ABSTRACT
Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants, and many are potent carcinogens. Benzo[a]pyrene (B[a]P), one of the best-studied PAHs, is metabolized ultimately to the genotoxin anti-B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE triggers stress responses linked to gene expression, cell death and survival. So far, the underlying mechanisms that initiate these signal transduction cascades are unknown. Here we show that BPDE-induced DNA damage is recognized by DNA damage sensor proteins to induce activation of the stress-activated protein kinase (SAPK) p38. Surprisingly, the classical DNA damage response, which involves the kinases ATM and ATR, is not involved in p38-SAPK activation by BPDE. Moreover, the induction of p38-SAPK phosphorylation also occurs in the absence of DNA strand breaks. Instead, increased phosphorylation of p38-SAPK requires the nucleotide excision repair (NER) and DNA damage sensor proteins XPC and mHR23B. Interestingly, other genotoxins such as cisplatin (CDDP), hydrogen peroxide and ultraviolet radiation also enhance XPC-dependent p38-SAPK phosphorylation. In contrast, anti-benzo[c]phenanthrene-3,4-dihydrodiol-1,2-epoxide, the DNA adducts of which are not properly recognized by NER, does not trigger p38-SAPK activation. As a downstream consequence, expression and secretion of the pro-inflammatory cytokine interleukin-6 is induced by BPDE and CDDP in vitro and by CDDP in the murine lung, and depends on XPC. In conclusion, we describe a novel pathway in which DNA damage recognition by NER proteins specifically leads to activation of p38-SAPK to promote inflammatory gene expression.
Subject(s)
Carcinogenesis/metabolism , DNA Adducts/metabolism , DNA Repair/physiology , Interleukin-6/biosynthesis , p38 Mitogen-Activated Protein Kinases/metabolism , 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide/metabolism , 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide/toxicity , Animals , Blotting, Western , Carcinogens/toxicity , Comet Assay , DNA Damage/drug effects , DNA Damage/physiology , DNA-Binding Proteins/metabolism , Enzyme-Linked Immunosorbent Assay , Fibroblasts , HeLa Cells , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutagens/toxicity , NIH 3T3 Cells , RNA, Small Interfering , Real-Time Polymerase Chain Reaction , Signal Transduction/physiology , TransfectionABSTRACT
Nowadays reports about mechanical problems in obstetrics are rare. Report about the occipito-posterior position. It may be possible that these increasing anomalies. The reason for this fetal acceleration are and changes in pelvic anatomy.
Subject(s)
Extraction, Obstetrical , Labor Presentation , Obstetric Labor Complications/therapy , Female , Fetal Death/etiology , Humans , Infant, Newborn , Male , Obstetric Labor Complications/etiology , Pregnancy , Pregnancy, Multiple , Risk FactorsABSTRACT
The effects of in vivo and in vitro methyl mercury (MeHg) treatments on the microtubule system of murine splenic lymphocytes were examined by immunofluorescence microscopy. In vitro exposures to 1 to 10 microM MeHg resulted in time- and concentration-dependent microtubule disassembly. Lymphocytes isolated from mice receiving a single 10 mg/kg injection displayed microtubule damage when examined 2 and 5 days post-treatment. The capacity of in vivo and in vitro treated lymphocytes to respond to the mitogen concanavalin A (Con A) was generally inhibited by MeHg. There was a good correlation between the degree of microtubule disassembly and the inhibition of mitogen responsiveness. In vivo and in vitro treatments that resulted in extensive microtubule damage suppressed the ConA response and blocked lymphocytes early in the stimulation sequence. In vitro MeHg treatment late in mitogenesis caused a rapid, concentration-dependent inhibition of [3H]thymidine incorporation. These results suggest that damage to the microtubule system can serve as an indicator of MeHg toxicity and may underlie the toxicant's effects on lymphocyte functions.
