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1.  Organophosphate-Induced Changes in the PKA Regulatory Function of Swiss Cheese/NTE Lead to Behavioral Deficits and Neurodegeneration 
PLoS ONE  2014;9(2):e87526.
Organophosphate-induced delayed neuropathy (OPIDN) is a Wallerian-type axonopathy that occurs weeks after exposure to certain organophosphates (OPs). OPs have been shown to bind to Neuropathy Target Esterase (NTE), thereby inhibiting its enzymatic activity. However, only OPs that also induce the so-called aging reaction cause OPIDN. This reaction results in the release and possible transfer of a side group from the bound OP to NTE and it has been suggested that this induces an unknown toxic function of NTE. To further investigate the mechanisms of aging OPs, we used Drosophila, which expresses a functionally conserved orthologue of NTE named Swiss Cheese (SWS). Treating flies with the organophosporous compound tri-ortho-cresyl phosphate (TOCP) resulted in behavioral deficits and neurodegeneration two weeks after exposure, symptoms similar to the delayed effects observed in other models. In addition, we found that primary neurons showed signs of axonal degeneration within an hour after treatment. Surprisingly, increasing the levels of SWS, and thereby its enzymatic activity after exposure, did not ameliorate these phenotypes. In contrast, reducing SWS levels protected from TOCP-induced degeneration and behavioral deficits but did not affect the axonopathy observed in cell culture. Besides its enzymatic activity as a phospholipase, SWS also acts as regulatory PKA subunit, binding and inhibiting the C3 catalytic subunit. Measuring PKA activity in TOCP treated flies revealed a significant decrease that was also confirmed in treated rat hippocampal neurons. Flies expressing additional PKA-C3 were protected from the behavioral and degenerative phenotypes caused by TOCP exposure whereas primary neurons were not. In addition, knocking-down PKA-C3 caused similar behavioral and degenerative phenotypes as TOCP treatment. We therefore propose a model in which OP-modified SWS cannot release PKA-C3 and that the resulting loss of PKA-C3 activity plays a crucial role in developing the delayed symptoms of OPIDN but not in the acute toxicity.
doi:10.1371/journal.pone.0087526
PMCID: PMC3928115  PMID: 24558370
2.  Soil flushing of cresols contaminated soil: application of nonionic and ionic surfactants under different pH and concentrations 
In this study, the viability of soil flushing on the removal of cresols (meta-, ortho-, and para-cresols) from contaminated soil has been investigated. High production and distribution of cresols in the environment indicate their potential for a widespread exposure to humans. The presence of these compounds in soil could cause a significant threat to environment, as they are toxic and refractory in nature. Cresols are persistent chemicals which are classified by the United State Environmental Protection Agency (U.S.EPA) as Group C, possible human carcinogens. Soil flushing is one of the soil remediation technologies which could by applied for treatment of hydrocarbon contaminated soil. Flushing of the contaminated soil samples was carried out by using sodium dodecyl sulfate (SDS) and Triton X-100 surfactant solutions at the concentrations of 0.1%, 0.2%, 0.3%, and 0.4% (W/W). Three acidic, neutral, and alkaline environments were utilized by adjusting pH of the washing solutions at 3, 7 and 12 to evaluate the effect of washing environment in removing cresols. The results of this research denote that the highest removal efficiencies of 79.6% and 83.51% were achieved for m-cresol and total o- and p-cresols, respectively, under the alkaline environment of pH12 at 0.4% (W/W) SDS concentration. Regarding performance of Triton X-100, the removal efficiencies of 80.26% and 80.14% for the above cresols were attained under similar conditions. Hence, illustrating the effectiveness of surfactants in soil flushing remediation of cresols contaminated soil.
