Aqueous film-forming foams (AFFFs), containing per- and polyfluoroalkyl substances (PFASs), are released into the environment during response to fire-related emergencies. Repeated historical applications of AFFF at military sites were a result of fire-fighter training exercises and equipment testing. Recent data on AFFF-impacted groundwater indicates that ∼25% of the PFASs remain unidentified. In an attempt to close the mass balance, a systematic evaluation of 3M and fluorotelomer-based AFFFs, commercial products, and AFFF-impacted groundwaters from 15 U.S. military bases was conducted to identify the remaining PFASs. Liquid chromatography quadrupole time-of-flight mass spectrometry was used for compound discovery. Nontarget analysis utilized Kendrick mass defect plots and a "nontarget" R script. Suspect screening compared masses with those of previously reported PFASs. Forty classes of novel anionic, zwitterionic, and cationic PFASs were discovered, and an additional 17 previously reported classes were observed for the first time in AFFF and/or AFFF-impacted groundwater. All 57 classes received an acronym and IUPAC-like name derived from collective author knowledge. Thirty-four of the 40 newly identified PFAS classes derive from electrochemical fluorination (ECF) processes, most of which have the same base structure. Of the newly discovered PFASs found only in AFFF-impacted groundwater, 11 of the 13 classes are ECF-derived, and the remaining two classes are fluorotelomer-derived, which suggests that both ECF- and fluorotelomer-based PFASs are persistent in the environment.

Glycyrrhizin, a pentacyclic triterpene glycoside, is the major phytochemical in licorice. This compound and its hydrolysis product glycyrrhetinic acid have been associated with the multiple therapeutic properties of licorice extracts. We have investigated the effects of 2-cyano substituted analogues of glycyrrhetinic acid on their cytotoxicities and activity as selective peroxisome proliferator -activated receptor ; (PPAR;) agonists. Methyl 2-cyano-3,11-dioxo-18B-olean-1,12-dien-30-oate (B-CDODA-Me) and methyl 2-cyano-3,11-dioxo-18A-olean-1,12-dien-30-oate (A-CDODA-Me) were more cytotoxic to colon cancer cells than their descyano analogues and introduction of the 2-cyano group into the pentacyclic ring system was necessary for the PPAR; agonist activity of A-CDODA-Me and B-CDODA-Me isomers. However, in mammalian two-hybrid assays, both compounds differentially induced interactions of PPAR; with coactivators, suggesting that these isomers, which differ only in the stereochemistry at C18 which affects conformation of the E-ring, are selective receptor modulators. This selectivity in colon cancer cells was shown for the induction of two proapoptotic proteins, namely caveolin-1 and the tumor-suppressor gene Krü ppel-like factor-4 (KLF-4). B-CDODA-Me but not A-CDODA-Me induced caveolin-1 in SW480 colon cancer cells, whereas caveolin-1 was induced by both compounds in HT-29 and HCT-15 colon cancer cells. The CDODA-Me isomers induced KLF-4 mRNA levels in HT-29 and SW480 cells but had minimal effects on KLF-4 expression in HCT-15 cells. These induced responses were inhibited by cotreatment with a PPAR; antagonist. This shows for the first time that PPAR; agonists derived from glycyrrhetinic acid induced cell-dependent caveolin-1 and KLF-4 expression through receptor-dependent pathways. [Mol Cancer Ther 2007;6(5):1588 -98]

Derivatives of oleanolic acid, ursolic acid and glycyrrhetinic acid substituted with electron withdrawing groups at the 2-position in the A-ring which also contains a 1-en-3-one structure are potent inhibitors of cancer cell growth. In this study, we have compared the effects of several 2-substituted analogs of triterpenoid acid methyl esters derived from ursolic and glycyrrhetinic acid on proliferation of KU7 and 253JB-V bladder and Panc-1 and Panc-28 pancreatic cancer cells. The results show that the 2-cyano and 2-trifluoromethyl derivatives were the most active compounds. The glycyrrhetinic acid derivatives with the rearranged C-ring containing the 9(11)-en-12-one structure were generally more active than the corresponding 12-en-11-one isomers. However, differences in growth inhibitory IC 50 values were highly variable and dependent on the 2-substitutent (CN vs. CF 3 ) and cancer cell context. Keywords glycyrrhetinate analogs; growth inhibition; bladder cancer; pancreatic cancerPentacyclic triterpenoid acids such as betulinic acid, oleanolic acid, ursolic acid, and glycyrrhetinic acid are phytochemicals that have been extensively used in traditional medicines for treatment of a wide variety of human ailments. 1-4 Most of these compounds exhibit antiinflammatory and anticarcinogenic activities as well as a large number of compound-specific effects. For example, the major bioactive component of licorice extracts is glycyrrhizic acid glycoside which is readily hydrolyzed to glycyrrhetinic acid and these extracts/compounds possess anti-inflammatory, antiviral and endocrine activities. 4 All of these triterpenoid acids have been used as building blocks for the synthesis of more active analogs. Oleanolic acid has been converted into 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), the Corresponding author: Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX , Email: ssafe@cvm.tamu.edu. * Both the authors contributed equally to this study.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. corresponding methyl ester (CDDO-Me) and other structurally-related analogs, and these compounds are potent anticancer agents. 5-9 These synthetic triterpenoids activate the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) 9 and also induce several other responses including apoptosis in various cancer cell lines. The cytotoxicity and antiinflammatory activity of CDDO-Me and related compounds are due to the 2-cyano group and the 1-en-3-one and 9-en-12-one functionalities in the A-and C-rings, respectively....

