Chlorella vulgaris (CV) was examined for its modulating effects on the reduction induced by lead (Pb) on the numbers of marrow hematopoietic stem cells (HSCs) (c-Kit +Lin -), granulocyte-macrophage progenitors (Gr1 +Mac1 +) and total bone marrow cellularity. In mice gavage-treated daily with 50mg/kg dose of CV for 10days, concomitant to a continuous offering of 1300ppm lead acetate in drinking water, the treatment with the algae recovered the significantly reduced numbers of these cell populations to control values. As CV may have a myelostimulating effect through the induction of cytokines, we evaluated its modulating effects on the production of IL-1α, TNF-α, IFN-γ, IL-10 and IL-6. Our results demonstrated that lead significantly impairs the production of IFN-γ, IL-1α and TNF-α and increases the production of IL-10 and IL-6 and that these effects are successfully modulated by the CV treatment. The activity of NK cells, reduced in Pb-exposed animals, was raised to levels higher than those of controls in the exposed group treated with CV. Treatment with the algae also stimulated the production of IFN-γ, IL-1α, TNF-α and NK cells activity in normal mice. In addition, zinc bone concentrations, reduced in lead-exposed mice, were partially, but significantly, reversed by the treatment with CV. © 2011 Elsevier Ltd.491129342941Apasheva, L.M., Gusareva, E.V., Kulinich, A.V., Study of the role of thiols in determining the radiosensitivity of various strains of Chlorella vulgaris (1972) Radiobiology, 12, pp. 904-906Barry, P.S., Letter: lead levels in blood (1975) Nature, 258, p. 775Bellinger, D.C., Lead (2004) Pediatrics, 113, pp. 1016-1022Bincoletto, C., Queiroz, M.L.S., The effect of lead on the bone marrow stem cells of mice infected with Listeria monocytogenes (1996) Vet. Hum. Toxicol., 38, pp. 186-190Bishayi, B., Sengupta, M., Synergism in immunotoxicology effects due to repeated combined administration of lead and arsenic in mice (2006) Int. Immunopharmacol., 6, pp. 454-464Blakley, B.K., Archer, D.L., Mitogen stimulation of lymphocytes exposed to lead (1982) Toxicol. Appl. Pharmacol., 62, pp. 183-189Brewer, G.J., Hill, G.M., Dick, R.D., Interactions of trace elements: clinical significance (1985) J. Am. Coll. Nutr., 4, pp. 33-38Cervi, L., MacDonald, A.S., Kane, C., Cutting edge: dendritic cells coupled with microbial and helminth antigens undergo modified maturation, segregate the antigens to distinct intracellular compartments, and concurrently induce microbe-specific Th1 and helminth-specific Th2 responses (2004) J. Immunol., 172, pp. 2016-2020Chen, S., Golemboski, K.A., Sanders, F.S., Persistent effect of in utero meso-2,3-dimercaptosuccinic acid (DMSA) on immune function and lead-induced immunotoxicity (1999) Toxicology, 132, pp. 67-79Choi, J.W., Kim, S.K., Association between blood lead concentrations and body iron status in children (2003) Arch. Dis. Child., 88, pp. 791-792Cobbett, C., Goldsbrough, P., Phytochelatins and metallothioneins: roles in heavy metal detoxification and homeostasis (2002) Annu. Rev. Plant Biol., 53, pp. 159-182Dantas, D.C.M., Queiroz, M.L.S., Effects of Chlorella vulgaris on bone marrow progenitor cells of mice infected with Listeria monocytogenes (1999) Int. J. Immunopharmacol., 21, pp. 499-508Dantas, D.C., Kaneno, R., Queiroz, M.L., The effects of Chlorella vulgaris in the protection of mice infected with Listeria monocytogenes. Role of natural killer cells (1999) Immunopharmacol. Immunotoxicol., 21, pp. 609-619Dietert, R.R., Piepenbrink, M.S., Lead and immune function (2006) Crit. Rev. Toxicol., 36, pp. 359-385Domen, J., Weissman, I.L., Self-renewal, differentiation or death: regulation and manipulation of hematopoietic stem cell fate (1999) Mol. Med. Today, 5, pp. 201-208Elenkov, I.J., Papanicolaou, D.A., Wilder, R.L., Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications (1996) Proc. Assoc. Am. Phys., 108, pp. 374-381Elenkov, I.J., Wilder, R.L., Chrousos, G.P., The sympathetic nerve-an integrative interface between two supersystems: the brain and the immune system (2000) Pharmacol. Rev., 52, pp. 