doi:10.1186/s40201-014-0129-z
PMCID: PMC4243191  PMID: 25426298
Contaminated soil; Cresols; SDS; Soil flushing; Surfactants; Triton X-100
3.  PCBs: structure–function relationships and mechanism of action 
Numerous reports have illustrated the versatility of polychlorinated biphenyls (PCBs) and related halogenated aromatics as inducers of drug-metabolizing enzymes and the activity of individual compounds are remarkably dependent on structure. The most active PCB congeners, 3,4,4′,5-tetra-, 3,3′,4,4′-tetra-, 3,3′,4,4′,5-penta- and 3,3′,4,4′,5,5′-hexachlorobiphenyl, are substituted at both para and at two or more meta positions. The four coplanar PCBs resembled 3-methylcholanthrene (3-MC) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) in their mode of induction of the hepatic drug-metabolizing enzymes. These compounds induced rat hepatic microsomal benzo(a)pyrene hydroxylase (aryl hydrocarbon hydroxylase, AHH) and cytochromes P-450a, P-450c and P-450d. 3,4,4′,5-Tetrachlorobiphenyl, the least active coplanar PCB, also induced dimethylaminoantipyrine N-demethylase and cytochromes P-450b+e and resembled Aroclor 1254 as an inducer of the mixed-function oxidase system. Like Aroclor 1254, all the mono-ortho- and at least eight di-ortho-chloro analogs of the coplanar PCBs exhibited a “mixed-type” induction pattern and induced microsomal AHH, dimethylaminoantipyrine NM-demethylase and cytochromes P-450a–P-450e. Quantative structure–activity relationships (QSARs) within this series of PCBs were determined by comparing their AHH induction potencies (EC50) in rat hepatoma H-4-II-E cells and their binding affinities (ED50) for the 2,3,7,8-TCDD cytosolic receptor protein. The results showed that there was an excellent correlation between AHH induction potencies and receptor binding avidities of these compounds and the order of activity was coplanar PCBs (3,3′,4,4′-tetra-, 3,3′,4,4′,5-penta- and 3,3′,4,4′,5,5′-hexachlorobiphenyls) > 3,4,4′,5-tetrachlorobiphenyl ~ mono-ortho coplanar PCBs > di-ortho coplanar PCBs. It was also apparent that the relative toxicities of this group of PCBs paralleled their biological potencies.
The coplanar and mono-ortho coplanar PCBs also exhibit differential effects in the inbred C57BL/6J and DBA/2J mice. These compounds induce AHH and cause thymic atrophy in the former “responsive” mice whereas at comparable or higher doses none of these effects are observed in the nonresponsive DBD/2J mice. Since the responsiveness of these two mice strains is due to the presence of the Ah receptor protein in the C57BL/6J mice and its relatively low concentration in the DBA/2J mice, the results for the PCB cogeners support the proposed receptor-mediated mechanism of action.
Although the precise structural requirements for ligand binding to the receptor have not been delineated, the halogenated aromatic hydrocarbons which exhibit the highest binding affinities for the receptor protein are approximate isostereomers of 2,3,7,8-TCDD. 2,3,4,4′,5-Pentachlorobiphenyl elicits effects which are qualitatively similar to that of TCDD and the presence of the lateral 4′-substituent is required for this activity. Thus the 4′-substituted 2,3,4,5-tetrachlorobiphenyls have been used as probes for determining the substituent characteristics which favor binding to the receptor protein. Multiple regression analysis of the competitive binding EC50 values for 13 substituents gave the following equation: log (1/EC50) = 1.53σ + 1.47π + 1.09 HB + 4.08 where σ is electronegativity, π is hydrophobicity, HB is hydrogen bonding and r is the correlation coefficient (r = 0.978). The utility of this equation in describing ligand:receptor interactions and correlations with toxicity are being studied with other halogenated hydrocarbons and PAHs.
PMCID: PMC1568577  PMID: 2992927
4.  Isolation and characterization of a novel 2-sec-butylphenol-degrading bacterium Pseudomonas sp. strain MS-1 
Biodegradation  2009;21(2):157-165.
A novel bacterium capable of utilizing 2-sec-butylphenol as the sole carbon and energy source, Pseudomonas sp. strain MS-1, was isolated from freshwater sediment. Within 30 h, strain MS-1 completely degraded 1.5 mM 2-sec-butylphenol in basal salt medium, with concomitant cell growth. A pathway for the metabolism of 2-sec-butylphenol by strain MS-1 was proposed on the basis of the identification of 3 internal metabolites—3-sec-butylcatechol, 2-hydroxy-6-oxo-7-methylnona-2,4-dienoic acid, and 2-methylbutyric acid—by gas chromatography-mass spectrometry analysis. Strain MS-1 degraded 2-sec-butylphenol through 3-sec-butylcatechol along a meta-cleavage pathway. Degradation experiments with various alkylphenols showed that the degradability of alkylphenols by strain MS-1 depended strongly on the position (ortho ≫ meta = para) of the alkyl substitute, and that strain MS-1 could degrade 2-alkylphenols with various sized and branched alkyl chain (o-cresol, 2-ethylphenol, 2-n-propylphenol, 2-isopropylphenol, 2-sec-butylphenol, and 2-tert-butylphenol), as well as a dialkylphenol (namely, 6-tert-butyl-m-cresol).