Perfluorooctane sulfonate (PFOS) is a global contaminant and is currently among the most prominent contaminants in human blood and wildlife samples. Although "total PFOS" (SigmaPFOS) analytical methods continue to be the most commonly used for quantification, recent analytical method developments have made it possible to resolve the various isomers of PFOS by HPLC-MS/MS. Characterized technical PFOS standards (i.e., containing a mixture of PFOS isomers) are now available that enable isomer specific quantification of PFOS, however the advantages of such an analysis have notyet been examined systematically. Herein, PFOS isomers have been individually quantified for the first time in real samples and the results are compared to a traditional SigmaPFOS method; the influence of analytical standards and isomer specific electrospray and MS/ MS behavior were also investigated. The two human serum standard reference materials chosen for analysis contained dramaticallydifferent PFOS isomer profiles (approximately 30-50% total branched isomers) emphasizing that isomer patterns should not be ignored and may provide useful information on exposure sources (i.e., direct exposure to PFOS vs indirect exposure from PFOS-precursors). Depending on the sample and the particular MS/MS transition chosen for SigmaPFOS analysis (i.e., 499-->80 or 499-->99), SigmaPFOS concentrations may be over- or underestimated compared to the isomer specific analysis. Differences in the extent of in-source fragmentation and MS/MS dissociation contributed to the systematic analytical bias. It was also shown that SigmaPFOS data are prone to interlaboratory variation due to various choices of PFOS standards and instrumental conditions used. In the future, for either SigmaPFOS or isomer specific PFOS analyses, we suggest that accuracy can be maximized and interlaboratory discrepancies minimized by using a common chemically pure technical PFOS standard characterized by 19F NMR.

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A new compound, 4-hydroxyheptachlorostyrene (4-OHHpCS), was identified as a major component in the chlorinated phenolic compound fraction of polar bear plasma. The structure was hypothesized to be 4-OH-HpCS based on mass spectral interpretation, the assumption that it was a metabolite of octachlorostyrene, and the similarity of the structure to hydroxylated polychlorinated biphenyls (OH-PCBs) identified in plasma. High-resolution, electron impact (EI) ionization mass spectrometry of the methylated compound indicated a molecular formula of C 9 H 3 OCl 7 and major fragment ions of [M -15] + , [M -35] + , and [M -43] + , which was a mass spectral pattern identical to a synthesized and methylated 4-OH-HpCS standard. The identity was further confirmed by matching gas chromatography (GC) retention times on three different GC columns of differing polarity. Levels of 4-OH-HpCS ranged from 2.89 to 22.9 ng/g wet weight in polar bear plasma (N ) 30) and constituted between 3.8 and 24.8% of the total quantified level of chlorinated phenolic compounds. The mean ratio of 4-OHHpCS to CB153 concentrations in polar bear plasma samples was 0.712 (( 0.580 SD), which suggests selective retention of the 4-OH-HpCS in plasma. The presumed mechanism of retention involves 4-OH-HpCS binding to transthyretin (TTR). The presence of TTR was confirmed for the first time in polar bear plasma by binding of 125 Ithyroxine (T 4 ), the natural ligand of TTR, to separated plasma proteins. The binding affinity of 4-OH-HpCS to human TTR was tested and found to be 1.1 relative to T 4 . This suggests that 4-OH-HpCS has the potential to disrupt T 4 and retinol transport, by analogy to OH-PCBs with similar structure. Metabolism of octachlorostyrene (OCS) is the most likely source of 4-OH-HpCS. OCS was shown to be present at low concentrations in polar bear tissues as well as in plasma of ringed seal, the principal prey species of polar bears. The ratio of 4-OH-HpCS to OCS and 4-OHHpCS to CB153 concentrations were 150-and 44-fold higher in polar bear plasma than in ringed seal plasma. This study indicates that the phenolic metabolites of relatively minor contaminants possess the capacity to bind to circulating proteins, and their significance as potential endocrine-disrupting agents may be underestimated.

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It is known that under liquid chromatography/electrospray tandem mass spectrometry (LC/ES-MS/MS) conditions, the perfluorocarboxylate anion [R(F)CO(2)](-) first loses CO(2) to give a perfluoroalkyl anion R(F)(-), [(M-H)-CO(2)](-), which can subsequently fragment to give inter alia lower mass carbanions. It has been suggested in a previous study that such secondary fragmentation involves cleavage of C(n)F(2n) segments. Our study of the LC/ES-MS/MS of a series of (13)C-labeled perfluoroalkyl carboxylic acids (PFCAs) indicates that fragmentation of the R(F)(-) anion does not involve simple 'unzipping' of a primary perfluoroalkyl anion of the type F(3)C(CF(2))(x)CF(2)(-). For example, we have discovered that the secondary transition for the mass-labeled PFOA, perfluoro-1,2,3,4-(13)C(4)-octanoic acid (MPFOA), gives two signals of equal intensity at m/z 169 and 172. We propose a mechanism of fragmentation that involves rapid fluorine shifts, after the initial decarboxylation, which generate a series of new anions prior to secondary and tertiary fragmentation.