Peripheral (lung-to-brain) exposure to diesel particulate matter induces oxidative stress and increased markers for systemic inflammation.

Combustion-derived air pollution is a complex environmental toxicant that has become a global health concern due to urbanization. Air pollution contains pro-inflammatory stimulants such as fine and ultrafine particulate matter, gases, volatile organic compounds, and metals. This study is focused on the particulate phase, which has been shown to induce systemic inflammation after chronic exposure due to its ability to travel to the lower airway, resulting in the activation of local immune cell populations, releasing acute phase reactants to mitigate ongoing inflammation. The systemic response is a potential mechanism for the co-morbidity associated with regions with high pollution and neuropathology. We exposed diesel particulate matter (DPM) to a pulmonary cell-derived in vitro model where macrophages mimic the diffusion of cytokines into the peripheral circulation to microglia. Alveolar macrophages (transformed U937) were inoculated with resuspended DPM in an acute exposure (24-h incubation) and analyzed for MCP-1 expression and acute phase reactants (IL-1ß, IL-6, IL-8, and TNF-α). Post-exposure serum was collected and filtered from cultured alveolar macrophages, introduced to a healthy culture of microglial cells (HMC3), and measured for neurotoxic cytokines, oxidative stress, and pattern recognition receptors. After DPM exposure, the macrophages significantly upregulated all measured acute phase reactants, increased H2O2 production, and increased MCP-1 expression. After collection and filtration to remove excess particulates, microglia cells were incubated with the collected serum for 48 h to allow for cytokine diffusion between the periphery of microglia. Microglia significantly upregulated IL-6, IL-8, and oxidative stress with a moderate increase in IL-1ß and TNF-α. As a marker required for signaling tissue damage, CD14 indicated that compared to direct inoculation of DPM, peripheral exposure resulted in the potent activation of microglia cells. The specificity and potency of the response have implications for neuropathology through lung-to-brain mechanisms after inhalation of environmental pollutants.

Evaluating Manganese, Zinc, and Copper Metal Toxicity on SH-SY5Y Cells in Establishing an Idiopathic Parkinson's Disease Model.

Parkinson's disease (PD) is a neurodegenerative condition marked by loss of motor coordination and cognitive impairment. According to global estimates, the worldwide prevalence of PD will likely exceed 12 million cases by 2040. PD is primarily associated with genetic factors, while clinically, cases are attributed to idiopathic factors such as environmental or occupational exposure. The heavy metals linked to PD and other neurodegenerative disorders include copper, manganese, and zinc. Chronic exposure to metals induces elevated oxidative stress and disrupts homeostasis, resulting in neuronal death. These metals are suggested to induce idiopathic PD in the literature. This study measures the effects of lethal concentration at 10% cell death (LC10) and lethal concentration at 50% cell death (LC50) concentrations of copper, manganese, and zinc chlorides on SH-SY5Y cells via markers for dopamine, reactive oxygen species (ROS) generation, DNA damage, and mitochondrial dysfunction after a 24 h exposure. These measurements were compared to a known neurotoxin to induce PD, 100 µM 6-hydroxydopamine (6-ODHA). Between the three metal chlorides, zinc was statistically different in all parameters from all other treatments and induced significant dopaminergic loss, DNA damage, and mitochondrial dysfunction. The LC50 of manganese and copper had the most similar response to 6-ODHA in all parameters, while LC10 of manganese and copper responded most like untreated cells. This study suggests that these metal chlorides respond differently from 6-ODHA and each other, suggesting that idiopathic PD utilizes a different mechanism from the classic PD model.

Synergistic cytotoxicity of bromoacetic acid and three emerging bromophenolic disinfection byproducts against human intestinal and neuronal cells.