595-638Faith, R.E., Luster, M.I., Kimmel, C.A., Effect of chronic developmental lead exposure on cell-mediated immune functions (1979) Clin. Exp. Immunol., 35, pp. 413-420Gurer, H., Ercal, N., Can antioxidants be beneficial in the treatment of lead poisoning? (2000) Free Radic. Biol. Med., 29, pp. 927-945Haeger-Aronsen, B., Schutz, A., Antagonistic effect in vivo of zinc on inhibition of delta-aminolevulinic acid dehydratase by lead (1976) Arch. Environ. Health, 31, pp. 215-220Hasegawa, T., Yohikai, Y., Okuda, M., Accelerated restoration of the leukocyte number and augmented resistance against Escherichia coli in cyclophosphamide-treated rats orally administered with a hot water extract of Chlorella vulgaris (1990) Int. J. Immunopharmacol., 12, pp. 883-891Hasegawa, T., Okuda, M., Nomoto, K., Augmentation of the resistance against Listeria monocytogenes by oral administration of a hot water extract of Chlorella vulgaris in mice (1994) Immunopharmacol. Immunotoxicol., 16, pp. 191-202Hasegawa, T., Kimura, Y., Hiromatsu, K., Effect of hot water extract of Chlorella vulgaris on cytokine expression patterns in mice with murine acquired immunodeficiency syndrome after infection with Listeria monocytogenes (1997) Immunopharmacology, 35, pp. 273-282Hasegawa, T., Noda, K., Kumamoto, S., Chlorella vulgaris culture supernatant (CVS) reduces psychological stress-induced apoptosis in thymocytes of mice (2000) Int. J. Immunopharmacol., 22, pp. 877-885Hemdan, N.Y.A., Emmrich, F., Adham, K., Dose-dependent modulation of the in vitro cytokine production of human immune competent cells by lead salts (2005) Toxicol. Sci., 86, pp. 75-83Heo, Y., Lee, W.T., Lawrence, D.A., Differential effects of lead and camp on development and activities of Th1- and Th2-lymphocytes (1998) Toxicol. Sci., 43, pp. 172-185Heyworth, C.M., Whetton, A.D., Nicholls, S.E., Stem cell factor directly stimulates the development of enriched granulocyte-macrophage colony-forming cells and promotes the effects of other colony-stimulating factors (1992) Blood, 80, pp. 2230-2236Horwitz, W., (2005) Official Methods of Analysis of the Association of Official Analytical Chemists, pp. 15-18. , AOAC, Gaithersburg, MarylandIbusuki, K., Minamishima, Y., Effects of Chlorella vulgaris extract on murine 659 cytomegalovirus infections (1990) Nat. Immun. Cell. Growth Regul., 9, pp. 121-128Jamieson, J.A., Taylor, C.G., Weiler, H.A., Marginal zinc deficiency exacerbates bone lead accumulation and high dietary zinc attenuates lead accumulation at the expense of bone density in growing rats (2006) Toxicol. Sci., 92, pp. 286-294Jarup, L., Hazards of heavy metal contamination (2003) Br. Med. Bull., 68, pp. 167-182Justo, G.Z., Silva, M.R., Queiroz, M.L.S., Effects of the Green algae Chlorella vulgaris on the response of the host hematopoietic system to intraperitoneal Ehrlich ascites tumor transplantation in mice (2001) Immunopharmacol. Immunotoxicol., 23, pp. 119-132Justo, G.Z., Durán, N., Queiroz, M.L., Natural killer cell activity, lymphocyte proliferation, and cytokine profile in tumor-bearing mice treated with MAPA, a magnesium aggregated polymer from Aspergillus oryzae (2003) Immunopharmacol. Immunotoxicol., 25, pp. 305-319Kim, S., Iizuka, K., Aguila, H.L., In vivo natural killer cell activities revealed by natural killer cell-deficient mice (2000) Proc. Natl. Acad. Sci. USA, 97, pp. 2731-2736King, L.E., Fraker, P.J., Zinc deficiency in mice alters myelopoiesis and hematopoiesis (2002) J. Nutr., 132, pp. 3301-3307Kishikawa, H., Song, R., Laurence, A., Interleukin-12 promoters enhanced resistance to Listeria monocytogenes infection of Pb-exposed mice (1997) Toxicol. Appl. Pharmacol., 147, pp. 180-189Konishi, F., Tanaka, K., Himeno, K., Antitumor effect induced by a hot water extract of Chlorella vulgaris (CE): resistance to meth A tumor growth mediated by CE-induced polymorphonuclear leukocytes (1985) Cancer Immunol. Immunother., 19, pp. 73-78Konishi, F., Tanaka, K., Kumamoto, S., Enhanced resistance against Escherichia coli infection by subcutaneous administration of the hot-water extract of Chlorella vulgaris