doi:10.1007/s10532-009-9290-y
PMCID: PMC2829128  PMID: 19705287
2-sec-Butylphenol; ortho-Substituted alkylphenol; Biodegradation; meta-Cleavage pathway
5.  Anaerobic ortho Dechlorination of Polychlorinated Biphenyls by Estuarine Sediments from Baltimore Harbor 
Reductive dechlorination of the ortho moiety of polychlorinated biphenyls (PCBs) as well as of meta and para moieties is shown to occur in anaerobic enrichments of Baltimore Harbor sediments. These estuarine sediments ortho dechlorinated 2,3,5,6-chlorinated biphenyl (CB), 2,3,5-CB, and 2,3,6-CB in freshwater or estuarine media within a relatively short period of 25 to 44 days. ortho dechlorination developed within 77 days in marine medium. High levels of ortho dechlorination (>90%) occurred when harbor sediments were supplied with only 2,3,5-CB. Incubation with 2,3,4,5,6-CB or 2,3,4,5-CB resulted in the formation of the ortho dechlorination product 3,5-CB; however, para dechlorination of these congeners always preceded ortho chlorine removal. ortho dechlorination of PCBs is an exceedingly rare event that has not been reported previously for marine or estuarine conditions. The activity was reproducible and could be sustained through sequential transfers. In contrast, freshwater sediments incubated under the same conditions exhibited only meta and para dechlorinations. The results indicate that unique anaerobic dechlorinating activity is catalyzed by microorganisms in the estuarine sediments from Baltimore Harbor.
PMCID: PMC1388898  PMID: 16535360
6.  Hydroxylated polychlorinated biphenyls as inhibitors of the sulfation and glucuronidation of 3-hydroxy-benzo[a]pyrene. 
Environmental Health Perspectives  2002;110(4):343-348.
Polychlorinated biphenyls (PCBs) can be metabolized by cytochromes P450 to hydroxylated biotransformation products. In mammalian studies, some of the hydroxylated products have been shown to be strong inhibitors of steroid sulfotransferases. As a part of ongoing research into the bioavailability of environmental pollutants in catfish intestine, we investigated the effects of a series of hydroxylated PCBs (OH-PCBs) on two conjugating enzymes, phenol-type sulfotransferase and glucuronosyltransferase. We incubated cytosolic and microsomal samples prepared from intestinal mucosa with 3-hydroxy-benzo[a]pyrene and appropriate cosubstrates and measured the effect of OH-PCBs on the formation of BaP-3-glucuronide and BaP-3-sulfate. We used PCBs with 4, 5, and 6 chlorine substitutions and the phenolic group in the ortho, meta, and para positions. OH-PCBs with the phenolic group in the ortho position were weak inhibitors of sulfotransferase; the median inhibitory concentration (IC50) ranged from 330 to 526 microM. When the phenol group was in the meta or para position, the IC50 was much lower (17.8-44.3 microM). The OH-PCBs were more potent inhibitors of glucuronosyltransferase, with IC50s ranging from 1.2 to 36.4 microM. The position of the phenolic group was not related to the inhibitory potency: the two weakest inhibitors of sulfotransferase, with the phenolic group in the ortho position, were 100 times more potent as inhibitors of glucuronosyltransferase. Inhibition of glucuronosyltransferase by low concentrations of OH-PCBs has not been reported before and may have important consequences for the bioavailability, bioaccumulation, and toxicity of other phenolic environmental contaminants.
PMCID: PMC1240796  PMID: 11940451
7.  Oxidative DNA Adducts Following Cu2+-Mediated Activation of Dihydroxy PCBs: Role of Reactive Oxygen Species1 
Free radical biology & medicine  2009;46(10):1346-1352.
Polychlorinated biphenyls (PCBs) are toxic industrial chemicals, complete carcinogens and efficacious tumor promoters. However, the mechanism(s) of PCB-mediated carcinogenicity remains largely undefined. One likely pathway by which these agents may play a role in carcinogenesis is the generation of oxidative DNA damage by redox cycling of dihydroxylated PCB metabolites. We have now employed a new 32P-postlabeling system to examine novel oxidative DNA lesions induced by Cu2+-mediated activation of PCB metabolites. 32P-Postlabeling of DNA incubated with various PCB metabolites resulted in over a dozen novel polar oxidative DNA adducts that were chromatographically similar for all active agents. The most potent metabolites tested were the hydroquinones (hydroxyl groups arranged para to each other) yielding polar oxidative adduct levels ranging from 55 to 142 adducts/106 nucleotides. PCB catechols, or ortho-dihydroxy metabolites, were up to 40% less active than their corresponding hydroquinone congeners while mono hydroxylated and quinone metabolites did not produce detectable oxidative damage over that of vehicle. With the exception of 2,4,5-Cl-2′,5′-dihydroxybiphenyl, this oxidative DNA damage appeared to be inversely related to chlorine content: no chlorine ≈ mono- > di- > tri-chlorinated metabolites. Importantly, copper, but not iron, was essential for activation of the PCB metabolites to these polar oxidative DNA adducts since in its absence or in the presence of the Cu+-specific scavenger, bathocuproine, no adducts were detected. Intervention studies with known reactive oxygen species (ROS) modifiers suggested that H2O2, singlet oxygen, hydroxyl radical and superoxide may also be involved in this PCB-mediated oxidative DNA damage. These data indicate a mechanistic role of several ROS, in addition to copper, in PCB-induced DNA damage and provide further support for oxidative DNA damage in PCB-mediated carcinogenesis.
doi:10.1016/j.freeradbiomed.2009.02.005
PMCID: PMC2744390  PMID: 19233261
PCBs; oxidative DNA adducts; 32P-postlabeling
8.  Analysis of the effects of exposure to polychlorinated biphenyls and chlorinated pesticides on serum lipid levels in residents of Anniston, Alabama 
Environmental Health  2013;12:108.
