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Arsenic: Chemistry, Occurrence, and Exposure 1. Arsenic Risk Assessment 4. Health Effects Chronic Arsenic Toxicity 6.

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Mechanism for Arsenic-Induced Toxic Effects 8. Arsenic Through the Gastrointestinal Tract Cutaneous Toxicology of Arsenic Arsenic-Induced Liver Injury Arsenic and Respiratory Disease Arsenical Kidney Toxicity Arsenic-Induced Developmental Neurotoxicity Arsenic, Kidney, and Urinary Bladder Disorders Arsenic and the Cardiovascular System Immunotoxic Effects of Arsenic Exposure Arsenic and Developmental Toxicity and Reproductive Disorders Arsenic and Cancer Medical Countermeasures—Chelation Therapy Powered by.

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Bone-marrow DCs differentiated in the presence of nicotine are functional but express increased surface costimulatory molecules and major histocompatibility antigens Nouri-Shirazi, Tinajero, and Guinet Therefore, these cells will have a lower threshold for inducing T cell responses. Similar effects were observed with exposure to organic dust associated with agriculture Poole et al. Urban aerosols also enhanced costimulatory molecule expression on dendritic cells, but unlike nicotine and organic dust, proinflammatory cytokines such as IL-1 and IL-6 were increased. This suggests that these DCs will induce a dysregulated and more robust inflammatory response.

Increased production of proinflammatory cytokines correlated with higher antigen specific immunoglobulin Ig G and IgE following intranasal ovalbumin challenge in a mouse model Yoshida et al. Exposure to environmental toxins also alters the function of specialized tissue resident macrophages such as alveolar macrophages in the lung and microglial cells in the brain Campbell ; Moreno et al. Manganese exposure in juvenille mice led to increased activation of microglia cells and upregulation of nitric oxide NO synthase, an enzyme critical for the production of reactive nitrogen intermediates Campbell ; Moreno et al.

These early effects resulted in alterations in glial cell function in adult mice.

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Pesticides such as lindane and dieldrin accumulate in the brain and enhance production of reactive oxygen by microglial cells Mao and Liu Alveolar macrophages are located at the interface between the host and the environment and are, therefore, constantly bombarded with a myriad of different environmental insults that can alter their function Bateson and Schwartz ; Bhalla et al. Ambient particulate matter and diesel exhaust act directly on human alveolar macrophages to suppress inflammatory cytokine production Sawyer et al.

While this seems counterintuitive to the initiation of chronic inflammation, these responses are critical for host defense and may lead to failure to eliminate pathogens and result in chronic inflammation. This study also showed that some particulates reduced inflammatory cytokines, but actually increased the neutrophil chemotactic factor IL Since neutrophils are a major mediator of tissue damage in response to inflammatory and infectious stimuli, these changes could lead to increased immune-mediated inflammatory tissue damage. Human blood-derived macrophages treated with arsenic displayed marked alterations in morphology, surface marker expression, phagocytic uptake, and cytokine secretion Lemarie et al.

In a mouse model, cigarette smoke reduced macrophage-mediated bacterial phagocytosis and clearance Phipps et al. Lastly, exposure of a mouse macrophage cell line to synthetic pyrethroid insecticides resulted in dramatically increased reactive oxygen response Zhang et al. To emphasize the linkage of DIT to innate immune dysfunction, a more detailed example involving the heavy metal lead Pb is shown in Figure 1.

Multiple genetic, life-stage, gender, nutritional, and environmental factors influence the sensitivity to Pb exposure Bishayi and Sengupta ; Bunn et al. Pb exposure of dendritic cells reduces phagocytosis and limits bactericidal activities of lysosomes necessary for bacterial killing Bishayi, Sengupta, and Ghosh This leads to increased sensitivity to bacterial infection.

The elevated risk of innate immune-mediated oxidative damage in tissues is further exacerbated by a Pb-induced reduction in cellular glutathione and defenses against oxidative damage Chetty et al. Alterations in innate immune cell function lead to a significant bias toward Th2 responses by effector T cells, which can also have their function directly affected by Pb exposure Gao and Lawrence ; Gao, Mondal, and Lawrence ; Heo, Lee, and Lawrence Together, these alterations largely define the hallmarks of Pb-induced immunotoxicity Dietert and Piepenbrink Although the vast majority of studies have examined the impact of single environmental risk factors on the developing immune system, it is important to recognize that synergistic or antagonistic interactions between categories of environmental risk factors both positive and negative can alter the relative likelihood for DIT and inflammation-promoted disease.