in cyclophosphamide-treated mice (1990) Cancer Immunol. Immunother., 32, pp. 1-7Konishi, F., Mitsuyama, M., Okuda, M., Protective effect of an acidic glycoprotein obtained from culture of Chlorella vulgaris against myelossuppression by 5-fluorouracil (1996) Cancer Immunol. Immunother., 42, pp. 268-274Kowolenko, M., Tracy, L., Lawrence, D., Early effects of lead on bone marrow cells responsiveness in mice challenged with Listeria monocytogenes (1991) Fundam. Appl. Toxicol., 17, pp. 75-82Kumamoto, S., Ando, Y., Yamada, A., Oral administration of hot water extracts of Chlorella vulgaris reduces IgE production against milk casein in mice (1999) Int. J. Immunoparmacol., 21, pp. 311-323Larsson, J., Karlsson, S., The role of Smad signaling in hematopoiesis (2005) Oncogene, 24, pp. 5676-5692López, C.E., Castro, J.M., Gonzáles, V., Determination of metal ions in algal solution samples by capillary electrophoresis (1998) J. Chromatogr. Sci., 36, pp. 352-356Lyman, S.D., Jacobsen, S.E., C-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities (1998) Blood, 91, pp. 1101-1134McCabe, M.J., Singh, K.P., Reiners, J.J., Lead intoxication impairs the generation of a delayed type hypersensitivity response (1999) Toxicology, 139, pp. 255-264Misawa, E., Sakurai, T., Yamada, M., Effects of macrophage colony-stimulating factor and interleukin-2 administration on NK1.1(+) cells in mice (2000) Int. J. Immunopharmacol., 22, pp. 967-977Muzzioli, M., Stecconi, R., Donnini, A., Zinc improves the development of human CD34+ cell progenitors towards Natural Killer cells and induces the expression of GATA-3 transcription factor (2007) Int. J. Biochem. Cell Biol., 39, pp. 955-965Noda, K., Ohno, N., Tanaka, K., A new type of biological response modifier from Chlorella vulgaris which needs protein moiety to show an antitumour activity (1998) Phytother. Res., 12, pp. 309-319Olfert, E.D., Cross, B.M., McWilliam, A.A., (1993) Guide to the Care and Use of Experimental Animals, 1, p. 1. , Canadian Council on Animal Care, OttawaOrange, J.S., Ballas, Z.K., Natural killer cells in human health and disease (2006) Clin. Immunol., 118, pp. 1-10Pawlik-Skowronska, B., Pirszel, J., Brown, M.T., Concentrations of phytochelatins and glutathione found in natural assemblages of seedweeds depend on species and metal concentrations of the habitat (2007) Aquat. Toxicol., 20, pp. 190-199Prasad, A.S., Effects of zinc deficiency on Th1 and Th2 cytokine shifts (2000) J. Infect. Dis., 182, pp. 62-68Queiroz, M.L.S., Bincoletto, C., Valadares, M.C., Effects of Chlorella vulgaris extract on cytokines production in Listeria monocytogenes infected mice (2002) Immunopharmacol. Immunotoxicol., 24, pp. 483-496Queiroz, M.L.S., Rodrigues, A.P.O., Bincoletto, C., Protective effects of Chlorella vulgaris in lead-exposed mice infected with Listeria monocytogenes (2003) Int. Immunopharmacol., 3, pp. 889-900Queiroz, M.L., Torello, C.O., Perhs, S.M., Chlorella vulgaris up-modulation of myelossupression induced by lead: the role of stromal cells (2008) Food Chem. Toxicol., 46, pp. 3147-3154Ramos, A.L., Torello, C.O., Queiroz, M.L.S., Chlorella vulgaris modulates immunomyelopoietic activity and enhances the resistance of tumor-bearing mice (2010) Nutr. Cancer., 62, pp. 1170-1180Rodriguez-Garcia, I., Guil-Guerrero, J.L., Evaluation of the antioxidant activity of three microalgal species for use as dietary supplements and in the preservation of foods (2008) Food Chem., 108, pp. 1023-1026Sarders, V.M., Baker, R.A., Ranner-Quinn, D.S., Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help (1997) J. Immunol., 158, pp. 4200-4210Schmitt, N., Anderson, T.W., Philion, J.J., Could zinc help protect children from lead poisoning? (1996) Can. Med. Assoc. J., 154, pp. 13-14Schuerwegh, A.J., Dombrecht, E.J., Stevens, W.J., Influence of pro-inflammatory (IL-1 alpha, IL-6, TNF-alpha, IFN-gamma) and anti-inflammatory (IL-4) cytokines on chondrocyte function (2003) Osteoarthritis Cartilage, 11, pp. 681-687Sinicropi, M.S., Amantea, D., Caruso, A., Chemical and biological properties of toxic metals and use of chelating agents for