Background
Anniston, Alabama, is the site of a former Monsanto plant where polychlorinated biphenyls (PCBs) were manufactured from 1929 until 1971. Residents of Anniston are known to have elevated levels of PCBs. The objective of the study was to test the hypothesis that levels of the various lipid components (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) are differentially associated with concentrations of total PCBs and total pesticides, and further that different congeners, congener groups and different pesticides do not have identical associations in serum samples obtained from Anniston residents in a cross-sectional study.
Methods
Fasting serum samples were obtained from 575 residents of Anniston who were not on any lipid-lowering medication and were analyzed for 35 PCB congeners, nine chlorinated pesticides, total cholesterol, LDL and HDL cholesterol and triglyceride concentrations. Associations between toxicant concentrations and lipid levels were determined using multiple linear regression analysis.
Results
We observed that elevated serum concentrations of lipids were associated with elevated serum concentrations of ΣPCBs and summed pesticides in analyses adjusted for age, race, gender, BMI, alcohol consumption, smoking and exercising status. The strongest associations were seen for PCB congeners with three, four, or at least eight substituted chlorines. Mono-ortho substituted congeners 74 and 156, di-ortho congeners 172 and 194, and tri- and tetra-ortho congeners 199, 196–203, 206 and 209 each were significantly associated with total lipids, total cholesterol and triglycerides. Serum concentrations of HCB and chlordane also had strong associations with lipid components.
Conclusions
Increased concentrations of PCBs and organochlorine pesticides are associated with elevations in total serum lipids, total cholesterol and triglycerides, but the patterns are different for different groups of PCBs and different pesticides. These observations show selective effects of different organochlorines on serum concentrations of different groups of lipids. This elevation in concentrations of serum lipids may be the basis for the increased incidence of cardiovascular disease found in persons with elevated exposures to PCBs and chlorinated pesticides.
doi:10.1186/1476-069X-12-108
PMCID: PMC3893492  PMID: 24325314
Cholesterol; Triglycerides; Persistent organic pollutants; LDL cholesterol; HDL cholesterol; Hexachlorobenzene; DDT; PCBs
9.  Cresyl Saligenin Phosphate, an Organophosphorus Toxicant, Makes Covalent Adducts with Histidine, Lysine and Tyrosine Residues of Human Serum Albumin 
Chemical research in toxicology  2012;25(8):1752-1761.
CBDP (2-(2-cresyl)-4H-1-3-2-benzodioxaphosphorin-2-oxide) is a toxic organophosphorus compound. It is generated in vivo from tri-ortho-cresyl phosphate (TOCP), a component of jet engine oil and hydraulic fluids. Exposure to TOCP was proven to occur on board aircraft by finding CBDP-derived phospho-butyrylcholinesterase in the blood of passengers. Adducts on BChE however do not explain the toxicity of CBDP. Critical target proteins of CBDP are yet to be identified. Our goal was to facilitate the search for the critical targets of CBDP by determining the range of amino acid residues capable of reacting with CBDP and characterizing the types of adducts formed. We used human albumin as a model protein. Mass spectral analysis of the tryptic digest of CBDP-treated human albumin revealed adducts on His-67, His-146, His-242, His-247, His-338, Tyr-138, Tyr-140, Lys-199, Lys-351, Lys-414, Lys-432, Lys-525. Adducts formed on tyrosine residues were different from those formed on histidines and lysines. Tyrosines were organophosphorylated by CBDP, while histidine and lysine residues were alkylated. This is the first report of an organophosphorus compound with both phosphorylating and alkylating properties. The hydroxybenzyl adduct on histidine is novel. The ability of CBDP to form stable adducts on histidine, tyrosine and lysine allows one to consider new mechanisms of toxicity from TOCP exposure.
doi:10.1021/tx300215g
PMCID: PMC3427739  PMID: 22793878
10.  REACTION OF CRESYL SALIGENIN PHOSPHATE, THE ORGANOPHOSPHORUS AGENT IMPLICATED IN THE AEROTOXIC SYNDROME, WITH HUMAN CHOLINESTERASES: MECHANISTIC STUDIES EMPLOYING KINETICS, MASS SPECTROMETRY AND X-RAY STRUCTURE ANALYSIS 
Chemical research in toxicology  2011;24(6):797-808.
