Academic journal article Environmental Health Perspectives

Effects of Developmental Activation of the Aryl Hydrocarbon Receptor by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin on Long-Term Self-Renewal of Murine Hematopoietic Stem Cells

Academic journal article Environmental Health Perspectives

Effects of Developmental Activation of the Aryl Hydrocarbon Receptor by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin on Long-Term Self-Renewal of Murine Hematopoietic Stem Cells

Article excerpt

Introduction

Since nutritional deficiency during pregnancy was first identified as a fundamental factor in the developmental origins of health and disease, there has been an explosion in the number of factors that have been identified as influencing lifetime health status for nearly every organ system in the body (Barker 2007; Haugen et al. 2015). Moreover, intrauterine environmental factors such as exogenous chemicals are clearly recognized to increase the risk for a spectrum of disorders that may appear during childhood and that can persist throughout life (Faulk and Dolinoy 2011; Haugen et al. 2015). Immune system function has been recognized as a particularly sensitive end point to changes in the intrauterine environment owing to its systemic distribution throughout the body and its importance for both host defense and immunoregulatory function (Dietert 2011; Winans et al. 2011). Specifically, human epidemiological studies have found associations between developmental exposures and an array of later-life immune deficiencies including changes in cord blood lymphocyte composition, increased wheezing events, and increased autoinflammatory disorders (Choi et al. 2010; Herr et al. 2010; Jedrychowski et al. 2014). Additionally, animal studies have found that transplacental exposures to chemicals that bind to and activate the aryl hydrocarbon receptor (AHR) adversely affect l ater-l ife immune effects by decreasing the immune response to influenza and by increasing autoimmune susceptibility in adults (Boule et al. 2014; Hogaboam et al. 2008; Mustafa et al. 2009). The diversity of adult diseases caused by related developmental exposures may be consistent with a two-hit mechanism whereby the prenatal exposure leads to epigenetic reprogramming of a progenitor cell that can have differential impacts on disease etiology depending on the genetic background, timing, and type of secondary environmental exposures. Indeed, this added complexity to the developmental origins of health and disease hypothesis has been proposed for other adult outcomes including neurodevelopmental, reproductive, and obesegenic disorders (Bruner-Tran and Osteen 2011; Lahiri and Maloney 2010; Wadhwa et al. 2009).

The importance of the AHR to human health is demonstrated in part by epidemiological studies based on the population in Seveso, Italy, that was accidentally exposed to the prototypical AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), where the risk for lymphatic and hematological cancers was found to be slightly elevated in adults (Consonni et al. 2008; Pesatori et al. 2009). Furthermore, U.S. Air Force veterans serving during the Vietnam War who were exposed to TCDD-contaminated Agent Orange were reported to be at greater risk for melanoma and prostate cancer than unexposed veterans (Akhtar et al. 2004). In both the Seveso cohort and among the Vietnam veterans, small sample sizes for relatively rare diseases have made it difficult to establish causal conclusions between TCDD exposure and disease. Nevertheless, the International Agency for Research on Cancer (IARC) has classified TCDD as a Group I human carcinogen based on sufficient epidemiological evidence for all cancers combined (Baan et al. 2009). Despite residual uncertainty regarding the carcinogenicity of TCDD in the general population, there is a need to identify and understand intergenerational impacts of dioxins given the unique vulnerability of children to developmental exposures (Landrigan and Goldman 2011). Notably, low-level background exposures to chemicals that activate the AHR occur primarily through dietary intake (Kvalem et al. 2012; Liem et al. 2000; Schecter et al. 2001). Furthermore, human developmental evidence specific to the immune system has been obtained from epidemiological studies that found an association between prenatal exposure to dioxins and dioxin-like PCBs and lower antibody titers for mumps and measles at preschool age (Weisglas-Kuperus et al. …

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