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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online February 6, 2006 as doi:10.1096/fj.05-4860fje. |
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* Sección Externa de Toxicología, CINVESTAV, San Pedro Zacatenco, México City, México;
Instituto Nacional de Salud Pública, Cuernavaca, Morelos, México; and
Jurisdicción Sanitaria 5, Secretaría de Salubridad y Asistencia, Zimapán, Hidalgo, México
1Correspondence: Sección Externa de Toxicología, CINVESTAV, Av. IPN 2508, San Pedro Zacatenco, México D. F. 07360, México. E-mail: lvega{at}cinvestav.mx
SPECIFIC AIMS
Human populations environmentally exposed to arsenic present high incidence of bladder, kidney, liver, and skin cancer. Arsenic exposure in mice inhibits T cell proliferation and macrophage activity, decreases CD4+ splenic cells number, and down-regulates contact hypersensitivity response to DNFB. Arsenic can produce inhibition as well as induction of proliferative responses depending on the doses, and an inhibition of IL-2 secretion in human lymphocytes in vitro. Arsenic inhibits lymphocyte proliferation in response to phytohemaglutinin (PHA) stimulus in adult human populations exposed to 412 µg/L of arsenic in drinking water. In 1997, Armienta et al. reported high levels of arsenic in the drinking water of the Zimapán community in the Mexican State of Hidalgo (0.014 to 1.09 mg/L of arsenic in drinking groundwater). Arsenic exposure increases the incidence of autoimmune-mediated diseases such as diabetes mellitus and other diseases related with immunosuppression such as the presence of skin cancer similar to that induced in immunosuppressed populations as a result of organ transplantation or HIV infection. Since the integrity of the immune system is necessary to guarantee an adequate immunosurveillance against tumor cells and response to infectious agents, the aim of the present study was to determine the toxic effects of arsenic exposure on the immune system of children.
PRINCIPAL FINDINGS
1. Ninety children aged 6–10 years (38 girls, 52 boys) comprised the studied population
No association was found between arsenic levels and exposure to other xenobiotics (P=0.346) with socioeconomic status (P=0.678) or age (P=0.345). We found a marginally significant (P=0.055) increase in the incidence of asthma, allergies, and parasitic infections on individuals with high arsenic levels in urine compared with individuals with arsenic levels lower than the reference value in urine (50 µg/L).
2. The main metabolite of arsenic excreted was dimethylarsenic (DMA, 74%), while the monomethylated (MMA) and the inorganic arsenic (iAs) showed lower excretion proportions: 15.5 and 10.5%, respectively
The proportional distribution of arsenic metabolites in the urine was not statistically different among boys and girls (P=0.815), indicating no alterations in the metabolism and excretion of arsenic.
3. Peripheral blood mononuclear cells subpopulations were evaluated by flow cytometry using direct fluorescent marked antibodies
Relative proportion of total T cells, Tc, B, or NK cells in fresh blood samples were not affected by arsenic exposure (P>0.1, Fig. 1
). We found a marginal decrease in Th cells and in Th/Tc ratio related with high concentrations of arsenic.
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4. Proliferative response of peripheral blood mononucleated cells (PBMC) to PHA, as determined by tritiated thymidine incorporation after 48 h of culture, was significantly decreased in association with an increase on arsenic concentration (Fig. 2 A)
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5. ELISA-sandwich of cytokines performed on supernatants recovered from cultured PBMC after 24 h of PHA activation showed that secretion of IL-2 was statistically significant reduced related with increasing concentration of arsenic (Fig. 2B )
The reduction on cell proliferation and IL-2 secretion were not associated (P=0.368), indicating that thereduction on IL-2 secretion was independent of cell proliferation.
6. Levels of IL-4, IL-10, and IFN-
secretion by PHA-activated PBMC were not associated with arsenic concentration (P> 0.1)
7. Secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) by LPS/IFN--stimulated macrophages was increased in association with increased arsenic concentration (Fig. 2F
)
CONCLUSIONS AND SIGNIFICANCE
Mean total arsenic concentration in urine from exposed individuals was 
4-fold higher than that considered acceptable for nonoccupational exposure in humans.
It has been reported that arsenic exposure can produce Bowen’s disease, where Hayashi et al. reported that Th/Tc cells ratio was decreased in adults with this disease. Moreover, a similar decrease in Th/Tc ratio as the one found in these children has been reported in Kaposi’s sarcoma, melanoma, skin carcinoma, and HIV patients. None of the individuals of this study with arsenic levels in urine above 150 µg/g creatinine had a Th/Tc ratio superior to 2. It is very suggestive that the change in Th/Tc cells ratio could be indicative of immunodepression and that this immunodepression precedes the clinical manifestation of typical skin alterations caused by arsenic exposure. Therefore, we suggest that Th/Tc cells ratio could be used as an early marker of effect, or even susceptibility to arsenic effects.
Arsenic exposure inhibited T lymphocytes proliferative response to PHA, as reported in adult human populations or in vitro studies. It also decreased IL-2 secretion as previously reported. The proportional relation between proliferation and IL-2 secretion indicates that IL-2 inhibition is not due to an inhibition on cell proliferation.
In addition to the T lymphocytes, another cell type that is important when an adequate immune response is activated is the monocytes (peripheral undifferentiated macrophages). These cells secrete cytokines that are related to the maturation, recruitment, and activation of other vicinal cells. One such factor is GM-CSF. It has been shown that GM-CSF plays an important role in cancer induction by arsenic exposure. We observed an increase on GM-CSF secretion of LPS/IFN- activated macrophages that was related with an increase in arsenic concentrations in the urine of the individuals. This observation agrees with previous reports on arsenic-treated human keratinocytes, where the authors find an increased transcription and secretion of GM-CSF. GM-CSF has been implicated in tumor promotion via mediating inflammatory cell influx and increasing dark cell numbers in mouse skin. Increased expression of GM-SCF has been shown in many skin diseases. Other studies have shown increased GM-CSF mRNA expression in lesion and lesion-free psoriatic skin, as well as in skin from patients with atopic dermatitis. These data indicate that elevated levels of GM-CSF may serve as an early biomarker for skin diseases associated with arsenic exposure.
Although interesting findings are reported here, the study presents certain limitations since the original design did not consider individuals with chronic diseases. Now that it has been established that arsenic exposure is related to an immunodepressed status, it is important to maintain an epidemiological surveillance of these populations exposed to arsenic to find a relation between arsenic exposure and the incidence of certain opportunistic diseases (those most related with immunodepression status), as well as chronic infections incidence.
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FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-4860fje;
This article has been cited by other articles:
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A. Lemarie, C. Morzadec, E. Bourdonnay, O. Fardel, and L. Vernhet Human macrophages constitute targets for immunotoxic inorganic arsenic. J. Immunol., September 1, 2006; 177(5): 3019 - 3027. [Abstract] [Full Text] [PDF]
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