Suppression of T Lymphocyte Proliferation to Antigenic and Mitogenic Stimuli by Benzo(α)pyrene and 2-Aminofluorene Metabolites

Lee, Mark E.; Urso, Paul

doi:10.1080/08923970701675069

Cited by 6 publications

(4 citation statements)

References 28 publications

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“…Although these limitations preclude the use of epidemiological studies in this analysis to obtain a better mechanistic understanding of the immunotoxicity of BaP, they do provide evidence that the immunotoxic effects observed in animals might also occur in humans. 36 Galvan et al 37,38 Allan et al 39 Blanton et al 40 De Jong et al 41 Holladay and Smith 42 Belitskaya-Levy et al 43 Carfi et al 44 Fang and Zhang 45 N'Jai et al 46 Carfi et al 44 Fujimaki et al 47 Halappanavar et al 48 Schellenberger et al 49 Davila et al 50 Hardin et al 51 Labib et al 52 Wojdani and Alfred 53 Dreij et al 54 Hwang et al 55 Kroese et al 56 Wojdani et al 57 Gao et al 58 Kawabata and White 59 Nebert et al 60,61 Developmental Krieger et al 62,63 Lee and Urso 64 Robinson et al 65 Lummus and Henningsen 66 Laupeze et al 67 Legraverend et al 68 Sagredo et al 69 Rodriguez et al 70 Lecureur et al 71 Lyte and Bick 72,73 Silkworth et al 74 Urso 75 Monteiro et al 76 Lyte et al 77 Shi et al 78 Urso and Johnson 79 Mounho et al 80<...>…”

Section: Plausibility Of Pah Immune Suppression In Humansmentioning

confidence: 99%

Using Immunotoxicity Information to Improve Cancer Risk Assessment for Polycyclic Aromatic Hydrocarbon Mixtures

Zaccaria

McClure

2013

Int J Toxicol

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Estimating cancer risk from environmental mixtures containing polycyclic aromatic hydrocarbons (PAHs) is challenging. Ideally, each mixture would undergo toxicity testing to derive a cancer slope factor (CSF) for use in site-specific cancer risk assessments. However, this whole mixture approach is extremely costly in terms of finances, time, and animal usage. Alternatively, if an untested mixture is "sufficiently similar" to a well-characterized mixture with a CSF, the "surrogate" CSF can be used in risk assessments. We propose that similarity between 2 mixtures could be established using an in vitro battery of genotoxic and nongenotoxic tests. An observed association between carcinogenicity and immunosuppression of PAHs suggests that the addition of immune suppression assays may improve this battery. First, using published studies of benzo[a]pyrene (BaP) and other PAHs, we demonstrated a correlation between the derived immune suppression relative potency factors (RPFs) for 9 PAHs and their respective cancer RPFs, confirming observations published previously. Second, we constructed an integrated knowledge map for immune suppression by BaP based on the available mechanistic information. The map illustrates the mechanistic complexities involved in BaP immunosuppression, suggesting that multiple in vitro tests of immune suppression involving different processes, cell types, and tissues will have greater predictive value for immune suppression in vivo than a single test. Based on these observations, research strategies are recommended to validate a battery of in vitro immune suppression tests that, along with tests for genotoxic and other nongenotoxic modes of cancer action, could be used to establish "sufficient similarity" of 2 mixtures for site-specific cancer risk assessments.

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Section: Plausibility Of Pah Immune Suppression In Humansmentioning

confidence: 99%

Using Immunotoxicity Information to Improve Cancer Risk Assessment for Polycyclic Aromatic Hydrocarbon Mixtures

Zaccaria

McClure

2013

Int J Toxicol

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“…However, a minor fraction of B[a]P is converted to B[a]P‐7,8‐dihydrodiol‐9, 10‐epoxide, which is highly reactive and carcinogenic. This metabolic pathway is mediated by the cytochrome P450 enzyme CYPIA1, also known as aryl hydrocarbon hydroxylase . Apart from its carcinogenic role, B[a]P is also known for its immunotoxicity …”

Section: Discussionmentioning

confidence: 99%

Differential response of T cells to an immunogen, a mitogen and a chemical carcinogen in a mouse model system