The aerotoxic syndrome is assumed to be caused by exposure to tricresyl phosphate (TCP), an anti-wear additive in jet engine lubricants and hydraulic fluids. CBDP (2-(ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one) is the toxic metabolite of tri-ortho-cresylphosphate, a component of TCP. Human butyrylcholinesterase (BChE; EC 3.1.1.8) and human acetylcholinesterase (AChE; EC 3.1.1.7) are irreversibly inhibited by CBDP. The bimolecular rate constants of inhibition (ki), determined under pseudo first-order conditions, displayed a biphasic time course of inhibition with ki 1.6×108 M−1min−1 and 2.7×107 M−1min−1 for E and E′ forms of BChE. The inhibition constants for AChE were one to two orders of magnitude slower than for BChE. CBDP-phosphorylated cholinesterases are non-reactivatable due to ultra fast “aging”. Mass spectrometry analysis showed an initial BChE adduct with an added mass of 170 Da from cresylphosphate, followed by dealkylation to a structure with an added mass of 80 Da. Mass spectrometry in 18O–water showed that 18O was incorporated only during the final aging step to form phospho-serine as the final “aged” BChE adduct. The crystal structure of CBDP-inhibited BChE confirmed that the phosphate adduct is the ultimate aging product. CBDP is the first organophosphorus agent that leads to a fully dealkylated phospho-serine BChE adduct.
doi:10.1021/tx100447k
PMCID: PMC3118852  PMID: 21438623
Acetylcholinesterase; butyrylcholinesterase; aerotoxic syndrome; organophosphate; CBDP; inhibition kinetics; aging; MALDI-TOF; X-ray crystallography; OPIDN; saligenin
11.  Polychlorinated biphenyl levels in the tissues of exposed and nonexposed humans. 
Environmental Health Perspectives  1994;102(Suppl 1):149-158.
Polychlorinated biphenyls (PCBs) are synthetic chemicals, manufactured in volume from about 1929 to the 1970s. Environmental contamination by PCBs has been documented in various substances, including human tissue. PCBs have been measured in human tissue by a variety of analytical methods. PCB levels have been reported as an approximation of total PCB content expressed in terms of a commercial mixture, by identification and quantification of chromatographic peaks, or by qualitative and quantitative characterization of specific congeners. Until recently, the coplanar mono-ortho- and di-ortho substituted PCBs, which are especially toxic and present in significant concentration in humans from industrial countries, had not been measured in human tissues. Examples of various types of commonly used analyses are presented in general population subjects and in persons who experienced special exposure. In this paper, the usefulness of PCB blood determinations following potential exposure is demonstrated, and their application in health studies is illustrated from a number of case studies. Coplanar PCB, mono-ortho-substituted and di-ortho-substituted PCB levels in human blood are presented and compared with polychlorinated dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in the U.S. population. Dioxin toxic equivalents for the two groups of chemicals are calculated and compared. It is found that mono-ortho-substituted and, to a lesser extent, coplanar PCBs, contribute substantially to dioxin toxic equivalents (TEq) in blood from U.S. adults. Because of substantial PCB contribution to dioxin toxic equivalents, total dioxinlike toxicity can only be determined if dioxins, dibenzofurans, and dioxinlike PCBs are measured.(ABSTRACT TRUNCATED AT 400 WORDS)
PMCID: PMC1566903  PMID: 8187704
12.  (E)-Methyl 3-(4-ethyl­phen­yl)-2-{2-[(E)-(hy­droxy­imino)­meth­yl]phen­oxy­meth­yl}acrylate 
In the title compound, C20H21NO4, the two benzene rings are almost perpendicular to each other, making a dihedral angle of 86.1 (7)°. The hy­droxy­ethanimine group is essentially coplanar with the benzene ring, the largest deviation from the mean plane of the hy­droxy­ethanimine [C=N—OH] group being 0.011 (1) Å for the O atom. An intra­molecular C—H⋯O hydrogen bond occurs. The mol­ecules are linked into cyclic centrosymmetric R 2 2(6) dimers via O—H⋯N hydrogen bonds. Inter­molecular C—H⋯O hydrogen bonds link the mol­ecules, forming a C(8) chain along the a axis. The crystal packing is further stabilized by C—H⋯π inter­actions.
doi:10.1107/S1600536811038359
PMCID: PMC3201344  PMID: 22058811
13.  4-Ethylphenyl-Cobalamin Impairs Tissue Uptake of Vitamin B12 and Causes Vitamin B12 Deficiency in Mice 
PLoS ONE  2013;8(9):e75312.