Exposure to more than one environmental risk factor for DIT can arise either through exposure to mixtures e. In the latter case of multiple sources, the exposures could occur simultaneously during development or during different life stages. This suggests the possibility that maternal diet might affect the risk of Pb-induced inflammatory dysfunction.

But there is evidence suggesting that the reverse is also likely where exposure to an immunotoxicant can overcome the beneficial effects of other immunomodulatory factors. Early-life farming environments protect against the risk of childhood asthma and atopy, which may be associated with changes among innate immune cell receptors and innate immune responses Ege et al.

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But other agriculturally-related exposures appear to undermine the benefit of a microbial-rich early-life environment. Hoppin et al. So, direct exposure to some pesticides during childhood may blunt the benefits of immune maturation in a diverse microbial environment. Similar interactive effects among risk factors were seen in a recent study from the Faroe Islands. Evidence suggests that prolonged breastfeeding can benefit innate immunity and effective immune balance when compared versus formula feeding Andersson et al. It also helps to reduce the risk of childhood asthma possibly via the innate immune modulating, soluble CD14 molecule Rothenbacher et al.

But exposure to environmental toxicants such as PCBs in the Faroe Island diet can undermine the normal benefit of breastfeeding. Grandjean et al. Therefore, it is important to consider the interactive effects of multiple or mixed exposures across all of innate immune development and not only the effects of a single environmental risk factor during a narrow period of immune development e.

Defects in fetal-neonatal innate immune development can lead to imbalanced and inappropriate responses that persist throughout a lifetime Bellinger, Lubahn, and Lorton ; Selgrade et al. These uncontrolled or inappropriate responses increase risk for later-life inflammatory disease. However, it is important to note that such later-life adverse outcomes are components of much broader immune-based disease patterns, which include depression, sleep disorders, sensory impairment, and cancer Dietert, Dietert, and Gavalchin Psychiatric disturbances such as depression and mood disorders correlate with developmentally-associated inflammatory dysfunction and resulting inflammatory disease Ahola et al.

For example, chronic overproduction of proinflammatory cytokines and disruption of the pro- and anti-inflammatory cytokine balance can contribute to an increased risk of depression, mood disturbances, suicidal behavior, and sleep disturbances Ferini-Strambi ; Janelidze et al. Beside the chronic nature of these conditions, it is clear that the underlying innate immune dysfunction and the dysregulated inflammation pattern act beyond the lung or gut to affect other major health parameters that negatively impact the quality of life and may require medical intervention.

Table 3 illustrates the extent to which inflammation-associated chronic diseases with putative early life risk factors affect most systems and organs of the body. Many of these diseases e. Chronic disease outcomes of inflammatory dysfunction are not restricted to non-cancerous conditions. When innate immune dysfunction and chronic inflammation persist across decades of life, two types of cancers are commonly observed: tissue-specific cancers and leukemic cancers Dietert Although chronic inflammatory diseases are often negatively correlated with the risk of cancer, the risk is often elevated for the tissue that is a target of persistent inflammatory insult Dietert, DeWitt, et al.

This can include both the risk of tissue-specific cancer itself Ji et al. Additionally, leukemic cancers are commonly associated with some forms of immune dysfunction-based patterns e. The mechanistic connection between chronic inflammation and cancer is linked to the high production of growth factors needed to repair tissue damage and an abundance of inflammatory cytokines Coussens and Werb ; Karin and Greten ; Terzic et al. Although low levels of inflammation promote tissue homeostasis, tumors take advantage of proinflammatory cytokines to promote their own survival and growth e.

Given the importance of inflammatory-based diseases across a lifetime Dietert and Zelikoff , increased attention to other health risks linked with innate immune dysfunction is needed. Effective management of innate immune maturation requires both avoidance of hazardous environmental chemicals, drugs, and physical factors, as well as promotion of positive factors such as prolonged breastfeeding, adequate vitamin D levels, and useful balances of dietary fatty acids Dietert, DeWitt, et al.

