To assess the effectiveness of selected food phytochemicals in reducing the toxic effects of the environmental toxicants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and p,p′-DDT (DDT), we tested the potencies of auraptene, nobiletin, zerumbone, and (±)-13-hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA) in reversing the inflammatory action of these toxicants in U937 human macrophages. Using quantitative RT–PCR as the initial screening assay, we identified antagonistic actions of zerumbone and auraptene against the action of TCDD and DDT in up-regulating the mRNA expressions of COX-2 and VEGF. The functional significance of the inhibitory action of zerumbone on COX-2 expression was confirmed by demonstrating its suppression of TCDD-induced activation of COX-2 gene expression in mouse MMDD1 cells. We tested auraptene on DDT-induced reactive oxygen species (ROS) formation in U937 macrophages and found that auraptene is a powerful agent antagonizing this action of DDT. To confirm the significance of these actions of zerumbone and auraptene at the cellular level, we assessed their influence on TCDD-induced apoptosis resistance in intact U937 macrophages and found that they are capable of reversing this action of TCDD. In conclusion, zerumbone and auraptene were identified to be the most effective agents in protecting U937 macrophages from developing these cell toxic effects of TCDD and DDT.

Abstract: Introduction: While previous studies propose pesticide exposure to be a risk factor for non-Hodgkin lymphoma (NHL) development, results are inconclusive. In addition, the impact of pesticide exposure on NHL survival is not well-established. Therefore, we identified NHL patients from the California Cancer Registry and linked these patients with the statewide pesticide use reporting database to determine the impact of pesticide exposure on NHL-related incidence and outcomes. Methods: Using the California Cancer Registry, we identified patients with a first primary diagnosis of NHL from 2010-2016 and linked these patients with CalEnviroScreen 3.0 to obtain production agriculture pesticide exposure to 70 chemicals from the state mandated Pesticide Use Reporting (PUR) by census tract from 2012-2014. In addition, data from PUR was integrated into a geographic information system that employs land use data to estimate cumulative exposure to specific pesticides previously associated with NHL (glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4-dimethylamine salt) between 10 years prior up to 1 year after NHL diagnosis. SEER*Stat software was used to calculate NHL subtype incidence rates by census tract pesticide use level. Multivariable cox proportional hazards regression models were used to evaluate the impact of total pesticide exposure from CalEnviroScreen 3.0 and individual pesticide exposure from geographic land use data on lymphoma-specific and overall survival. Results: Among 35,808 NHL patients identified, 44.2% were exposed to pesticide in their census tract of residence. Pesticide exposure was higher in Hispanic/Latino (46.5%) and non-Hispanic white (45.6%) then Asian/Pacific Islander (37.2%) and African American (34.9%) patients with NHL. Glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4-dimethylamine salt exposure was reported in 34.1%, 26.0%, 10.6%, 14.0% and 12.8% of NHL patients, respectively. Pesticide exposure was not associated with increased NHL incidence by NHL subtype or subgroups defined by sociodemographic factors. Total pesticide exposure at time of diagnosis was not associated with lymphoma-specific or overall survival. In addition, no association was consistently found between glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4 dimethylamine salt exposure and lymphoma-specific or overall survival. Conclusion: In this large population-based study of neighborhood agricultural pesticide exposure, pesticide exposure was noted to be prevalent among patients diagnosed with NHL, with high pesticide exposure particularly observed in Hispanics/Latinos and non-Hispanic whites. However, pesticide exposure was not consistently associated with increased NHL incidence or worse NHL lymphoma-specific or overall survival. Disclosures: Poh: Acrotech: Honoraria; Incyte: Research Funding; Morphosys: Consultancy. Tuscano: BMS: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding.

Abstract Background Urban particulate matter (PM) has been epidemiologically correlated with multiple cardiopulmonary morbidities and mortalities, in sensitive populations. Children exposed to PM are more likely to develop respiratory infections and asthma. Although PM originates from natural and anthropogenic sources, vehicle exhaust rich in polycyclic aromatic hydrocarbons (PAH) can be a dominant contributor to the PM2.5 and PM0.1 fractions and has been implicated in the generation of reactive oxygen species (ROS). Objectives Current studies of ambient PM are confounded by the variable nature of PM, so we utilized a previously characterized ethylene-combusted premixed flame particles (PFP) with consistent and reproducible physiochemical properties and 1) measured the oxidative potential of PFP compared to ambient PM, 2) determined the ability of PFPs to generate oxidative stress and activate the transcription factor using in vitro and ex vivo models, and 3) we correlated these responses with antioxidant enzyme expression in vivo. Methods We compared oxidative stress response (HMOX1) and antioxidant enzyme (SOD1, SOD2, CAT, and PRDX6) expression in vivo by performing a time-course study in 7-day old neonatal and young adult rats exposed to a single 6-hour exposure to 22.4 μg/m3 PFPs. Results We showed that PFP is a potent ROS generator that induces oxidative stress and activates Nrf2. Induction of the oxidative stress responsive enzyme HMOX1 in vitro was mediated through Nrf2 activation and was variably upregulated in both ages. Furthermore, antioxidant enzyme expression had age and lung compartment variations post exposure. Of particular interest was SOD1, which had mRNA and protein upregulation in adult parenchyma, but lacked a similar response in neonates. Conclusions We conclude that PFPs are effective ROS generators, comparable to urban ambient PM2.5, that induce oxidative stress in neonatal and adult rat lungs. PFPs upregulate a select set of antioxidant enzymes in young adult animals, that are unaffected in neonates. We conclude that the inability of neonatal animals to upregulate the antioxidant response may, in part, explain enhanced their susceptibility to ultrafine particles, such as PFP.

Abstract Background The purpose of the present study was to investigate activation of inflammatory markers in human macrophages derived from the U937 cell line after exposure to particulate matter (PM) collected on dairy farms in California and to identify the most potent components of the PM. Methods PM from different dairies were collected and tested to induce an inflammatory response determined by the expression of various pro-inflammatory genes, such as Interleukin (IL)-8, in U937 derived macrophages. Gel shift and luciferase reporter assays were performed to examine the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Toll-like-receptor 4 (TLR4). Results Macrophage exposure to PM derived from dairy farms significantly activated expression of pro-inflammatory genes, including IL-8, cyclooxygenase 2 and Tumor necrosis factor-alpha, which are hallmarks of inflammation. Acute phase proteins, such as serum amyloid A and IL-6, were also significantly upregulated in macrophages treated with PM from dairies. Coarse PM fractions demonstrated more pro-inflammatory activity on an equal-dose basis than fine PM. Urban PM collected from the same region as the dairy farms was associated with a lower concentration of endotoxin and produced significantly less IL-8 expression compared to PM collected on the dairy farms. Conclusion The present study provides evidence that the endotoxin components of the particles collected on dairies play a major role in mediating an inflammatory response through activation of TLR4 and NF-κB signaling.