para-Phenylene-bridged spirobi(triarylamine) dimer 2, in which π conjugation through four redox-active triarylamine subunits is partially segregated by the unique perpendicular conformation, was prepared and characterized by structural, electrochemical, and spectroscopic methods. Quantum chemical calculations (DFT and CASSCF) predicted that the frontier molecular orbitals of 2 are virtually fourfold degenerate, so that the oxidized states of 2 can give intriguing electronic and magnetic properties. In fact, the continuous-wave ESR spectroscopy of radical cation 2(*+) showed that the unpaired electron was trapped in the inner two redox-active dianisylamine subunits, and moreover was fully delocalized over them. Magnetic susceptibility measurements and pulsed ESR spectroscopy of the isolated salts of 2, which can be prepared by treatment with SbCl(5), revealed that the generated tetracation 2(4+) decomposed mainly into a mixture of 1) a decomposed tetra(radical cation) consisting of a tri(radical cation) moiety and a trianisylamine radical cation moiety (≈75%) and 2) a diamagnetic quinoid dication in a tetraanisyl-p-phenylendiamine moiety and two trianisylamine radical cation moieties (≈25%). Furthermore, the spin-quartet state of the tri(radical cation) moiety in the decomposed tetra(radical cation) was found to be in the ground state lying 30 cal mol(-1) below the competing spin-doublet state.
Permethrin has been shown to increase lung adenomas in female CD-1 mice, but not in male mice or Wistar rats. The proposed mode of action (MOA) for permethrin-induced female mouse lung tumor formation involves morphological changes in Club cells; increased Club cell proliferation; increased Club cell hyperplasia, and lung tumor formation. In this study, the treatment of female CD-1 mice with tumorigenic doses (2500 and 5000 ppm) of permethrin, but not with a non-tumorigenic dose (20 ppm), for 14 and/or 28 days increased Club cell replicative DNA synthesis. Global gene expression analysis of female mouse lung samples demonstrated that permethrin treatment up-regulated three genes associated with cell proliferation, namely aldehyde dehydrogenase 3a1 (Aldh3a1), oxidative stress induced growth inhibitor 1 and thioredoxin reductase 1. Treatment with 2500 and 5000 ppm, but not 20 ppm, permethrin for 7 days produced significant increases in mRNA levels of these three genes. Immunohistochemical analysis demonstrated that Club cell secretory protein, CYP2F2, and ALDH3A1 colocalized in Club cells; confirmed by flow cytometry analysis of lung cells employing KI67 as a cell proliferation marker. Overall, the present data extend the proposed MOA by demonstrating that Club cells are the primary initial target of permethrin administration in female mouse lung. As humans are quantitatively much less sensitive to agents that increase Club cell proliferation and lung tumor formation in mice, it is most likely that permethrin could not produce lung tumors in humans. This conclusion is supported by available negative epidemiological data from a number of studies.
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