This review highlights one of the major problems in the preclinical safety screening of drugs and in the safety screening of environmental chemicals for immunotoxicity. To date, the primary focus of immune safety assessment has been on histopathology combined with a limited number of adaptive immune responses usually directed against protein or xenogeneic cell antigens Dietert , Comprehensive innate immune analysis and assessment of inflammatory regulation in response to infectious agent challenge is rarely required in adult safety assessment FDA S8 guidelines , although such protocols are available Burleson and Burleson , ; Neff-LaFord et al.

This is a significant problem if protocols utilized for immune assessment lack the capacity for evaluating the regulation of inflammation. Adult immunotoxicity assessment is not routine FDA S8 guidelines and, when performed, usually lacks measures of inflammatory responses. Relevant innate immune assessment of the developing immune system is even less common.

Handbook of Arsenic Toxicology

The list of chronic inflammatory diseases shown in Table 3 and their relative importance to public health underscores the need for such immune safety information. Given the immature status of the innate immune system in the neonate and the risk for drug and chemical exposures to cause inflammatory dysfunction in later life, a priority should be given for ensuring that drug and chemical safety screening is designed to detect developmentally-induced inflammatory dysfunction.

A promising focus for the evaluation of innate immune-directed immunotoxicity in neonates and adults is the family of pattern recognition receptors PRRs including the Toll-like receptors TLRs. TLR stimulation initiates inflammatory cytokine secretion and leads to maturation of dendritic cells Medzhitov, Preston-Hurlburt, and Janeway , which is critical to induce effector T cell responses.

Depending on the cues that dendritic cells receive during this maturational process, different types of effector T cell responses can occur Mazzoni et al. The importance of appropriate regulation of these responses initiated through TLRs is highlighted in inflammation-mediated autoimmune disease, such as systemic lupus erythematosus. In mouse models of lupus, inappropriate and uncontrolled responses through TLRs result in overproduction of cytokines, and type I interferons, which results in inflammatory damage Leadbetter et al. Therefore, it is critical to understand the molecular mechanisms regulating these receptors and consider the effects of environmental exposures on their expression and regulation.

Recent studies suggest that traditional mRNA profiles of innate immune genes, such as TLRs, are insufficient to correlate receptor expression with inflammatory responses. Instead, modifications of TLRs after protein synthesis determine the magnitude of cellular responses. For example, mRNA levels do not necessarily correlate with protein function, since intracellular localization and proteolytic processing control cellular response to TLR9 ligands Barton, Kagan, and Medzhitov ; Chockalingam et al.

Therefore, to determine the effects of environmental exposure on innate immune function, new targets and assays are desperately needed.

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We propose that new targets to evaluate innate immune function are 1 to examine the effect of prenatal exposure to toxicants on TLR signaling in neonatal and adult macrophages and dendritic cells and 2 to determine whether processes such as bacterial killing by adult macrophages, which depends in part on recognition of the bacterium through TLRs, is reduced by prenatal exposure to toxicants. Since these types of evaluations are lacking in current safety testing, we may be underestimating the effect that prenatal and early life exposures have on immune cell function.

The newborn emerges with an immune system that favors Th2 adaptive responses and lacks the innate immune maturity that will be needed to effectively protect the child. Prenatal or postnatal environmental conditions that impair the continued and effective maturation of the innate immune system create a hyperinflammatory state. Dysfunctional innate immunity alters host responses to infections. This in turn causes tissue damage and promotes chronic inflammation. DIT has the potential to affect the ability of resident innate immune cells in their seeding of organs, expansion-repopulation of cells in the organ, acquisition of specialized phenotypes, interaction with other resident cells in the tissue, response to environmental stimuli, and recruitment of additional immune cells to the tissue.

Yet, to date, the functional status of these cells following early-life exposure to drugs or environmental chemicals is usually only known retrospectively and is rarely, if ever, evaluated in required safety testing Dietert , We argue that it is not possible to evaluate the risk that a chemical or drug poses without determining its effect on the functional status of resident innate immune cells and its potential to elevate the risk of later-life inflammatory disease.

The authors thank Janice Dietert for her editorial suggestions. Europe PMC requires Javascript to function effectively. Recent Activity. The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Toxicol Environ Chem. Author manuscript; available in PMC Jun PMID: Cynthia A.