Background:A rich body of literature exists that has demonstrated adverse human health effects following exposure to ambient air particulate matter (PM), and there is strong support for an important role of ultrafine (nanosized) particles. At present, relatively few human health or epidemiology data exist for engineered nanomaterials (NMs) despite clear parallels in their physicochemical properties and biological actions in in vitro models.Objectives:NMs are available with a range of physicochemical characteristics, which allows a more systematic toxicological analysis. Therefore, the study of ultrafine particles (UFP, <100 nm in diameter) provides an opportunity to identify plausible health effects for NMs, and the study of NMs provides an opportunity to facilitate the understanding of the mechanism of toxicity of UFP.Methods:A workshop of experts systematically analyzed the available information and identified 19 key lessons that can facilitate knowledge exchange between these discipline areas.Discussion:Key lessons range from the availability of specific techniques and standard protocols for physicochemical characterization and toxicology assessment to understanding and defining dose and the molecular mechanisms of toxicity. This review identifies a number of key areas in which additional research prioritization would facilitate both research fields simultaneously.Conclusion:There is now an opportunity to apply knowledge from NM toxicology and use it to better inform PM health risk research and vice versa. https://doi.org/10.1289/EHP424

We have previously reported that airborne particulate matter air pollution (PM) activates the intrinsic apoptotic pathway in alveolar epithelial cells through a pathway that requires the mitochondrial generation of reactive oxygen species (ROS) and the activation of p53. We sought to examine the source of mitochondrial oxidant production and the molecular links between ROS generation and the activation of p53 in response to PM exposure. Using a mitochondrially targeted ratiometric sensor (Ro-GFP) in cells lacking mitochondrial DNA ( 0 cells) and cells stably expressing a small hairpin RNA directed against the Rieske iron-sulfur protein, we show that site III of the mitochondrial electron transport chain is primarily responsible for fine PM (PM 2.5 )-induced oxidant production. In alveolar epithelial cells, the overexpression of SOD1 prevented the PM 2.5 -induced ROS generation from the mitochondria and prevented cell death. Infection of mice with an adenovirus encoding SOD1 prevented the PM 2.5 -induced death of alveolar epithelial cells and the associated increase in alveolar-capillary permeability. Treatment with PM 2.5 resulted in the ROS-mediated activation of the oxidant-sensitive kinase ASK1 and its downstream kinase JNK. Murine embryonic fibroblasts from ASK1 knock-out mice, alveolar epithelial cells transfected with dominant negative constructs against ASK1, and pharmacologic inhibition of JNK with SP600125 (25 M) prevented the PM 2.5 -induced phosphorylation of p53 and cell death. We conclude that particulate matter air pollution induces the generation of ROS primarily from site III of the mitochondrial electron transport chain and that these ROS activate the intrinsic apoptotic pathway through ASK1, JNK, and p53.Epidemiologic studies have consistently demonstrated a strong link between the daily levels of particulate matter air pollution Ͻ2.5 m in diameter (PM 2.5 ) 3 and PM Ͻ10 m in diameter (PM 10 ) and cardiopulmonary morbidity and mortality (1-3). In humans, exposure to PM 10 has been associated with an increase in mortality from ischemic cardiovascular events including stroke and myocardial infarction, an acceleration in the age-related decline in lung function in normal adults, impairment in normal lung development in children, exacerbations of asthma in children and adults, accelerated atherosclerosis in women, increased rates of lung cancer, and the development of myocardial ischemia in men with stable coronary artery disease (4 -10). The intracellular generation of reactive oxygen species (ROS) has emerged as a common mechanism by which particulates might initiate signaling pathways that end in these diverse pathologic conditions (11). We have reported that the PM-induced generation of ROS requires a functional electron transport chain, suggesting that PM might induce the inadvertent transfer of electrons from one or more sites in the electron transport chain to molecular oxygen (12).One of the mechanisms by which exposure to PM can contribute to alveolar epithelial dysfunction, lung injury an...