Halogenated disinfection byproducts (halo-DBPs) are drinking water contaminants of great public health concern. Nine haloaliphatic DBPs have been regulated by the U.S. Environmental Protection Agency and various halophenolic compounds have been identified as emerging DBPs. In this study, we evaluated the cytotoxic interactions of the regulated bromoacetic acid and three emerging bromophenolic DBPs, i.e., 2,4,6-tribromophenol, 3,5-dibromo-4-hydroxybenzoic acid, and 3,5-dibromo-4-hydroxybenzaldehyde. Cytotoxicity was measured for each DBP individually as well as each of their mixtures using in vitro human epithelial colorectal adenocarcinoma (Caco-2) and neuroblastoma (SH-SY5Y) cells. Concentration addition (CA) model and isobolographic analysis were employed to characterize the interactions among the DBPs. Our results show that the cytotoxicity of four bromo-DBPs against both cell-types followed the descending rank order of bromoacetic acid > 2,4,6-tribromophenol > 3,5-dibromo-4-hydroxybenzaldehyde > 3,5-dibromo-4-hydroxybenzoic acid. Compared with the toxicity data in literature, our finding that bromoacetic acid showed higher cytotoxicity than bromophenolic DBPs was consistent with the results from Chinese hamster ovary cells (a commonly used in vitro model of DBP toxicological studies); but different from the results obtained from in vivo biological models. Significantly, with CA model prediction, we found that mixtures of four bromo-DBPs exhibited synergistic cytotoxic effects on both human cell types. Isobolographic analysis of binary DBP mixtures revealed that, for Caco-2 cells, bromoacetic acid, 2,4,6-tribromophenol, and 3,5-dibromo-4-hydroxybenzoic acid induced synergism; for SH-SY5Y cells, bromoacetic acid induced synergism with all three bromophenolic DBPs. The production of reactive oxidative species (ROS) induced by DBP mixtures could be an important reason for the synergistic cytotoxicity.

Silver and Copper Nanoparticles Induce Oxidative Stress in Bacteria and Mammalian Cells.

Silver and copper nanoparticles (AgNPs and CuNPs) coated with stabilizing moieties induce oxidative stress in both bacteria and mammalian cells. Effective antibacterial agents that can overcome existing mechanisms of antibacterial resistance will greatly improve biomedical interventions. In this study, we analyzed the effect of nanoparticle-induced stress. Escherichia coli and normal human bronchial epithelial (BEAS-2B) cells were selected for this study. The nanoparticle constructs tested showed low toxicity to mammalian cells except for the polyvinylpyrrolidone-surface-stabilized copper nanoparticles. In fact, both types of copper nanoparticles used in this study induced higher levels of reactive oxygen species than the surface-stabilized silver nanoparticles. In contrast to mammalian cells, the surface-stabilized silver and copper nanoparticles showed varying levels of toxicity to bacteria cells. These data are expected to aid in bridging the knowledge gap in differential toxicities of silver and copper nanoparticles against bacteria and mammalian cells and will also improve infection interventions.

Nanoliposomal Delivery of MicroRNA-203 Suppresses Migration of Triple-Negative Breast Cancer through Distinct Target Suppression.

Triple-negative breast cancers affect thousands of women in the United States and disproportionately drive mortality from breast cancer. MicroRNAs are small, non-coding RNAs that negatively regulate gene expression post-transcriptionally by inhibiting target mRNA translation or by promoting mRNA degradation. We have identified that miRNA-203, silenced by epithelial-mesenchymal transition (EMT), is a tumor suppressor and can promote differentiation of breast cancer stem cells. In this study, we tested the ability of liposomal delivery of miR-203 to reverse aspects of breast cancer pathogenesis using breast cancer and EMT cell lines. We show that translationally relevant methods for increasing miR-203 abundance within a target tissue affects cellular properties associated with cancer progression. While stable miR-203 expression suppresses LASP1 and survivin, nanoliposomal delivery suppresses BMI1, indicating that suppression of distinct mRNA target profiles can lead to loss of cancer cell migration.

Physical, chemical, and toxicological characterization of fibrillated forms of cellulose using an in vitro gastrointestinal digestion and co-culture model.

Fibrillated cellulose is a next-generation material in development for a variety of applications, including use in food and food-contact materials. An alternative testing strategy including simulated digestion was developed to compare the physical, chemical, and biological characteristics of seven different types of fibrillated cellulose, following European Food Safety Authority guidance. Fibrillated forms were compared to a conventional form of cellulose which has been used in food for over 85 years and has Generally Recognized as safe regulatory status in the USA. The physical and chemical characterization of fibrillated celluloses demonstrate that these materials are similar physically and chemically, which composed of the same fundamental molecular structure and exhibit similar morphology, size, size distribution, surface charge, and low levels of impurities. Simulated gastrointestinal and lysosomal digestions demonstrate that these physical and chemical similarities remain following exposure to conditions that mimic the gastrointestinal tract or intracellular lysosomes. A toxicological investigation with an advanced intestinal co-culture model found that exposure to each of the fibrillated and conventional forms of cellulose, in either the pristine or digested form at 0.4% by weight, showed no adverse toxicological effects including cytotoxicity, barrier integrity, oxidative stress, or inflammation. The results demonstrate the physical, chemical, and biological similarities of these materials and provide substantive evidence to support their grouping and ability to read-across data as part of a food safety demonstration.