Gene expression of inflammatory molecules in circulating lymphocytes from arsenic-exposed human subjects.

Wu, Meei-Maan; Chiou, Hung Yi; Ho, Ing-Kang; Chen, Chien-Jen; Lee, Te‐Chang

doi:10.1289/ehp.6396

Cited by 202 publications

(119 citation statements)

References 68 publications

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“…The present study was therefore designed to investigate effects of As 2 O 3 on NADPH-oxidase expression and activity in human primary macrophages. Our results demonstrate that low micromolar concentrations of As 2 O 3 (0.5-1 M), in the range of iAs blood levels measured in chronically exposed humans (10 -60 g/l) (22,23), induced phosphorylation and membrane translocation of p47 phox and subsequent ROS formation through a ROCK/p38-kinase pathway. In addition, we show that NADPH oxidase-derived ROS were likely involved in metalloid-induced secretion of the chemokine CCL18, but not in As 2 O 3 -triggered morphological changes due to actin cytoskeleton reorganization.…”

Section: Norganic Arsenic (Ias)mentioning

confidence: 55%

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Lemarié

Bourdonnay

Morzadec

et al. 2008

The Journal of Immunology

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Inorganic arsenic is an immunotoxic environmental contaminant to which millions of humans are chronically exposed. We recently demonstrated that human primary macrophages constituted a critical target for arsenic trioxide (As2O3), an inorganic trivalent form. To specify the effects of arsenic on macrophage phenotype, we investigated in the present study whether As2O3 could regulate the activity of NADPH oxidase, a major superoxide-generating enzymatic system in human phagocytes. Our results show that superoxide levels were significantly increased in a time-dependent manner in blood monocyte-derived macrophages treated with 1 μM As2O3 for 72 h. Concomitantly, As2O3 induced phosphorylation and membrane translocation of the NADPH oxidase subunit p47phox and it also increased translocation of Rac1 and p67phox. Apocynin, a selective inhibitor of NADPH oxidases, prevented both p47phox translocation and superoxide production. NADPH oxidase activation was preceded by phosphorylation of p38-kinase in As2O3-treated macrophages. The p38-kinase inhibitor SB-203580 prevented phosphorylation and translocation of p47phox and subsequent superoxide production. Pretreatment of macrophages with the Rho-kinase inhibitor Y-27632 was found to mimic inhibitory effects of SB-203580 and to prevent As2O3-induced phosphorylation of p38 kinase. Treatment with As2O3 also resulted in an increased secretion of the proinflammatory chemokine CCL18 that was fully inhibited by both apocynin and SB-203580. Taken together, our results demonstrate that As2O3 induced a marked activation of NADPH oxidase in human macrophages, likely through stimulation of a Rho-kinase/p38-kinase pathway, and which may contribute to some of the deleterious effects of inorganic arsenic on macrophage phenotype.

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Section: Norganic Arsenic (Ias)mentioning

confidence: 55%

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Lemarié

Bourdonnay

Morzadec

et al. 2008

The Journal of Immunology

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“…This could have contributed to the decreased efficacy of in vivo antimonials in our model because part of their mode of action is driven by the immune system (28). However, the current literature is sporadic and can be contradictory (31,32), so no concrete conclusions can be drawn without further work in this area. Moreover, it cannot explain the parasite resistance observed in vitro in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis

Perry

Wyllie

Raab

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Bihar, India, is the only region where arsenic contamination of drinking water coexists alongside endemic visceral leishmaniasis and where widespread resistance to pentavalent antimonial drugs (e.g., Pentostam) occurs. We have proposed that selection for parasite resistance in infected individuals exposed to environmental arsenic results in cross-resistance to the related metalloid antimony. To test this hypothesis, we have serially passaged Leishmania donovani in mice receiving arsenic in drinking water at environmentally relevant levels. In support of this hypothesis, we show that after five monthly passages, Leishmania parasites become stably resistant to Pentostam in vitro and in vivo.

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“…Furthermore, increased arsenic exposure is associated with decreased proliferative response to mitogen (phytohemagutinin) stimulation in CD4+ cells. Patients with arsenic-induced skin cancer showed increased gene expression of inflammatory molecules, such as IL-1b, IL-6, CD14, C-C and C-X-C chemokine motif ligand [104]. Impaired delayed-type hypersensitivity response to 2,4-dinitrochlorobenzene was observed in patients with As-BD.…”

Section: Immunological Dysfunction In Arsenic-induced Skin Cancermentioning

confidence: 99%

Arsenic Carcinogenesis in the Skin

2006

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SummaryChronic arsenic poisoning is a world public health issue. Long-term exposure to inorganic arsenic (As) from drinking water has been documented to induce cancers in lung, urinary bladder, kidney, liver and skin in a dose-response relationship. Oxidative stress, chromosomal abnormality and altered growth factors are possible modes of action in arsenic carcinogenesis. Arsenic tends to accumulate in the skin. Skin hyperpigmentation and hyperkeratosis have long been known to be the hallmark signs of chronic As exposure. There are significant associations between these dermatological lesions and risk of skin cancer. The most common arsenic-induced skin cancers are Bowen's disease (carcinoma in situ), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Arsenic-induced Bowen's disease (As-BD) is able to transform into invasive BCC and SCC. Individuals with As-BD are considered for more aggressive cancer screening in the lung and urinary bladder. As-BD provides an excellent model for studying the early stages of chemical carcinogenesis in human beings. Arsenic exposure is associated with G2/M cell cycle arrest and DNA aneuploidy in both cultured keratinocytes and As-BD lesions. These cellular abnormalities relate to the p53 dysfunction induced by arsenic. The characteristic clinical figures of arsenic-induced skin cancer are: (i) occurrence on sun-protected areas of the body; (ii) multiple and recrudescent lesions. Both As and UVB are able to induce skin cancer. Arsenic treatment enhances the cytotoxicity, mutagenicity and clastogenicity of UV in mammalian cells. Both As and UVB induce apoptosis in keratinocytes by caspase-9 and caspase-8 signaling, respectively. Combined UVB and As treatments resulted in the antiproliferative and proapoptotic effects by stimulating both caspase pathways in the keratinocytes. UVB irradiation inhibited mutant p53 and ki-67 expression, as well as increased in the number of apoptotic cells in As-BD lesions which resulted in an inhibitory effect on proliferation. As-UVB interaction provides a reasonable explanation for the rare occurrences of arsenical cancer in the sun-exposed skin. The multiple and recurrent skin lesions are associated with cellular immune dysfunction in chronic arsenism. A decrease in peripheral CD4+ cells was noticed in the inhabitants of arsenic exposure areas. There was a decrease in the number of Langerhans cells in As-BD lesion which results in an impaired immune function on the lesional sites. Since CD4+ cells are the target cell affected by As, the interaction between CD4+ cells and epidermal keratinocytes under As affection might be closely linked to the pathogenesis of multiple occurrence of arsenic-induced skin cancer. In this

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Gene expression of inflammatory molecules in circulating lymphocytes from arsenic-exposed human subjects.

Cited by 202 publications

References 68 publications

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis

Arsenic Carcinogenesis in the Skin

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