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A polycyclic aromatic hydrocarbon-enriched environmental chemical mixture enhances AhR, antiapoptotic signaling and a proliferative phenotype in breast cancer cells.

ABSTRACT: Emerging evidence suggests the role of environmental chemicals, in particular endocrine-disrupting chemicals (EDCs), in progression of breast cancer and treatment resistance, which can impact survival outcomes. However, most research tends to focus on tumor etiology and the effect of single chemicals, offering little insight into the effects of realistic complex mixture exposures on tumor progression. Herein, we investigated the effect of a polycyclic aromatic hydrocarbon (PAH)-enriched EDC mixture in a panel of normal and breast cancer cells and in a tumor organoid model. Cells or organoids in culture were treated with EDC mixture at doses estimated from US adult intake of the top four PAH compounds within the mixture from the National Health and Nutrition Examination Survey database. We demonstrate that low-dose PAH mixture (6, 30 and 300 nM) increased aryl hydrocarbon receptor (AhR) expression and CYP activity in estrogen receptor (ER) positive but not normal mammary or ER-negative breast cancer cells, and that upregulated AhR signaling corresponded with increased cell proliferation and expression of antiapoptotic and antioxidant proteins XIAP and SOD1. We employed a mathematical model to validate PAH-mediated increases in AhR and XIAP expression in the MCF-7 ER-positive cell line. Furthermore, the PAH mixture caused significant growth increases in ER-negative breast cancer cell derived 3D tumor organoids, providing further evidence for the role of a natural-derived PAH mixture in enhancing a tumor proliferative phenotype. Together, our integrated cell signaling, computational and phenotype analysis reveals the underlying mechanisms of EDC mixtures in breast cancer progression and survival.

SUBMITTER: Gearhart-Serna LM

PROVIDER: S-EPMC7791619 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNowadays, effects of fine particulate matter (PM2.5) are well-documented and related to oxidative stress and pro-inflammatory response. Nevertheless, epidemiological studies show that PM2.5 exposure is correlated with an increase of pulmonary cancers and the remodeling of the airway epithelium involving the regulation of cell death processes. Here, we investigated the components of Parisian PM2.5 involved in either the induction or the inhibition of cell death quantified by different parameters of apoptosis and delineated the mechanism underlying this effect.ResultsIn this study, we showed that low levels of Parisian PM2.5 are not cytotoxic for three different cell lines and primary cultures of human bronchial epithelial cells. Conversely, a 4 hour-pretreatment with PM2.5 prevent mitochondria-driven apoptosis triggered by broad spectrum inducers (A23187, staurosporine and oligomycin) by reducing the mitochondrial transmembrane potential loss, the subsequent ROS production, phosphatidylserine externalization, plasma membrane permeabilization and typical morphological outcomes (cell size decrease, massive chromatin and nuclear condensation, formation of apoptotic bodies). The use of recombinant EGF and specific inhibitor led us to rule out the involvement of the classical EGFR signaling pathway as well as the proinflammatory cytokines secretion. Experiments performed with different compounds of PM2.5 suggest that endotoxins as well as carbon black do not participate to the antiapoptotic effect of PM2.5. Instead, the water-soluble fraction, washed particles and organic compounds such as polycyclic aromatic hydrocarbons (PAH) could mimic this antiapoptotic activity. Finally, the activation or silencing of the aryl hydrocarbon receptor (AhR) showed that it is involved into the molecular mechanism of the antiapoptotic effect of PM2.5 at the mitochondrial checkpoint of apoptosis.ConclusionsThe PM2.5-antiapoptotic effect in addition to the well-documented inflammatory response might explain the maintenance of a prolonged inflammation state induced after pollution exposure and might delay repair processes of injured tissues.

