Impact of developmental lead exposure on splenic factors

Abstract

Lead (Pb) is known to alter the functions of numerous organ systems, including the hematopoietic and immune systems. Pb can induce anemia and can lower host resistance to bacterial and viral infections. The anemia is due to Pb’s inhibition of hemoglobin synthesis and Pb’s induction of membrane changes, leading to early erythrocyte senescence. Pb also increases B-cell activation/proliferation and skews T-cell help (Th) toward Th2 subset generation. The specific mechanisms for many of the Pb effects are, as yet, not completely understood. Therefore, we performed gene expression analysis, via microarray, on RNA from the spleens of developmentally Pb-exposed mice, in order to gain further insight into these Pb effects. Splenic RNA microarray analysis indicated strong up-regulation of genes coding for proteolytic enzymes, lipases, amylase, and RNaseA. The data also showed that Pb affected the expression of many genes associated with innate immunity. Analysis of the microarray results via GeneSifter software indicated that Pb increased apoptosis, B-cell differentiation, and Th2 development. Direct up-regulation by Pb of expression of the gene encoding the heme-regulated inhibitor (HRI) suggested that Pb can decrease erythropoiesis by blocking globin mRNA translation. Pb’s high elevation of digestive/catabolizing enzymes could generate immunogenic self peptides. With Pb’s potential to induce new self-peptides and to enhance the expression of caspases, cytokines, and other immunomodulators, further evaluation of Pb’s involvement in autoimmune phenomena, especially Th2-mediated autoantibody production, and alteration of organ system activities is warranted.

Developmental lead effects on behavior and brain gene expression in male and female BALB/cAnNTac mice

“…The microarray results indicated that Pb up-regulated gene expression of numerous catabolic enzymes, including carboxypeptidases, chymotrypsin-like proteins, and metalloproteinases (Table S1). In accord with the results reported here the effect of developmental Pb-exposure on protease gene expression has been observed in Drosophila (Ruden et al, 2009) and in mouse spleen (Kasten-Jolly et al, 2010). Brain inflammation is known to generate behavior changes and has been shown to be the root cause of neurodegenerative diseases, such as Alzheimer’s disease.…”

“…The Pb-exposure decreased transcript levels of IL-6 and IFN receptors and increased transcript levels of IL-7 and IL-4 receptors. Pb increased gene expression of IL-7 in the female mouse spleen (Kasten-Jolly et al, 2010) and qRT-PCR measurement of IL-7 gene expression in male and female whole brain indicated that IL-7 gene expression was increased by Pb in females and was not changed by Pb in males (Fig. 6).…”

The Completed Self: An Immunological View of the Human-Microbiome Superorganism and Risk of Chronic Diseases

“…Major developmental immunotoxicants such as the heavy metals, lead, mercury, and cadmium and dioxin are known to impact innate immune cell responses to challenge and to promote inappropriate inflammatory responses leading to tissue damage. For example, Kasten-Jolly et al [129] found that developmental exposure of mice to lead targeted changes in innate immune cell gene expression as a major outcome. They further argued that the multi-system adverse effects following developmental lead exposure could be related to systemic inflammation.…”

Early life environment and developmental immunotoxicity in inflammatory dysfunction and disease

“…Environmental interference during development of the innate immune system has the potential to limit the normal expansion of immune function and result in Th2-biased immunity or inappropriate/chronic inflammatory responses (Gao, Mondal, and Lawrence 2007; Kasten-Jolly, Heo, and Lawrence, 2010) and is, therefore, an important consideration for childhood vaccine development (Philbin and Levy 2009). Newborns have an inherently immature immune system (Zhao et al 2008), and the default profile of immune responses during pregnancy and at birth is Th2-biased (Kollmann et al 2009; Lee et al 2008; White et al 2010).…”