Biomedical subjects

Mikael Harju

Publications and source records attributed to Mikael Harju.

7 recordsLinked to original sources

PubMed2004

Olfactory mucosal toxicity screening and multivariate QSAR modeling for chlorinated benzene derivatives.

The olfactory mucosa (OM) is an important target for metabolism-dependent toxicity of drugs and chemicals. Several OM toxicants share a 2,6-dichlorinated benzene structure. The herbicides dichlobenil (2,6-dichlorobenzonitrile) and chlorthiamide (2,6-dichlorothiobenzamide) and the environmental dichlobenil metabolite 2,6-dichlorobenzamide all induce toxicity in the OM following covalent binding in the Bowman's glands. In addition, we have shown that 2,6-dichlorophenyl methylsulfone targets the Bowman's glands and is probably the most potent OM toxicant so far described. These findings suggest that the 2,6-positioning of chlorines in combination with an electron-withdrawing group in the primary position of the benzene ring is an arrangement that facilitates OM toxicity. This study examined the physicochemical characteristics of the 2,6-dichlorinated OM toxicants. A number of 2,6-dichlorinated benzene derivatives with various types of substituents in primary position were tested for OM toxicity in mice. In addition, some other 2,6- and 2,5-substituted benzene derivatives were examined. Two novel OM toxicants, 2,6-dichlorobenzaldehyde oxime and 2,6-dichloronitrobenzene, were identified. By the use of partial least squares projection to latent structures with discriminant analysis (PLS-DA) a preliminary quantitative structure-activity relationship (QSAR) model was built also using reported OM toxicity data. Physicochemical properties positively correlated with olfactory mucosal toxicity were identified as molecular dipolar momentum and the electronic properties of the substituent. Inversely correlated descriptors were variables describing the hydrophobicity, electronic properties of the molecule such as electron affinity and the electronic charge on the primary carbon. In conclusion, this preliminary PLS-DA model shows that a 2,6-dichlorinated benzene derivative with a large, polar, and strong electron-withdrawing substituent in the primary position has the potential of being a potent OM toxicant in mice.

Animals↗

PubMed2003

Comprehensive two-dimensional gas chromatography of the 209 polychlorinated biphenyls.

Comprehensive two-dimensional gas chromatography (GC x GC) of the 209 polychlorinated biphenyls (CBs) was carried out using a longitudinally modulated cryogenic system (LMCS) and liquid carbon dioxide as cryogen. The effluent from a non-polar column was modulated and further separated on either a polar or a shape-selective second-dimension column. Five GC x GC column combinations were evaluated, with DB-XLB as the first column in each case. DB-XLB separates more congeners than any other GC column currently available. When combined with a biscyanopropyl siloxane (SP-2340 or BPX70) or smectic liquid crystal (LC-50) second-dimension column in a GC x GC system many additional CBs can be separated. In total, 176 and 181 of the 209 congeners were separated (Rs = 0.5) on the column combinations DB-XLB/SP-2340 and DB-XLB/LC-50, respectively. Of the 136 CBs present in any Aroclor mixture at concentrations greater than 0.05% (w/w), 126 were resolved using either of these two column combinations. The seven frequently measured CBs 28, 52, 101, 118, 138, 153, 180, and the WHO-PCBs 77, 81, 105, 114, 118, 123, 126, 156. 157, 167, 169 and 189 were all separated from Aroclor CBs on the DB-XLB/LC-50 column set, whereas CBs 118 and 131 coeluted on the DB-XLB/SP-2340 column set. In addition, three technical CB formulations (Aroclors 1232, 1248 and 1260) and a seal blubber sample (Halichoerus grypus) from the Baltic Sea were analyzed. Similar peak patterns were found for Aroclor 1260 and the CBs in the seal blubber, facilitating use of this technical CB formulation to identify the CBs in the blubber by GC x GC. Individual CBs in environmental samples, such as seal blubber, may be identified semi-automatically by matching the samples GC x GC profiles to a template generated using a standard containing all 209 CBs. Using such a template, 64 CBs were identified in the grey seal blubber sample.

Animals↗

PubMed2003

Determination of atropisomeric and planar polychlorinated biphenyls, their enantiomeric fractions and tissue distribution in grey seals using comprehensive 2D gas chromatography.

High prevalence of uterine occlusions and sterility is found among Baltic ringed and grey seal. Polychlorinated biphenyls (CBs) are suspected to be the main cause. The CB concentrations are higher in affected than in healthy animals, but the natural variation is considerable. Thus, it might be possible to assess the health status of seals by CB analysis. The ratios of chiral compounds (enantiomeric fractions (EFs)) such as atropisomeric CBs are of particularinterest, since these may reflect differences in metabolic rates. An analytical procedure was developed and used to determine the levels of atropisomeric CBs, planar-CBs (WHO-PCBs) and total CBs in seals of different health status. Comprehensive 2D gas chromatography (GC x GC) was used to separate the target analytes from other CBs and interferences and a micro electron-capture detector (microECD) was used for detection. EFs of the atropisomeric CBs were difficult to determine as the levels were low and the interferences many. Two column combinations bad to be used to avoid biased results-both had a chiral column as first-dimension column. The second-dimension column was coated with either a high-polarity cyanopropyl or a liquid crystal phase. EFs were determined for five atropisomeric CBs, i.e. CBs 91,95, 132, 149 and 174. The results were verified by GC x GC-time-of-flight mass spectrometry (TOF-MS). Some atropisomeric CBs had EFs that deviated strongly from the racemic-mixture value. The deviations were larger in liver than blubber, which indicates enantioselective metabolism. However, there was no selective passage of the studied atropisomeric CBs across placenta and no selective blood-brain barrier. Similarly, no correlation between EFs and health status was observed, although there was a correlation between the total CB levels and health status.

