOA serum concentrations compared to a 24% difference in concentrations between males and females in the background population. Uncertainties in the modeling and the data are identified and discussed.
... In this study, PFOS and PFOA were analyzed in 81 whole blood-urine paired samples from general adults and pregnant women in Tianjin, China. PFOS and PFOA were detected in 48 and 76% of adult urine (AU) samples, with geometric mean (GM) concentrations of 0.011 and 0.008 ng/mL, respectively; whereas relatively low PFOS and PFOA concentrations were found in maternal urine (MU) samples, with GM concentrations of 0.006 and 0.003 ng/mL, respectively. For PFOA, the coefficients of Pearson's correlation between whole blood concentrations and creatinine-adjusted and creatinine-unadjusted urinary concentrations were 0.348 (p=0.013) and 0.417 (p=0.002), respectively. The GM urinary elimination rates of PFOS (PFOSUER) and PFOA (PFOAUER) were 16 and 25%, respectively, for adults. These results indicate that urine is an important pathway of excretion of perfluoroalkyl substances (PFASs). The partitioning ratios of PFAS concentration between urine and whole blood (PFASU/B) in pregnant women (PFOSU/B, 0.0004; PFOAU/B, 0.0011) were significantly lower (p=0.025 for PFOSU/B, p=0.017 for PFOAU/B) than the ratios found in non-pregnant women (PFOSU/B, 0.0013; PFOAU/B, 0.0028). Furthermore, our results suggest a clear gender difference in the urinary elimination of PFOA, with male adults (31%) having significantly higher PFOAUER than that of female adults (19%). PFOSUER was significantly inversely correlated with age (r=-0.334, p=0.015); these findings suggest that urinary elimination of PFOS is faster in young adults than in the elderly.
either carboxylic acids or alcohols are normally needed. We found that the directcondensation of equimolar amounts of carboxylic acids and alcohols could be achieved using hafnium(IV) or zirconium(IV) salts. These metal salts are highly effective as catalysts for the selective esterification of primary alcohols with carboxylic acids in the presence of secondary alcohols or aromatic alcohols. The present
An Efficient, Overall [4+1] Cycloadditon of 1,3-Dienes and Nitrene Precursors
作者：Qiong Wu、Jian Hu、Xinfeng Ren、Jianrong Steve Zhou
DOI：10.1002/chem.201101630
日期：2011.10.4
Intermolecular cycloadditions of conjugated dienes and nitreneprecursors usually produce aziridines. A generally useful method was lacking to directly provide the [4+1] cycloadducts, 3‐pyrrolines. We have realized this transformation by using an uniquely active catalyst, copper(II) 1,1,1,5,5,5‐hexafluoroacetylacetonate ([Cu(hfacac)2]). The method is applicable to a wide array of dienes with good yields
[EN] CRYSTALLINE AND LIQUID CRYSTALLINE 25-HYDROXY-CHOLEST-5-EN-3-SULFATE SODIUM AND METHODS FOR PREPARING SAME<br/>[FR] 25-HYDROXY-CHOLEST-5-EN-3-SULFATE SODIQUE CRISTALLIN ET CRISTALLIN LIQUIDE ET SES PROCÉDÉS DE PRÉPARATION
申请人：DURECT CORP
公开号：WO2021133976A1
公开（公告）日：2021-07-01
Crystalline and liquid crystalline forms of 25HC3S sodium are described herein. The disclosure includes Forms I, II, III, V, IX, XI, and XIII of 25HC3S sodium and combinations thereof. Pharmaceutical formulations of said forms, or combinations thereof, and methods of treating or preventing disease such as hypercholesterolemia, hypertriglyceridemia, and conditions related to fat accumulation and inflammation (e.g., non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, acute kidney injury (AKI), psoriasis, and atherosclerosis) are further disclosed herein. Methods for preparing 25HC3S are also provided
[EN] QUINOLIN-4-ONE AND 4(1H)-CINNOLINONE COMPOUNDS AND METHODS OF USING SAME<br/>[FR] COMPOSÉS DE QUINOLIN-4-ONE ET DE 4(1H)-CINNOLINONE ET PROCÉDÉS D'UTILISATION ASSOCIÉS
申请人：FREQUENCY THERAPEUTICS INC
公开号：WO2020163816A1
公开（公告）日：2020-08-13
The present disclosure relates to quinolin-4-one and 4(1H)-cinnolinone compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells, including inducing the stem/progenitor cells to proliferate while maintaining, in the daughter cells, the capacity to differentiate into tissue cells.
Perfluoroalkylation of Olefins by Electrooxidation of Perfluoroalkanoic Acids: Relations between Product-Selectivity and Current Density and Structures of Olefins
作者：Kenji Uneyama、Shunsuke Watanabe、Yukio Tokunaga、Kouichi Kitagawa、Yasuhiro Sato
DOI：10.1246/bcsj.65.1976
日期：1992.7
Electrooxidation of perfluoroalkanoicacids RfCO2H (Rf = CF3, C3F7, C7F15 together with CHF2, CH2F) in the presence of electron-deficient olefins (methyl acrylate, methyl methacrylate, acrylamide, and acrylonitrile) provided perfluoroalkylated products. The electrolysis was conducted in MeCN–H2O (7 : 1) using platinum electrodes in an undivided cell. Dimerization of methyl acrylate accompanying perfluoroalkylation
在缺电子烯烃（丙烯酸甲酯、甲基丙烯酸甲酯、丙烯酰胺和丙烯腈）存在下，全氟链烷酸 RfCO2H（Rf = CF3、C3F7、C7F15 以及 CHF2、CH2F）的电氧化得到全氟烷基化产物。电解是在 MeCN-H2O (7:1) 中使用铂电极在未分隔的电池中进行的。伴随全氟烷基化的丙烯酸甲酯二聚反应在 20 mA cm-2 电流密度下以 40-50% 的产率发生。在高电流密度（100-200 mA cm-2）下，丙烯酰胺中碳-碳双键的 1,2-加成占主导地位。另一方面，三氟甲基和乙酰氨基的1,2-加成以及三氟甲基和羟基的1,2-加成发生在甲基丙烯酸甲酯的低电流密度（<5 mA cm-2）电解中。