Coβ-4-ethylphenyl-cob(III) alamin (EtPhCbl) is an organometallic analogue of vitamin B12 (CNCbl) which binds to transcobalamin (TC), a plasma protein that facilitates the cellular uptake of cobalamin (Cbl). In vitro assays with key enzymes do not convert EtPhCbl to the active coenzyme forms of Cbl suggesting that administration of EtPhCbl may cause cellular Cbl deficiency. Here, we investigate the in vivo effect of EtPhCbl in mice and its ability, if any, to induce Cbl deficiency. We show that EtPhCbl binds to mouse TC and we examined mice that received 3.5 nmol/24h EtPhCbl (n=6), 3.5 nmol/24h CNCbl (n=7) or NaCl (control group) (n=5) through osmotic mini-pumps for four weeks. We analyzed plasma, urine, liver, spleen, submaxillary glands and spinal cord for Cbl and markers of Cbl deficiency including methylmalonic acid (MMA) and homocysteine (tHcy). Plasma MMA (mean±SEM) was elevated in animals treated with EtPhCbl (1.01±0.12 µmol/L) compared to controls (0.30±0.02 µmol/L) and CNCbl (0.29±0.01 µmol/L) treated animals. The same pattern was observed for tHcy. Plasma total Cbl concentration was higher in animals treated with EtPhCbl (128.82±1.87 nmol/L) than in CNCbl treated animals (87.64±0.93 nmol/L). However, the organ levels of total Cbl were significantly lower in animals treated with EtPhCbl compared to CNCbl treated animals or controls, notably in the liver (157.07±8.56 pmol/g vs. 603.85±20.02 pmol/g, and 443.09±12.32 pmol/g, respectively). Differences between the three groups was analysed using one-way ANOVA and, Bonferroni post-hoc test. EtPhCbl was present in all tissues, except the spinal cord, accounting for 35-90% of total Cbl. In conclusion, treatment with EtPhCbl induces biochemical evidence of Cbl deficiency. This may in part be caused by a compromised tissue accumulation of Cbl.
doi:10.1371/journal.pone.0075312
PMCID: PMC3779197  PMID: 24073261
14.  (Z)-Methyl 2-[(2-eth­oxy-6-formyl­phen­oxy)meth­yl]-3-(4-ethyl­phen­yl)acrylate 
The title compound, C22H24O5, consists of two substituted benzene rings linked by an ethyl acrylate group. The dihedral angle between the two benzene rings is 58.39 (7)°. The crystal packing is governed by two C—H⋯O inter­actions, one of which forms centrosymmetric dimers with a graph-set descriptor of R 2 2(18).
doi:10.1107/S1600536811046587
PMCID: PMC3238902  PMID: 22199755
15.  A second monoclinic polymorph of di-μ-chlorido-bis­(chlorido{2-[(4-ethyl­phen­yl)imino­meth­yl]pyridine-κ2 N,N′}copper(II)) 
The title compound, [Cu2Cl4(C14H14N2)2], is a new polymorph of a previously reported compound [Dehghanpour et al. (2011 ▶). Acta Cryst. E67, m1296]. The current polymorph was obtained from an acetonitrile solution of the title compound. Like the first polymorph, it is monoclinic (space group P21/c). The unique CuII ion in the title centrosymmetric dinuclear complex is in a distorted trigonal–bipyramidal coordination environment formed by the bis-­chelating N-heterocyclic ligand, two bridging Cl ligands and one terminal Cl ligand. In the crystal, weak C—H⋯Cl hydrogen bonds are observed in addition to π–π stacking inter­actions, with a centroid–centroid distance of 3.6597 (18) Å.
doi:10.1107/S1600536812026347
PMCID: PMC3393187  PMID: 22807755
16.  N-[(3-Ethyl­phen­yl)carbamo­thio­yl]-2,2-di­phenyl­acetamide 
In the title mol­ecule, C23H22N2OS, the di­phenyl­acetyl and ethyl­benzene groups adopt a trans–cis conformation, respectively, with respect to the S atom across the (S=)C—N bonds. This conformation is stabilized by an intra­molecular N—H⋯O hydrogen bond and a weak C—H⋯S hydrogen bond. The ethyl-substituted benzene ring forms dihedral angles of 87.53 (15) and 73.94 (15)° with the phenyl rings. In the crystal, N—H⋯O hydrogen bonds link mol­ecules into chains along [100]. A weak C—H⋯π inter­action is also observed.
doi:10.1107/S1600536813014268
PMCID: PMC3772456  PMID: 24046599
17.  2-[(4-Ethyl­phen­yl)imino­meth­yl]-3,5-dimethoxy­phenol 
The title compound, C17H19NO3, adopts the phenol–imine tautomeric form, with a resonance-assisted O—H⋯N intra­molecular hydrogen bond [O⋯N = 2.551 (3) Å]. The dihedral angle between the two benzene rings is 45.42 (7)°. The two meth­oxy groups are coplanar with the attached benzene ring [C—O—C—C torsion angles = −1.1 (5) and 3.2 (4)°].
