Lead

A variety of environmental and occupational metals have been identified that alter immune function in humans and laboratory rodents (Zelikoff and Thomas 1995). One such metal is lead, a naturally occurring element found in the earth's crust as well as throughout the biosphere. Present-day concentrations of lead in the atmosphere are due primarily to anthropogenic sources, with insignificant contribution from natural sources. Lead exposure to both humans and animals at sufficiently toxic doses results in renal, hematopoietic, and central nervous system dysfunction. Lead has also been demonstrated to be a potent immunotoxicant in mice and rats as well as a developmental immunotoxicant in rats.

Early work by Luster et al. (1978) and Faith et al. (1979) examined the developmental immunotoxic effects of chronic pre- and postnatal exposure of rats to low levels of lead acetate in drinking water. Weanling (21-day-old) female Sprague-Dawley (SD) rats were exposed to lead acetate at concentrations of 25 and 50 ppm in their drinking water until 10 weeks of age. These female rats were then mated with untreated males and continued on the same lead acetate concentrations throughout gestation and lactation. Offspring of these females were weaned at 21 days of age and continued on the same lead exposure through immune function testing between 35 and 45 days of age. These lead exposures resulted in decreased thymus weights, compared to controls, but did not alter body weight nor result in overt signs of toxicity. The IgG antibody response to sheep red blood cells (SRBCs), as well as the IgM antibody plaque-forming cell (PFC) response to SRBCs, were both suppressed at 25 and 50 ppm lead acetate (Luster et al. 1978). The mitogen-stimu-lated lymphoproliferative (LP) responses of splenic lymphocytes to phytohaemaglu-tinin (PHA) and Concanavalin A (ConA) were suppressed at both lead acetate concentrations (Faith et al. 1979). Blood lead determinations in these studies indicated that the observed levels were comparable to blood levels found in many children in urban areas during the early 1970s (Caprio et al. 1974; Committee on Biological Effects 1972).

More recently, Miller et al. (1998), Chen et al. (1999), and Bunn et al. (2001a; 2001b) examined the developmental immunotoxic effects of lead acetate in the drinking water of female rats at different periods of development during pre- and postbreeding: during breeding and pregnancy; two weeks prior to mating and through parturition; throughout pregnancy; or on gestation day (GD) 3 to 9 or GD 15 to 21, respectively, for each study. In 13-week-old Fischer 344 female rat offspring (male offspring were not evaluated), the total blood leukocyte count, the delay-type hypersensitivity (DTH) response to keyhole limpet hemocyanin (KLH), and splenic inter-feron-g (IFNg) production were depressed at 250 ppm (Miller et al. 1998; Chen et al. 1999). In contrast, macrophage tumor necrosis factor-a (TNFa) and nitric oxide production, and splenic interleukin-4 (IL-4) production were elevated at 250 ppm lead acetate (Miller et al. 1998; Chen et al. 1999).

A comparison of the effect that lead acetate in the drinking water of rat dams has on the developing immune system of both male and female offspring was determined in studies by Bunn et al. (2001a; 2001b). Female offspring of F344 rat dams exposed to 250 ppm lead acetate in drinking water from GD 2 through pregnancy displayed persistent suppression of the DTH responses to KLH at both 5 and 13 weeks of age, while male offspring were not affected at either age (Bunn et al. 2001a). The DTH response to KLH was also suppressed in 12-week-old female offspring of pregnant SD rats given 500 ppm lead acetate in their drinking water during late gestation (i.e., access to lead acetate only during GD 15 to 21), but not during early gestation (GD 3 to 9). These same female offspring exhibited a persistent increase in IL-10 production. In contrast, 13-week-old male offspring did not display a decrease in the DTH response following either early or late gestational lead exposure (Bunn et al. 2001b). Taken together, these data indicate that prenatal lead exposure of rats leads to persistent alterations in immune function of adult offspring, with females being more sensitive than males.

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