Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational toxicants, which are a major human health concern in the U.S. and abroad. Previous research has focused on the genotoxic events caused by high molecular weight PAHs, but not on non-genotoxic events elicited by low molecular weight PAHs. We used an isomeric pair of low molecular weight PAHs, namely 1-Methylanthracene (1-MeA) and 2-Methylanthracene (2-MeA), in which only 1-MeA possessed a bay-like region, and hypothesized that 1-MeA, but not 2-MeA, would affect non-genotoxic endpoints relevant to tumor promotion in murine C10 lung cells, a non-tumorigenic type II alveolar pneumocyte and progenitor cell type of lung adenocarcinoma. The non-genotoxic endpoints assessed were dysregulation of gap junction intercellular communication function and changes in the major pulmonary connexin protein, connexin 43, using fluorescent redistribution and immunoblots, activation of mitogen activated protein kinases (MAPK) using phosphospecific MAPK antibodies for immunoblots, and induction of inflammatory genes using quantitative RT-PCR. 2-MeA had no effect on any of the endpoints, but 1-MeA dysregulated gap junctional communication in a dose and time dependent manner, reduced connexin 43 protein expression, and altered membrane localization. 1-MeA also activated ERK1/2 and p38 MAP kinases. Inflammatory genes, such as cyclooxygenase 2, and chemokine ligand 2 (macrophage chemoattractant 2), were also upregulated in response to 1-MeA only. These results indicate a possible structure-activity relationship of these low molecular weight PAHs relevant to non-genotoxic endpoints of the promoting aspects of cancer. Therefore, our novel findings may improve the ability to predict outcomes for future studies with additional toxicants and mixtures, identify novel targets for biomarkers and chemotherapeutics, and have possible implications for future risk assessment for these PAHs.

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Aims/hypothesis The destruction of pancreatic beta cells leading to type 1 diabetes in humans is thought to occur mainly through apoptosis and necrosis induced by activated macrophages and T cells, and in which secreted cytokines play a significant role. The transcription factor nuclear factor kappa-B (NF-κB) plays an important role in mediating the apoptotic action of cytokines in beta cells. We therefore sought to determine the changes in expression of genes modulated by NF-κB in human islets exposed to a combination of IL1β, TNF-α and IFN-γ. Methods Microarray and gene set enrichment analysis were performed to investigate the global response of gene expression and pathways modulated in cultured human islets exposed to cytokines. Validation of a panel of NF-κB-regulated genes was performed by quantitative RT-PCR. The mechanism of induction of BIRC3 by cytokines was examined by transient transfection of BIRC3 promoter constructs linked to a luciferase gene in MIN6 cells, a mouse beta cell line. Results Enrichment of several metabolic and signalling pathways was observed in cytokine-treated human islets. In addition to the upregulation of known pro-apoptotic genes, a number of anti-apoptotic genes including BIRC3, BCL2A1, TNFAIP3, CFLAR and TRAF1 were induced by cytokines through NF-κB. Significant synergy between the cytokines was observed in NF-κB-mediated induction of the promoter of BIRC3 in MIN6 cells. Conclusions/interpretation These findings suggest that, via NF-κB activation, cytokines induce a concurrent antiapoptotic pathway that may be critical for preserving islet integrity and viability during the progression of insulitis in type 1 diabetes.

Primary varicella-zoster virus (VZV) infection in humans produces varicella (chickenpox),Varicella zoster virus (VZV) is a ubiquitous, exclusively human, and highly neurotropic herpesvirus. Primary infection causes varicella (chickenpox), during which VZV replicates in the cells of every visceral organ and the skin (12). VZV establishes lifelong latency in neurons of cranial nerve ganglia, dorsal root ganglia, and autonomic ganglia along the entire neuraxis (9,11,17). VZV reactivates in elderly and immunocompromised individuals to produce shingles (herpes zoster), frequently complicated by chronic pain (postherpetic neuralgia) (10) and other serious neurological and ocular disorders, such as VZV vasculopathy, myelopathy, and retinal necrosis.Analyses of latently infected human ganglia obtained postmortem within 24 h after death have provided useful information on the configuration and abundance of the VZV genome and the limited extent of viral gene expression (reviewed in reference 6). However, such studies are hampered by lack of sufficient tissue, RNA degradation postmortem, and possible virus reactivation after death. Because no satisfactory animal model exists to study the interaction of VZV with neurons, alternate models have been developed. For example, immunedeficient SCID mice have had human neural stem cells or human ganglia transplanted, followed by infection with VZV and examination of infected neurons (2, 21). VZV has been also shown to infect cultured neurons from guinea pig enteric ganglia (8). An in vitro model of cultured human neurons infected with VZV provides an opportunity to study the molecular events leading to the establishment of VZV latency and reactivation. Here, we developed a system in which human neural stem cells (NSCs) were induced to differentiate into neurons, infected with VZV, observed carefully, and analyzed for viral gene expression and for markers of apoptosis.