doi:10.1107/S1600536809004784
PMCID: PMC2968664  PMID: 21582206
18.  2-(3-Bromo-4-ethyl­phen­yl)-2-methyl­propanoic acid 
In the title compound, C12H15BrO2, the carboxyl group forms a dihedral angle of 78.4 (3)° with the benzene ring plane. In the crystal, mol­ecules are linked into centrosymmetric dimers by pairs of O—H⋯O hydrogen bonds.
doi:10.1107/S1600536809036769
PMCID: PMC2970189  PMID: 21577932
19.  3-[(E)-(4-Ethyl­phen­yl)imino­meth­yl]benzene-1,2-diol 
The title compound, C15H15NO2, adopts the enol–imine tautomeric form. The dihedral angle between the two benzene rings is 48.1 (1)°. Intra­molecular O—H⋯N and O—H⋯O hydrogen bonds generate S(6) and S(5) ring motifs, respectively. In the crystal, mol­ecules are linked into centrosymmetric R 2 2(10) dimers via pairs of O—H⋯O hydrogen bonds and the dimers may interact through very weak by π–π inter­actions [centroid–centroid distance = 4.150 (1) Å]. The ethyl group is disordered over two orientations, with occupancies of 0.587 (11) and 0.413 (11).
doi:10.1107/S1600536809029924
PMCID: PMC2977215  PMID: 21583717
20.  2,4,6,8-Tetra­kis(4-ethyl­phen­yl)-3,7-diaza­bicyclo­[3.3.1]nonan-9-one 
The bicyclo­[3.3.1]nonane ring in the title compound, C39H44N2O, adopts a chair–boat conformation with the four benzene rings being directed away from the carbonyl group. The presence of C—H⋯O contacts leads to helical supra­molecular chains along the b axis.
doi:10.1107/S1600536810016569
PMCID: PMC2979421  PMID: 21579409
21.  (E)-2-[(2-Ethyl­phen­yl)imino­meth­yl]-6-methoxy­phenol 
The mol­ecule of the title compound, C16H17NO2, adopts the phenol–imine tautomeric form with a strong intra­molecular O—H⋯N hydrogen bond and an E conformation with respect to the azomethine C=N bond. The dihedral angle between the aromatic rings is 21.23 (9)°. The ethyl group is disordered over two orientations with occupancies of 0.598 (6) and 0.402 (6). In the crystal, the mol­ecules are linked into chains along the b axis by C—H⋯π inter­actions.
doi:10.1107/S1600536809055573
PMCID: PMC2979675  PMID: 21579722
22.  Synthesis and characterization of new poly(ortho ester amidine) copolymers for nonviral gene delivery 
Polymer  2011;52(4):921-932.
A new type of pH-labile cationic polymers, poly(ortho ester amidine) (POEAmd) copolymers, has been synthesized and characterized with potential future application as gene delivery carriers. The acid-labile POEAmd copolymer was synthesized by polycondensation of a new ortho ester diamine monomer with dimethylaliphatimidates, and a non-acid-labile polyamidine (PAmd) copolymer was also synthesized for comparison using a triethylene glycol diamine monomer. Both copolymers were easily dissolved in water, and can efficiently bind and condense plasmid DNA at neutral pH, forming nano-scale polyplexes. The physico-chemical properties of the polyplexes have been studied using dynamic light scattering, gel electrophoresis, ethidium bromide exclusion, and heparin competition. The average size of the polyplexes was dependent on the amidine: phosphate (N:P) ratio of the polymers to DNA. Polyplexes containing the acid-labile POEAmd or the non-acid-labile PAmd showed similar average particle size, comparable strength of condensing DNA, and resistance to electrostatic destabilization. They also share similar metabolic toxicity to cells as measured by MTT assay. Importantly, the acid-labile polyplexes undergo accelerated polymer degradation at mildly-acid-pHs, resulting in increasing particle size and the release of intact DNA plasmid. Polyplexes from both types of polyamidines caused distinct changes in the scattering properties of Baby Hamster Kidney (BHK-21) cells, showing swelling and increasing intracellular granularity. These cellular responses are uniquely different from other cationic polymers such as polyethylenimine and point to stress-related mechanisms specific to the polyamidines. Gene transfection of BHK-21 cells was evaluated by flow cytometry. The positive yet modest transfection efficiency by the polyamidines (acid-labile and non-acid-labile alike) underscores the importance of balancing polymer degradation and DNA release with endosomal escape. Insights gained from studying such acid-labile polyamidine-based DNA carriers and their interaction with cells may contribute to improved design of practically useful gene delivery systems.
doi:10.1016/j.polymer.2010.12.057
PMCID: PMC3072224  PMID: 21479119
Copolymer; Ortho ester; Gene delivery
23.  Neurodevelopmental toxicity of prenatal polychlorinated biphenyls (PCBs) by chemical structure and activity: a birth cohort study 
Environmental Health  2010;9:51.
