Jaroslav Janošek

Cytotoxicity and aryl hydrocarbon receptor‐mediated activity of N‐heterocyclic polycyclic aromatic hydrocarbons: Structure‐activity relationships

Toxic effects of many persistent organic pollutants (e.g., polychlorinated biphenyls or polychlorinated dibenzo-p-dioxins and furans) are mediated via the aryl hydrocarbon receptor (AhR). Although polycyclic aromatic hydrocarbons (PAHs) and their derivatives also activate AhR, their toxic effects remain to be fully elucidated. In the present study, we used the in vitro H4IIE-luc transactivation cell assay to investigate cytotoxicity and potencies to activate AhR by 29 individual PAHs and their N-heterocyclic derivatives (aza-PAHs). The aza-PAHs were found to be significantly more cytotoxic and more potent inducers of AhR than their unsubstituted analogues. Several aza-PAHs, such as dibenz[a,h]acridine or dibenz[a,i]acridine, activated AhR within picomolar concentrations, comparable to the effects of reference 2,3,7,8-tetrachlorodibenzo-p-dioxin. Ellipsoidal volume, molar refractivity, and molecular size were the most important descriptors derived from the modeling of quantitative structure-activity relationships for potencies to activate AhR. Comparable relative toxic potencies (induction equivalency factors) for individual aza-PAHs are derived, and their use for evaluation of complex contaminated samples is discussed.

Photochemistry of Valerophenone in Solid Solutions

Abstract Photoreactivity of valerophenone was investigated in frozen solid solvents: benzene, cyclohexane, t -butanol, hexadecane, and water. Different product and mass distributions were followed during the course of the photoreaction. It was evidenced that a portion of ketone molecules is almost unreactive in the solid state due to physical restraints of the solid solvent cavity. Free rotation along the C–C bonds becomes difficult inside the cavity and it is probable that larger conformational changes are totally restricted. It was shown that a fraction of molecules having the favorable conformation for hydrogen abstraction reacts with the same photochemical efficiency no matter what solvent was used. The elimination/cyclization ratio of the Norrish Type II reaction was studied as a function of temperature. Variation of the ratios, characteristic for each solvent, diminished with decreasing temperature what has been rationalized in terms of the effective reaction cavity. The semi-empirical PM3 method and molecular mechanics MM3 force field calculations were performed to evaluate stabilities of the ground state valerophenone conformations.

Interference of contaminated sediment extracts and environmental pollutants with retinoid signaling

Retinoids are known to regulate important processes such as differentiation, development, and embryogenesis. Some effects, such as malformations in frogs or changes in metabolism of birds, could be related to disruption of the retinoid signaling pathway by exposure to organic contaminants. A new reporter gene assay has been established for evaluation of the modulation of retinoid signaling by individual chemicals or environmental samples. The bioassay is based on the pluripotent embryonic carcinoma cell line P19 stably transfected with the firefly luciferase gene under the control of a retinoic acid-responsive element (clone P19/ A15). The cell line was used to characterize the effects of individual chemicals and sediments extracts on retinoid signaling pathways. The extracts of sediments from the River Kymi, Finland, which contained polychlorinated dioxins and furans and polycyclic aromatic hydrocarbons (PAHs), significantly increased the potency of all-trans retinoic acid (ATRA), while no effect was observed with the extract of the sediment from reference locality. Considerable part of the effect was caused by the labile fraction of the sediment extracts. Also, several individual PAHs potentiated the effect of ATRA; on the other hand, 2,3,7,8-tetrachlorodibenzo-p-dioxin and several phthalates showed slightly inhibiting effect. These results suggest that PAHs could be able to modulate the retinoid signaling pathway and that they could be responsible for a part of the proretinoid activity observed in the sediment extracts. However, the effects of PAHs on the retinoic acid signaling pathways do not seem to be mediated directly by crosstalk with aryl hydrocarbon receptor.