Animals↗

PubMed2003

Multivariate characterization of polycyclic aromatic hydrocarbons using semi-empirical molecule orbital calculations and physical data.

Multivariate characterization of 60 polycyclic aromatic hydrocarbons (PAHs) was performed using data from literature and semi-empirical molecular orbital calculations. This dataset was analyzed by principal component analysis and projections to latent structures by means of partial least square. The PAHs were found to distribute in the chemical domain in several groups mainly governed by the number of aromatic rings and the number of five-membered rings. The multivariate model and training set was used to predict GC retention times on a non-polar column (DB-5). Using a 2(4) experimental design on the principal components of the chemical characterization model, a test set of PAHs was selected dependent on the distribution in the chemical domain of the PAHs. Such a test set is expected to improve selection of PAHs for future testing and modeling of both biological and chemical responses. Although the model of GC retention times was good, the precision was however not good enough for practical use.

Environmental Pollutants↗

PubMed2002

Effects of temperature and flow regulated carbon dioxide cooling in longitudinally modulated cryogenic systems for comprehensive two-dimensional gas chromatography.

Two different modes of temperature regulation in longitudinally modulated cryogenic systems (LMCSs) for comprehensive two-dimensional gas chromatography (GC x GC) were compared. Carbon dioxide was used as coolant. In the first mode of operation, the temperature of the trap was regulated to pre-set temperature using a digital temperature controller ("the constant temperature mode"). In the second, the temperature was regulated to a fixed negative offset to the oven temperature by using a constant flow of CO2 ("the constant flow mode"). A number of problems were occasionally observed using the constant temperature mode: (1) severe band broadening of high boiling analytes in the second dimension; (2) non-Gaussian reconstructed first-dimension peak profiles; (3) high background due to modulation of first-dimension column bleed. It was concluded that these problems were associated with inefficient solute remobilization at low LMCS trap temperatures (1 and 2) or large trap temperature fluctuations (3). These problems could be avoided or significantly reduced by using the constant flow mode. Best results were obtained as the trap temperature was kept about 70 degrees C below the oven temperature.

Carbon Dioxide↗

PubMed2002

Multivariate physicochemical characterisation and quantitative structure-property relationship modelling of polybrominated diphenyl ethers.

Levels of polybrominated diphenyl ethers (PBDEs) are increasing in the environment and may cause long-term environmental problems. Developing a model describing the chemical variation among the 209 possible congeners would be a useful step in any systematic approach for assessing the fate and risk posed by the PBDEs. Therefore, 40 physicochemical descriptors were derived for all PBDEs using a semi-empirical method (AM1), molecular mechanics, and empirically estimated parameters. Descriptors included heats of formation, frontier molecular orbital energies, atomic charges, dipole moments, logP values, and molecular surface areas. Principal component analysis (PCA) was used to evaluate the descriptors. The first four PCs, explaining 76% of the variation in the data, described the size, charge distribution and symmetric elements of the congeners. A quantitative structure-activity relationship model was constructed based on data for dioxin-like activity (using the luciferase bioassay) for 17 PBDEs with the partial least squares method. In addition, quantitative structure-property relationship models for gas chromatographic relative retention times on four capillary columns were developed. These models proved suitable to assist in the identification of untested PBDEs. Based on the results of the PCA, a factorial design was applied for selecting 21 representative congeners. PBDEs 11, 13, 17, 32, 35, 47, 53, 77, 85, 99, 119, 135, 153, 155, 156, 169, 176, 181, 190, 192, and 209. The spacing of these congeners in the physicochemical domain maximises the coverage of key factors such as molecular size and substitution pattern. Consideration of the selected congeners should be useful for guiding the synthesis of new compounds for use in future studies of the fate and biological effects of PBDEs.

Biological Assay↗

PubMed2002

Accumulation and elimination of 16 polycyclic aromatic compounds in the earthworm (Eisenia fetida).

Accumulation and elimination of different polycyclic aromatic compounds (PACs) were studied in earthworms (Eisenia fetida) exposed to contaminated soil from an old gasworks site. In total, 12 polycyclic aromatic hydrocarbons (PAHs), two N- and S-heterocyclic PACs, and two PAC-quinones were included in the study. Peak-shaped accumulation curves were found for many of the compounds. After 19 d of exposure, the ratio between concentrations in worm lipids and soil organic matter was 0.02 on average. The half-lives of the PACs were relatively long, between 2 and 11 d. The elimination rate constants, k2, correlated both with literature-derived octanol-water partition coefficients (Kow) for PAHs (r2 = 0.93) and the computed polarizability (r2 = 0.88) of all the compounds. The elimination rate constants of PAHs are comparable to those of PCBs found in earlier studies, and the linear regression coefficient, r2, of k2 against Kow for PAHs and PCBs together was 0.93.

Animals↗