Background
Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxins. Although there is growing evidence to support an association between PCBs and deficits of neurodevelopment, the specific mechanisms are not well understood. The potentially different roles of specific PCB groups defined by chemical structures or hormonal activities e.g., dioxin-like, non-dioxin like, or anti-estrogenic PCBs, remain unclear. Our objective was to examine the association between prenatal exposure to defined subsets of PCBs and neurodevelopment in a cohort of infants in eastern Slovakia enrolled at birth in 2002-2004.
Methods
Maternal and cord serum samples were collected at delivery, and analyzed for PCBs using high-resolution gas chromatography. The Bayley Scales of Infant Development -II (BSID) were administered at 16 months of age to over 750 children who also had prenatal PCB measurements.
Results
Based on final multivariate-adjusted linear regression model, maternal mono-ortho-substituted PCBs were significantly associated with lower scores on both the psychomotor (PDI) and mental development indices (MDI). Also a significant association between cord mono-ortho-substituted PCBs and reduced PDI was observed, but the association with MDI was marginal (p = 0.05). Anti-estrogenic and di-ortho-substituted PCBs did not show any statistically significant association with cognitive scores, but a suggestive association between di-ortho-substituted PCBs measured in cord serum and poorer PDI was observed.
Conclusion
Children with higher prenatal mono-ortho-substituted PCB exposures performed more poorly on the Bayley Scales. Evidence from this and other studies suggests that prenatal dioxin-like PCB exposure, including mono-ortho congeners, may interfere with brain development in utero. Non-dioxin-like di-ortho-substituted PCBs require further investigation.
doi:10.1186/1476-069X-9-51
PMCID: PMC2939589  PMID: 20731829
24.  N-(2,4-Dinitro­phen­yl)-N′-(1-p-tolyl­ethyl­idene)hydrazine 
In the title mol­ecule, C15H14N4O4, the dihedral angle between the two benzene rings is 2.21 (7)°. An intra­molecular N—H⋯O hydrogen bond generates an S(6) ring motif. The mean planes of the ortho- and para-nitro groups make dihedral angles of 2.17 (17) and 2.05 (16)°, respectively, with the benzene ring to which they are attached. In the crystal structure, weak inter­molecular C—H⋯O hydrogen bonds generate R 2 2(7), R 2 2(13) and R 2 1(10) ring motifs, linking symmetry-related mol­ecules into extended chains along the b axis. In addition, there are inter­molecular C⋯C [3.332 (2)–3.343 (2) Å] contacts which are shorter than the sum of the van der Waals radii. The crystal structure is further stabilized by inter­molecular C—H⋯π and π–π stacking inter­actions [centroid–centroid distance = 3.8090 (9) Å].
doi:10.1107/S1600536809009957
PMCID: PMC2969085  PMID: 21582553
25.  Metabolism of Phenol and Cresols by Mutants of Pseudomonas putida 
Journal of Bacteriology  1973;113(3):1112-1120.
Mutant strains of Pseudomonas putida strain U have been obtained which are deficient in enzymes of the degradative pathways of phenol and cresols. Mutant strains deficient in catechol 2, 3-oxygenase accumulated the appropriate catechol derivative from cresols. A mutant strain which would not grow on either phenol or a cresol was shown to be deficient in both 2-hydroxymuconic semialdehyde hydrolase and a nicotinamide adenine dinucleotide, oxidized form, (NAD+)-dependent aldehyde dehydrogenase. When this strain was grown in the presence of phenol or a cresol, the appropriate product of meta fission of these compounds accumulated in the growth medium. A partial revertant of this mutant strain, which was able to grow on ortho- and meta-cresol but not para-cresol, was shown to have regained only the hydrolase activity. This strain was used to show that the products of meta ring fission of the cresols and phenol are metabolized as follows: (i) ortho- and meta-cresol exclusively by a hydrolase; (ii) para-cresol exclusively by a NAD+-dependent aldehyde dehydrogenase; (iii) phenol by both a NAD+-dependent dehydrogenase and a hydrolase in the approximate ratio of 5 to 1. This conclusion is supported by the substrate specificity and enzymatic activity of the hydrolase and NAD+-dependent aldehyde dehydrogenase enzymes of the wild-type strain. The results are discussed in terms of the physiological significance of the pathway. Properties of some of the mutant strains isolated are discussed.
PMCID: PMC251671  PMID: 4347965

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