Prenatal cadmium exposure dysregulates sonic hedgehog and Wnt/β-catenin signaling in the thymus resulting in altered thymocyte development

Abstract

Cadmium (Cd) is both an environmental pollutant as well as a component of cigarette smoke. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports in the literature of immunomodulatory effects of prenatal exposure to Cd. The sonic hedgehog (Shh) and Wnt/β-catenin pathways are required for thymocyte maturation. Several studies have demonstrated that Cd exposure affects these pathways in different organ systems. This study was designed to investigate the effect of prenatal Cd exposure on thymocyte development, and to determine if these effects were linked to dysregulation of Shh and Wnt/β-catenin pathways. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose (10 ppm) of Cd throughout pregnancy and effects on the thymus were assessed on the day of birth. Thymocyte phenotype was determined by flow cytometry. A Gli:luciferase reporter cell line was used to measure Shh signaling. Transcription of target genes and translation of key components of both signaling pathways was assessed using real-time RT-PCR and western blot, respectively. Prenatal Cd exposure increased the number of CD4+ cells and a subpopulation of double-negative cells (DN; CD4-CD8-), DN4 (CD44-CD25-). Shh and Wnt/β-catenin signaling were both decreased in the thymus. Target genes of Shh (Patched1 and Gli1) and Wnt/β-catenin (c-fos, and c-myc) were affected differentially among thymocyte subpopulations. These findings suggest that prenatal exposure to Cd dysregulates two signaling pathways in the thymus, resulting in altered thymocyte development.

Metal chelation therapy in rheumathoid arthritis: a case report

“…In addition, children environmentally exposed to arsenic and lead could have an altered macrophage function showing alteration in nitric oxide and superoxide production (Pineda-Zavaleta et al 2004). It was proved that prenatal cadmium exposure can dysregulate some signals in the thymus, leading to altered thymocyte development (Hanson et al 2010). Finally, the adjuvant action of aluminium and its association with autoimmunity has been abundantly demonstrated (Marrack et al 2009;Israeli et al 2009).…”

“…Indeed, all heavy metals have been demonstrated to affect myelo-monocytic seeding and maturation in tissues; in particular, mercury affects T cell differentiation, selection and peripheral seeding and lead can modify dendritic cell maturation and function (Dietert 2009). Prenatal cadmium exposure alters thymocyte maturation in mice (Hanson et al 2010). Human peripheral mononuclear blood cells in vitro exposed to lead salts increase their susceptibility to pathologic agents and ability to promote TH2-dominated immune responses (Hemdan et al 2005).…”

Effects of Metallic Elements on Reproduction and Development

“…Cadmium also dysregulated two signaling pathways in the thymus, resulting in altered thymocyte development (Hanson et al, 2010). Hanson and colleagues (2012) suggested that even very low levels of Cd exposure during gestation can result in long-term detrimental effects on the immune system of the offspring, and that these effects are, to some extent, sex specific.…”

Environmental Alterations of Epigenetics Prior to the Birth

“…Prenatal exposure to cadmium has been shown to lead to altered thymocyte development (Hanson, Brundage, Schafer, Tou, & Barnett, 2010), aberrant immune response (Holaskova, Elliott, Hanson, Schafer, & Barnett, 2012), and decreased birth weight in a sex-specific manner (Kippler et al, 2013). The sex-specific toxicity is also correlated with differential methylation between girls and boys based on cord blood sample from exposed newborns and blood from 4–5 year children of Bangladesh (Kippler et al, 2013).…”