Project description:Relative importance of multiple indoor and outdoor venues on personal exposure concentrations to pro-carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) remains poorly understood. This is particularly challenging because many c-PAHs share sources and occur as a complex mixture. Accurate and precise apportionment of personal exposure according to exposure venues could aid in the understanding of human health effects due to a given source. Here, we partitioned indoor and personal exposure concentrations to seven c-PAHs and pyrene according to the indoor- and outdoor-origins.A simultaneous, integrated monitoring of personal, indoor and outdoor concentrations of nine PAHs was conducted in 75 homes for a consecutive 48-hour period across a two-year period in Kraków, Poland. Due to few known indoor sources for chrysene, we used this PAH species as a tracer for infiltration of outdoor PAHs. Personal and indoor concentrations of seven c-PAHs and pyrene were apportioned to home indoor, non-home indoor and outdoor origins.Using Chrysenein/Chryseneout as proxy for an infiltration factor, Finf, infiltrated PAHs of outdoor origin are overall higher in concentration than those emitted from the indoor origin. Average contribution by the outdoor sources on B[a]A, B[b]F, and B[k]F were 92%, 79%, and 78% across all seasons, respectively. In contrast, in homes where a household member smoked, average contributions by the outdoor sources on B[ghi]P, B[a]P, D[ah]A, and IP were lower (i.e., 67%, 65%, 67%, and 66%, respectively). Season-averaged contributions by the outdoor sources on personal exposure to B[a]A, B[b]F, and B[k]F were 92%, 74%, and 77%, respectively. On the other hand, season-averaged home indoor source contributions on personal exposure to B[a]A, B[b]F, and B[k]F were estimated at 6%, 15%, and 19%, respectively. Similar contributions by season-averaged home indoor sources on personal exposure were estimated at 28% for B[ghi]P, 31% for B[a]P, 25% for D[ah]A, and 28% for IP.Of the seven c-PAHs, B[a]A, B[b]F, and B[k]F are enriched in indoor and personal exposure concentrations from the outdoor coal-combustion. B[ghi]P, B[a]P, D[a,h]A, and IP, PAHs with some of the highest carcinogenic and mutagenic potencies, are considerably enriched by cigarette smoke in addition to the outdoor sources.

Project description:Historic industrial pollution of the Elizabeth River, Virginia resulted in polycyclic aromatic hydrocarbon (PAH) contamination in sediments. Atlantic killifish (Fundulus heteroclitus) inhabiting the Atlantic Wood (AW) industrial site adapted to complex PAH mixture at this Superfund site. Their embryos have proved highly resistant to cardiac abnormalities indicative of PAH toxicity. In this study, embryos spawned from adults collected at AW and King's Creek (KC), a reference site, were exposed at 24 h post fertilization (hpf) to Elizabeth River Sediment Extract (ERSE), a complex PAH mixture, in a range of concentrations (0, 5.04, 50.45, 100.90, 151.35, or 252.25 µg/L total PAHs). Embryos were processed for histology at 144 hpf to enable evaluations of hearts at tissue and cellular levels. Morphometry and severity scoring were used to evaluate the extent of alterations. Unexposed embryos were similar in both populations. ERSE exposure resulted in multiple changes to hearts of KC embryos but not AW. Alterations were particularly evident in KC embryos exposed to concentrations above 1% ERSE (50.45 µg/L), which had thinner ventricular walls and larger pericardial edema. Individuals with moderate pericardial edema maintained arrangement and proximity of heart chambers, but changes were seen in ventricular myocytes. Severe pericardial edema was prevalent in exposed KC embryos and typically resulted in tube heart formation. Ventricles of tube hearts had very thin walls composed of small, basophilic cells and lacked trabeculae. Edematous pericardial fluid contained small amounts of proteinaceous material, as did controls, and was free of cells. This fluid was primarily unstained, suggesting water influx due to increased permeability. The use of histological approaches provided more specific detail for tissue and cellular effects in hearts of embryos exposed to PAHs and enabled understanding of potential links to later life effects of early life exposure.

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A polycyclic aromatic hydrocarbon-enriched environmental chemical mixture enhances AhR, antiapoptotic signaling and a proliferative phenotype in breast cancer cells.

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