Kaur

Saxena

Chandra

2019

J Biochem & Molecular Tox

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In this study, we examined the relative immune response of T-lymphocytes and its intracellular cholesterol homeostasis, in a mouse model system, after treatment with immunogen, mitogen, and carcinogen. We studied the T-lymphocyte percentage, their LDL-receptor expression, along with the levels of serum interleukins (IL-2, IFNγ, IL-4, and IL-10) and intracellular cholesterol concentration (cytoplasmic and nuclear). The mitogen was found to be a better stimulator of T-cell marker expressions than the immunogen; though the immunogen was more effective on immunogenic response as was marked from interleukin levels. The chemical carcinogen benzo-α-pyrene at low concentration acted potentially like a mitogen but a reduced immune response was apparent at a carcinogenic dose.The findings in our study focus on the effect of carcinogenic dose of benzo-α-pyrene (BaP) on T-cell immunity. Benzo-α-pyrene causes immunosuppression through restriction of the T-cell population by targeting intracellular cholesterol. K E Y W O R D S benzo-alpha-pyrene, cholesterol, cytokines, LDL receptor, pokeweed mitogen, T cells, tetanus toxoid J Biochem Mol Toxicol. 2019;33:e22290.wileyonlinelibrary.com/journal/jbt Differential response of T cells to an immunogen, a mitogen and a chemical carcinogen in a mouse model system.

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“…The metabolic progression of B(α)P toward carcinogenicity is a function of the BPDE-DNA complex (Luch 2005), and it seemed plausible that this complex is responsible for immunosuppression. However, we found that most of the intermediate metabolites of B(α)P are immunosuppressive (Lee and Urso 2007) and that BPDE-DNA is only partly involved in and not completely responsible for immunosuppression (MoolenaarWirsiy et al 2007). Thus, we hypothesize that thirdparty entities play a decisive role in contributing to immunosuppression.…”

Section: Introductionmentioning

confidence: 94%

“…The most studied PAH, as well as perhaps the strongest carcinogen, is benzo(α)pyrene [B(α)P], a ubiquitous environmental pollutant that is found in such sources as commercial (automobile exhausts; Grimmer and Pott 1983); domestic (cigarette smoke ;Hecht 1999;Phillips 2002), and industry (foundry workers; Santella et al 1993). When this carcinogen enters into a mammalian organism, it is metabolized by the P450 enzyme system to several carcinogenic metabolic intermediates that are immunosuppressive (Lee and Urso 2007). The metabolic progression of B(α)P toward carcinogenicity is a function of the BPDE-DNA complex (Luch 2005), and it seemed plausible that this complex is responsible for immunosuppression.…”

Section: Introductionmentioning

confidence: 98%

The role of adherent cells in the immunosuppressed state of mouse progeny transplacentally exposed to benzo(α)pyrene

Urso

Kramer

2008

In Vitro Cell.Dev.Biol.-Animal

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In recent studies, we showed that murine fetal liver cells from progeny exposed to benzo(alpha)pyrene in utero by intraperitoneal injection of the dam at midpregnancy (12 d) suppressed cell proliferation in an allogeneic mixed lymphocyte response. On the other hand, fetal liver cells from the corn oil (vehicle for the carcinogen)-exposed progeny (control) appeared to enhance proliferation. Suppression or enhancement appeared to be mediated by fetal liver bearing CD8+ and Lyt 1+ (CD5+) cells. Despite these manifestations, the role of third-party cells needs to be considered. As a first premise, adherent cells were targeted as possible third-party cells. To test the role of the adherent cells, liver cells from benzo(alpha)pyrene-exposed fetuses were treated with ficoll-hypaque, and the interface cells were fractionated through glass wool or nylon wool. It is known that adhering cells, macrophages and B cells, readily attach to glass or nylon wool. The effluent cells and the adherent cells were cultured with syngeneic responder cells and allogeneic stimulator cells in a mixed lymphocyte response. The results showed that benzo(alpha)pyrene-effluent cells led to the enhancement of proliferation in the mixed lymphocyte response, while benzo(alpha)pyrene-adherent cells led to suppression. The effluent and adherent cells of corn oil controls did not modify cell proliferation in the mixed lymphocyte response. These data suggest that a third-party cell, reasonably the macrophage or possibly B cells or both, since these are adherent cells, play a decided role in mediating suppression in the benzo(alpha)pyrene-exposed progeny.

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Suppression of T Lymphocyte Proliferation to Antigenic and Mitogenic Stimuli by Benzo(α)pyrene and 2-Aminofluorene Metabolites

Cited by 6 publications

References 28 publications

Using Immunotoxicity Information to Improve Cancer Risk Assessment for Polycyclic Aromatic Hydrocarbon Mixtures

Using Immunotoxicity Information to Improve Cancer Risk Assessment for Polycyclic Aromatic Hydrocarbon Mixtures

Differential response of T cells to an immunogen, a mitogen and a chemical carcinogen in a mouse model system

The role of adherent cells in the immunosuppressed state of mouse progeny transplacentally exposed to benzo(α)pyrene

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