PCBs, a group of 209 individual congeners, are ubiquitous environmental pollutants and classified as probable human carcinogens. One major route of exposure is by inhalation of these industrial compounds, possibly daily from inner city air and/or indoor air in contaminated buildings. Hallmarks of aging and carcinogenesis are changes in telomere length and telomerase activity. We hypothesize that semi-volatile PCBs, like those found in inner city air, are capable of disrupting telomerase activity and altering telomere length. To explore this possibility, we exposed human skin keratinocytes to a synthetic Chicago Airborne Mixture (CAM) of PCBs, or the prominent airborne PCB congeners, PCB28 or PCB52 for up to 48 days and determined telomerase activity, telomere length, cell proliferation, and cell cycle distribution. PCBs 28, 52 and CAM significantly reduced telomerase activity from days 18–48. Telomere length was shortened by PCB52 from day 18 and PCB28 and CAM from days 30 on. All PCBs decreased cell proliferation from day 18; only PCB52 produced a small increase of cells in G0/G1 of the cell cycle. This significant inhibition of telomerase activity and reduction of telomere length by PCB congeners suggest a potential mechanism by which these compounds could lead to accelerated aging and cancer.

Aims: This study determined whether acute radiation-induced liver injury seen in Sirtuin3-/ -mice after exposure to Cs-137 c-rays was mediated by superoxide anion (O 2 -). Results: Male wild-type (WT) and SIRT3-/ -mice were given 2 · 2 Gy whole-body radiation doses separated by 24 h and livers were harvested 20 h after the second dose. Ex vivo measurements in fresh frozen liver sections demonstrated 50% increases in dihydroethidium oxidation from SIRT3 -/ -animals, relative to WT animals, before irradiation, but this increase was not detected 20 h after radiation exposure. In addition, irradiated livers from SIRT3-/ -animals showed significant hydropic degeneration, loss of MitoTracker Green FM staining, increased immunohistochemical staining for 3-nitrotyrosine, loss of Ki67 staining, and increased mitochondrial localization of p53. These parameters of radiation-induced injury were significantly attenuated by an intraperitoneal injection of 2 mg/kg of the highly specific superoxide dismutase mimic, GC4401, 30 min before each fraction. Innovation: Sirtuin 3 (SIRT3) is believed to regulate mitochondrial oxidative metabolism and antioxidant defenses in response to acute radiation-induced liver injury. This work provides strong evidence for the causal role of O 2 -in the liver injury process initiated by whole-body irradiation in SIRT3-/ -mice. Conclusion: These results support the hypothesis that O 2 -mediates acute liver injury in SIRT3

The toxicity of polychlorinated biphenyls (PCBs) has been attributed widely to receptor-mediated effects, buttressed by the popularity of the Toxic Equivalency Factor. We propose that a crucial toxic mechanism of lower-chlorinated PCBs is their enzymatic biotransformation to electrophiles, including quinoid metabolites, that bind intracellular sulfhydryl groups, such as those found in microtubulin and enzymes like telomerase. To test this hypothesis, we have examined micronuclei induction, cell cycle, and telomere shortening in cells in culture. Our findings show a large increase in micronuclei frequency and cell cycle perturbation in V79 cells, and a marked decrease in telomere length in HaCaT cells exposed to 2-(4'-chlorophenyl)-1,4-benzoquinone (PCB3pQ).

The extensive body of literature regarding the interaction of polychlorinated biphenyls (PCBs) with transcription factors (receptors) has great value to understand similarities and distinctions and in formulating hypotheses regarding the activity of polybrominated diphenyl ethers (PBDEs) toward those same receptors. Our goal is to present the most comprehensive overview of PBDE effects on AhR, CAR, PXR, ER, AR, PR, DHT, TH, T3, T4 and IGF, as well as hypothetical biological activities of PPAR, RyR, GR and GABA. Aside the influence of the conformation of the ligand, we discuss its constitution influencing the binding affinity: size and polarizability, hydrophilicity, Gibbs free energy of solvation, inductive and mesomeric effects. We evaluate the techniques to determine the biologically relevant conformation of these halogenated hydrocarbons, including computation methods, X-ray and microwave spectroscopy. A novel fluoro-tagged ligand approach holds promise as tools for illuminating the steric and electronic effects in ligand-receptor interaction. Based on our assessment, we predict that PBDEs do not exhibit AhR activity themselves, but impurities are responsible for these effects.

Minnesota has been grappling with extensive per- and polyfluoroalkyl substances (PFASs) groundwater contamination since 2002, in a major metropolitan setting. As toxicological information has accumulated for these substances, the public health community has become increasingly aware of critically sensitive populations. The accumulation of some PFAS in women of childbearing age, and the placental and breastmilk transfer to their offspring, require new risk assessment methods to protect public health. The traditional water guidance paradigm is inadequate to address maternal-to-infant transfer of accumulated levels of perfluorooctanoate (PFOA), in particular. Even short exposures during infancy have dramatic impacts on serum levels for many years. In addition, developmental effects are the critical effects anchoring recent risk assessments. In response, the Minnesota Department of Health created an Excel-based model that incorporates chemical-specific properties and exposure parameters for early life stages. Serum levels were assessed in both formula-fed and breastfed infants, with placental transfer in both scenarios. Peak breastfed infant serum levels were 4.4-fold higher than in formula-fed infants, with both of these scenarios producing serum levels in excess of the adult steady-state level. The development and application of this model to PFOA are described.