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Ether-à-go-go-1 (Eag1) potassium channels are potential tools for detection and therapy of numerous cancers. Here, we show human Eag1 (hEag1) regulation by cancer-associated factors. We studied hEag1 gene expression and its regulation by estradiol, antiestrogens, and human papillomavirus (HPV) oncogenes (E6/E7). Primary cultures from normal placentas and cervical cancer tissues; tumor cell lines from cervix, choriocarcinoma, keratinocytes, and lung; and normal cell lines from vascular endothelium, keratinocytes, and lung were used. Reverse transcription-PCR (RT-PCR) experiments and Southern blot analysis showed Eag1 expression in all of the cancer cell types, normal trophoblasts, and vascular endothelium, in contrast to normal keratinocytes and lung cells. Estradiol and antiestrogens regulated Eag1 in a cell type-dependent manner. Real-time RT-PCR experiments in HeLa cells showed that Eag1 estrogenic regulation was strongly associated with the expression of estrogen receptor-A. Eag1 protein was detected by monoclonal antibodies in normal placenta and placental blood vessels. Patch-clamp recordings in normal trophoblasts treated with estradiol exhibited potassium currents resembling Eag1 channel activity. Eag1 gene expression in keratinocytes depended either on cellular immortalization or the presence of HPV oncogenes. Eag1 protein was found in keratinocytes transfected with E6/E7 HPV oncogenes. Cell proliferation of E6/E7 keratinocytes was decreased by Eag1 antibodies inhibiting channel activity and by the nonspecific Eag1 inhibitors imipramine and astemizole; the latter also increased apoptosis. Our results propose novel oncogenic mechanisms of estrogen/ antiestrogen use and HPV infection. We also suggest Eag1 as an early indicator of cell proliferation leading to malignancies and a therapeutic target at early stages of cellular hyperproliferation. [Cancer Res 2009;69(8):3300-7]

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Exposure of human populations to chronically elevated levels of ambient particulate matter air pollution < 2.5 μm in diameter (PM2.5) has been associated with an increase in lung cancer incidence. Over 70% of lung cancer cell lines exhibit promoter methylation of the tumor suppressor p16, an epigenetic modification that reduces its expression. We exposed mice to concentrated ambient PM2.5 via inhalation, 8 hours daily for 3 weeks and exposed primary murine alveolar epithelial cells to daily doses of fine urban PM (5 µg/cm2). In both mice and alveolar epithelial cells, PM exposure increased ROS production, expression of the DNA methyltransferase 1 (DNMT1), and methylation of the p16 promoter. In alveolar epithelial cells, increased transcription of DNMT1 and methylation of the p16 promoter were inhibited by a mitochondrially targeted antioxidant and a JNK inhibitor. These findings provide a potential mechanism by which PM exposure increases the risk of lung cancer.

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The physicochemical properties and biological behavior of sintered-bovine-derived hydroxyapatite (BHAp) are here reported and compared to commercial synthetic-HAp (CHAp). Dense ceramics were sintered for 2 h and 4 h at 1200 °C to investigate their microstructure–structure–in-vitro behavior relationship for both HAp ceramics. Densification was directly proportional to sintering time, showing a grain coarsening behavior with a greater effect on BHAp. Lattice parameters, crystallite size, cell volume and Ca/P ratio were determined by Rietveld refinement of X-ray diffraction (XRD) patterns using GSAS®. Ionic substitutions (Na+, Mg2+, CO32−) related to BHAp structure were associated with their position changes in the vibrational modes and correlated with the structural parameters obtained from the XRD analysis. Variations in the structural parameters and surface morphology were also evaluated after different soaking periods in simulated body fluid, which is associated with the formation of bone-like apatite layer and thus bioactivity. Mitochondrial activity (MTS) and lactate dehydrogenase (LDH) assays showed that the material released by the ceramics does not induce toxicity after exposure in human fetal osteoblastic (hFOB) cells. Furthermore, no statistically significant differences were found between the HAp obtained from different sources. These results show that BHAp can be used with no restrictions for the same biomedical applications as CHAp.