the pharmacological treatment of metal poisoning (2010) Arch. Toxicol., 84, pp. 501-520Slaveykova, V., Wilkinson, K.J., Physicochemical aspects of lead bioaccumulation by Chlorella vulgaris (2002) Environ. Sci. Technol., 36, pp. 969-975Souza-Queiroz, J., Malacrida, S.A., Justo, G.Z., Myelopoietic response in mice exposed to acute cold/restraint stress: modulation by Chlorella vulgaris prophylactic treatment (2004) Immunopharmacol. Immunotoxicol., 26, pp. 455-467Souza-Queiroz, J., Torello, C.O., Palermo-Neto, J., Hematopoietic response of rats exposed to the impact of an acute psychophysiological stressor on responsiveness to an in vivo challenge with Listeria monocytogenes: modulation by Chlorella vulgaris prophylactic treatment (2008) Brain Behav. Immun., 22, pp. 1056-1065Spangrude, G.J., Heimfeld, S., Weissman, I.L., Purification and characterization of mouse hematopoietic stem cells (1988) Science, 241, pp. 58-62Tanaka, K., Konishi, F., Himeno, K., Augmentation of anti tumor resistance by a strain of unicellular green algae, Chlorella vulgaris (1984) Cancer Immunol. Immunother., 17, pp. 90-94Tanaka, K., Koga, T., Konishi, F., Augmentation of host defense by a unicellular green alga, Chlorella vulgaris, to Escherichia coli infection (1986) Infect. Immun., 53, pp. 267-271Tanaka, K., Yamada, A., Noda, K., A novel glycoprotein obtained from Chlorella vulgaris strain CK22 shows antimetastatic immunopotentiation (1998) Cancer Immunol. Immunother., 45, pp. 313-320Traviesso, L., Canizares, R.O., Borja, R., Heavy metal removal by microalgae (1999) Bull. Environ. Contam. Toxicol., 62, pp. 144-151Van Den Heuvel, R.L., Leppens, H., Schoeters, G.E., Lead and catechol hematotoxicity in vitro using human and murine hematopoietic progenitor cells (1999) Cell Biol. Toxicol., 15, pp. 101-110Veglio, F., Beolchini, F., Removal of metals by biosorption: a review (1997) Hydrometallurgy, 44, pp. 301-316Vijayavel, K., Anbuselvam, C., Balasubramanian, M.P., Antioxidant effect of the marine algae Chlorella vulgaris against naphthalene-induced oxidative stress in the albino rats (2007) Mol. Cell Biochem., 303, pp. 39-44Virgolini, M.B., Chen, K., Weston, D.D., Interactions of chronic lead exposure and intermittent stress: consequences for brain-catecholamine systems and associated behaviors and HPA axis function (2005) Toxicol. Sci., 87, pp. 469-482Vivier, E., Tomasello, E., Baratin, M., Functions of natural killer cells (2008) Nat. Immunol., 95, pp. 503-510Westerman, M.P., Pfitzer, E., Ellis, L.D., Concentrations of lead in bone in plumbism (1965) N. Engl. J. Med., 23, pp. 1246-1250Wilde, E.W., Benemann, J.R., Bioremoval of heavy metals by the use of microalgae (1993) Biotechnol. Adv., 11, pp. 781-812Winneke, G., Zinc to prevent lead poisoning (1996) Can. Med. Assoc. J., 154, pp. 1622-1623Woiciechowsky, C., Asadullah, K., Nestler, D., Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury (1998) Nat. Med., 4, pp. 808-813Wong, S.L., Nakamoto, L., Wainwright, J.F., Detection of toxic organometallic complexes in waste waters using algal assays (1997) Arch. Environ. Contam. Toxicol., 32, pp. 358-366Yamaguchi, M., Role of zinc in bone formation and bone resorption (1998) J. Trace Elem. Exp. Med., 11, pp. 119-135Yamamoto, N., Zou, J.P., Li, X.F., Regulatory mechanisms for production of IFN-γ and TNF by antitumor T cells or macrophages in the tumor-bearing state (1995) J. Immunol., 154, pp. 2281-2290Zhang, X., Okutsu, M., Kanemi, O., Effect of foot shock stress on the interferon-γ production of murine intestinal intraepithelial lymphocytes (2005) Immunol. Lett., 100, pp. 170-176Zhao, X., Ren, G., Liang, L., Brief report: interferon-gamma induces expansion of Lin(-) Sca-1(+)C-Kit(+) cells (2010) Stem Cells, 28, pp. 122-126Zhou, D., Kusnecov, A.W., Shurin, M.R., Exposure to physical and psychological stressors elevates plasma interleukin-6: relationship to the activation of hypothalamic-pituitary-adrenal axis (1993) Endocrinology, 133, pp. 2523-2530Zwirner, N.W., Domaica, C.I., Cytokine regulation of natural killer cell effector functions (2010) Biofactors, 36, pp. 274-288