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Carbon nanotubes (CNTs) represent a major class of engineered nanomaterials that are being used in diverse fields. However, their use has increasingly become a concern because of their carcinogenic potential. Accumulating evidence has demonstrated that certain types of CNTs are carcinogenic or tumor-promoting in animal models. However, the underlying molecular and cellular mechanisms are unclear. Here, we report that chronic exposure to single-walled (SW) CNTs results in the induction of Slug, a key transcription factor that induces an epithelial–mesenchymal transition (EMT), in human lung epithelial cells. We show that SWCNT-induced Slug upregulation plays a critical role in the aggressive phenotype of SWCNT-exposed cells, which includes increased cell migration, invasion, and anchorage-independent cell growth. Our in vivo studies also show that SWCNT-induced Slug upregulation and EMT activation play a pivotal role in tumor formation and metastasis. Our findings illustrate a direct link between CNT-induced Slug upregulation, EMT activation, and tumor formation and metastasis, and they highlight the potential of CNT-induced Slug upregulation as a target for future risk assessment and prevention of CNT-associated diseases.

The biological effect of benzene on the hematopoietic system has been known for over a century. The rapid advancement in understanding the biology of hematopoietic stem cells (HSCs) and cancer stem cells (CSCs) in recent years has renewed interest in investigating the role of stem cells in benzene-induced malignancy and bone marrow depression. The interplay between benzene and stem cells is complex involving the stem cell, progenitor, and HSC niche compartments of the bone marrow. In this prospect, benzene metabolites formed through metabolism in the liver and bone marrow cause damage in hematopoietic cells via multiple mechanisms that, in addition to traditionally recognized chromosomal aberration and covalent binding, incorporate oxidative stress, alteration of gene expression, apoptosis, error-prone DNA repair, epigenetic regulation, and disruption of tumor surveillance. However, benzene-exposed individuals exhibit variable susceptibility to benzene effect that arises, in part, from genetic variations in benzene metabolism, DNA repair, genomic stability, and immune function. These new studies of benzene leukemogenesis and hematotoxicity are expected to provide insights into how environmental and occupational chemicals affect stem cells to cause cancer and toxicity, which impact the risk assessment, permissible level, and therapy of benzene exposure.

Carbon nanotubes (CNTs) are novel materials with unique electronic and mechanical properties. The extremely small size, fiberlike shape, large surface area, and unique surface chemistry render their distinctive chemical and physical characteristics and raise potential hazards to humans. Several reports have shown that pulmonary exposure to CNTs caused inflammation and lung fibrosis in rodents. The molecular mechanisms that govern CNT lung toxicity remain largely unaddressed. Here, we report that multiwalled carbon nanotubes (MWCNTs) have potent, dose-dependent toxicity on cultured human lung cells (BEAS-2B, A549, and WI38-VA13). Mechanistic analyses were carried out at subtoxic doses (≤20 μg/mL, ≤ 24 h). MWCNTs induced substantial ROS production and mitochondrial damage, implicating oxidative stress in cellular damage by MWCNT. MWCNTs activated the NF-κB signaling pathway in macrophages (RAW264.7) to increase the secretion of a panel of cytokines and chemokines (TNFα, IL-1β, IL-6, IL-10, and MCP1) that promote inflammation. Activation of NF-κB involved rapid degradation of IκBα, nuclear accumulation of NF-κBp65, binding of NF-κB to specific DNA-binding sequences, and transactivation of target gene promoters. Finally, MWCNTs induced the production of profibrogenic growth factors TGFβ1 and PDGF from macrophages that function as paracrine signals to promote the transformation of lung fibroblasts (WI38-VA13) into myofibroblasts, a key step in the development of fibrosis. Our results revealed that MWCNTs elicit multiple and intertwining signaling events involving oxidative damage, inflammatory cytokine production, and myofibroblast transformation, which potentially underlie the toxicity and fibrosis in human lungs by MWCNTs.

Exposure to cadmium (Cd) elicits a range of adverse responses including oxidative damage and cancer. The molecular targets of Cd remain largely unidentified. Here, we analyzed the function and signal transduction of transcription factor Nrf2 in protection against Cd-induced oxidative stress. Wild-type (Nrf2 (+/+)) mouse embryonic fibroblasts (MEF) produced reactive oxygen species (ROS) at a low level, whereas treatment with Cd significantly increased the ROS production. On the other hand, Nrf2 knockout (Nrf2 (-/-)) MEF cells exhibited an elevated level of ROS under a basal condition, and Cd dramatically increased the ROS production at concentrations as low as 2 microM, resulting in increased sensitivity to Cd-induced cell death. Cd induced the basal and inducible expression of cytoprotective enzymes NQO1 and HO1 in WT MEF cells, but induction was lost in Nrf2 (-/-) MEF cells. Induction of the genes required antioxidant response elements (ARE) as Cd drove ARE-dependent reporter expression and Cd-activated Nrf2 bound to endogenous AREs in mouse hepa1c1c7 cells. Activation of Nrf2 by Cd involved stabilization of the Nrf2 protein, increased formation of Nrf2/Keap1 complex in the cytoplasm, translocation of the complex into the nucleus, and subsequently disruption of the complex. Lastly, Nrf2 was found ubiquitinated in the cytoplasm but deubiquitinated in the nucleus. The study provided a mechanistic transcriptional model in which Cd activates Nrf2 through a metal-activated signaling pathway involving a dynamic interplay between ubiquitination/deubiquitination and complex formation/dissociation of Nrf2 and Keap1.