Nitric oxide and superoxide anion production in monocytes from children exposed to arsenic and lead in region Lagunera, Mexico Ana Patricia Pineda-Zavaleta, a Gonzalo Garcı ´a-Vargas, b Victor H. Borja-Aburto, a,c Leonor C. Acosta-Saavedra, a Eunice Vera Aguilar, a Arı ´stides Go ´mez-Mun ˜oz, a Mariano E. Cebria ´n, a and Emma S. Caldero ´n-Aranda a, * a Seccio ´n Externa de Toxicologı ´a, Centro de Investigacio ´n y de Estudios Avanzados, I.P.N. Av. Instituto Polite ´cnico Nacional 2508, Col. San Pedro Zacatenco, Me ´xico, D.F. 07360, Mexico b Facultad de Medicina, Universidad Jua ´rez del Estado de Durango, La Salle 1 y Sixto Ugalde, Go ´mez Palacio, Durango 35050, Mexico c Coordinacion de Salud en el Trabajo, Instituto Mexicano del Seguro Social, Me ´xico, D.F., Mexico Received 1 July 2003; accepted 8 October 2003 Available online 10 May 2004 Abstract We evaluated in Mexican children environmentally exposed to arsenic and lead monocyte nitric oxide (NO) and superoxide anion production in response to direct activation with interferon-g (IFN-g) + lipopolysaccharide (LPS). The integrity of Th1-regulated cellular immune response when monocytes were indirectly activated was also evaluated. Most children lived near a primary lead smelter. Lead and arsenic contamination in soil and dust by far exceeded background levels. As levels in water were between 10 and 30 ppb. Most children (93%) had urinary arsenic (AsU) concentrations above 50 Ag/l (range 16.75 – 465.75) and 65% had lead blood levels (PbB) above 10 Ag/dl (range 3.47 – 49.19). Multivariate analyses showed that NO production in monocytes activated indirectly was negatively associated with both PbB and AsU. Superoxide production in directly activated monocytes was negatively associated with AsU but positively associated with PbB. The models including the interaction term for AsU and PbB suggested the possibility of a negative interaction for NO production and a positive interaction for superoxide. There were indications of differential gender-based associations, NO production in indirectly activated monocytes obtained from girls was negatively associated with AsU but not with PbB. Superoxide production was positively associated with PbB in both directly and indirectly activated monocytes from boys but the latter was negatively associated with AsU. These effects are consistent with immune system abnormalities observed in human populations exposed to Pb or As. Further studies in larger populations are required to characterize As and Pb interactions and the mechanism(s) underlying the observed effects. D 2004 Elsevier Inc. All rights reserved. Keywords: Lead; Arsenic; Immunotoxicity; Superoxide; Nitric oxide; Children Introduction Arsenic is an ubiquitous element occurring naturally in our environment. Exposure to arsenic represents a health risk associated not only with its overt toxic effects but also with subtle to profound alterations in the immune system. Several studies have shown that gallium arsenide (GaAs) suppressed the primary antibody response and the induced T cell proliferation and that it also decreased CD25 expression and IL-2 and IL-4 secretion (Burns and Munson, 1993; Sikorski et al., 1991). The As component of GaAs was shown to be the major contributor to the GaAs-induced immunosuppression (Burns et al., 1991). Studies on human peripheral blood lymphocytes stimu- lated with PHA have shown that As treatment inhibited cell proliferation (Petres et al., 1977). A significant reduc- tion in PHA-induced proliferation was also shown in lymphocytes obtained from subjects chronically exposed to As (Ostrosky-Wegman et al., 1991). Previous studies have shown that sodium arsenite impairs several signaling pathways and induce apoptosis in non-stimulated murine lymphocytes, thymocytes, and human mononuclear cells (Bustamante et al., 1997; Fuente et al., 2002; Hossain et 0041-008X/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.taap.2003.10.034 * Corresponding author. Seccio ´n Externa de Toxicologı ´a, CINVES- TAV-IPN, P.O. Box 14-740, Me ´xico, D.F. 07360, Mexico. Fax: +52-55- 57477111. E-mail address: scalder@mail.cinvestav.mx (E.S. Caldero ´n-Aranda). www.elsevier.com/locate/ytaap Toxicology and Applied Pharmacology 198 (2004) 283– 290