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BackgroundKey characteristics (KCs), properties of agents or exposures that confer potential hazard, have been developed for carcinogens and other toxicant classes. KCs have been used in the systematic assessment of hazards and to identify assay and data gaps that limit screening and risk assessment. Many of the mechanisms through which pharmaceuticals and occupational or environmental agents modulate immune function are well recognized. Thus KCs could be identified for immunoactive substances and applied to improve hazard assessment of immunodulatory agents.ObjectivesThe goal was to generate a consensus-based synthesis of scientific evidence describing the KCs of agents known to cause immunotoxicity and potential applications, such as assays to measure the KCs.MethodsA committee of 18 experts with diverse specialties identified 10 KCs of immunotoxic agents, namely, 1) covalently binds to proteins to form novel antigens, 2) affects antigen processing and presentation, 3) alters immune cell signaling, 4) alters immune cell proliferation, 5) modifies cellular differentiation, 6) alters immune cell-cell communication, 7) alters effector function of specific cell types, 8) alters immune cell trafficking, 9) alters cell death processes, and 10) breaks down immune tolerance. The group considered how these KCs could influence immune processes and contribute to hypersensitivity, inappropriate enhancement, immunosuppression, or autoimmunity.DiscussionKCs can be used to improve efforts to identify agents that cause immunotoxicity via one or more mechanisms, to develop better testing and biomarker approaches to evaluate immunotoxicity, and to enable a more comprehensive and mechanistic understanding of adverse effects of exposures on the immune system. https://doi.org/10.1289/EHP10800.

BackgroundExposure to the bioaccumulative pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) has been associated with increased risk of insulin resistance and obesity in humans and experimental animals. These effects appear to be mediated by reduced brown adipose tissue (BAT) thermogenesis, which is regulated by the sympathetic nervous system. Although the neurotoxicity of DDT is well-established, whether DDT alters sympathetic innervation of BAT is unknown. We hypothesized that perinatal exposure to DDT or DDE promotes thermogenic dysfunction by interfering with sympathetic regulation of BAT thermogenesis.MethodsPregnant C57BL/6 J mice were administered environmentally relevant concentrations of DDTs (p,p'-DDT and o,p'-DDT) or DDE (p,p'-DDE), 1.7 mg/kg and 1.31 mg/kg, respectively, from gestational day 11.5 to postnatal day 5 by oral gavage, and longitudinal body temperature was recorded in male and female offspring. At 4 months of age, metabolic parameters were measured in female offspring via indirect calorimetry with or without the β3 adrenergic receptor agonist, CL 316,243. Immunohistochemical and neurochemical analyses of sympathetic neurons innervating BAT were evaluated.ResultsWe observed persistent thermogenic impairment in adult female, but not male, mice perinatally exposed to DDTs or p,p'-DDE. Perinatal DDTs exposure significantly impaired metabolism in adult female mice, an effect rescued by treatment with CL 316,243 immediately prior to calorimetry experiments. Neither DDTs nor p,p'-DDE significantly altered BAT morphology or the concentrations of norepinephrine and its metabolite DHPG in the BAT of DDTs-exposed mice. However, quantitative immunohistochemistry revealed a 20% decrease in sympathetic axons innervating BAT in adult female mice perinatally exposed to DDTs, but not p,p'-DDE, and 48 and 43% fewer synapses in stellate ganglia of mice exposed to either DDTs or p,p'-DDE, respectively, compared to control.ConclusionsThese data demonstrate that perinatal exposure to DDTs or p,p'-DDE impairs thermogenesis by interfering with patterns of connectivity in sympathetic circuits that regulate BAT.

There is increasing evidence supporting the characterization of the pesticide DDT and its metabolite, DDE, as obesogens and metabolic disruptors. Elucidating the mechanism is critical to understanding whether the association of DDT and DDE with obesity and diabetes is in fact causal. One area of research investigating the etiology of metabolic diseases is mitochondrial toxicity. Several studies have found associations between mitochondrial defects and insulin resistance, cellular respiration, substrate utilization, and energy expenditure. Although the mitotoxicity of DDT and DDE was established 20-40 years ago, it was not viewed in the light of the diseases faced today; therefore, it is prudent to reexamine the mitotoxicity literature for mechanistic support of DDT and DDE as causal contributors to obesity and diabetes, as well as associated diseases, such as cancer and Alzheimer's disease. This review aims to focus on studies investigating the effect of DDT or DDE on mammalian mitochondrial oxidative phosphorylation. We illustrate that both DDT and DDE impair the electron transport chain (ETC) and oxidative phosphorylation. We conclude that there is reasonable data to suggest that DDT and DDE target specific complexes and processes within the mitochondria, and that these insults could in turn contribute to the role of DDT and DDE in mitochondria-associated diseases.

ABSTRACT Aflatoxins (AFs) and fumonisins (FBs) can co-contaminate foodstuffs and have been associated with hepatocellular and esophageal carcinomas in humans at high risk for exposure. One strategy to reduce exposure (and toxicity) from contaminated foodstuffs is the dietary inclusion of a montmorillonite clay (UPSN) that binds AFs and FBs in the gastrointestinal tract. In this study, the binding capacity of UPSN was evaluated for AFB1, FB1 and a combination thereof in Fischer 344 rats. Rats were pre-treated with different dietary levels of UPSN (0.25% or 2%) for 1 week. Rats were gavaged with a single dose of either 0.125 mg AFB1 or 25 mg FB1 per kg body weight and a combination thereof in the presence and absence of an aqueous solution of UPSN. The kinetics of mycotoxin excretion were monitored by analyzing serum AFB1-albumin, urinary AF (AFM1) and FB1 biomarkers over a period of 72 h. UPSN decreased AFM1 excretion by 88-97%, indicating highly effective binding. FB1 excretion was reduced, to a lesser extent, ranging from 45% to 85%. When in combination, both AFB1 and FB1 binding occurred, but capacity was decreased by almost half. In the absence of UPSN, the combined AFB1 and FB1 treatment decreased the urinary biomarkers by 67% and 45% respectively, but increased levels of AFB1-albumin, presumably by modulating its cytochrome metabolism. UPSN significantly reduced bioavailability of both AFB1 and FB1 when in combination; suggesting that it can be utilized to reduce levels below their respective thresholds for affecting adverse biological effects. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aflatoxins (AFs) and fumonisins (FBs) can co-contaminate foodstuffs and have been associated with hepatocellular and esophageal carcinomas in humans at high risk for exposure. One strategy to reduce exposure (and toxicity) from contaminated foodstuffs is the dietary inclusion of a montmorillonite clay (UPSN) that binds AFs and FBs in the gastrointestinal tract. In this study, the binding capacity of UPSN was evaluated for AFB1, FB1 and a combination thereof in Fischer 344 rats. Rats were pre-treated with different dietary levels of UPSN (0.25% or 2%) for 1 week. Rats were gavaged with a single dose of either 0.125 mg AFB1 or 25 mg FB1 per kg body weight and a combination thereof in the presence and absence of an aqueous solution of UPSN. The kinetics of mycotoxin excretion were monitored by analyzing serum AFB1 -albumin, urinary AF (AFM1) and FB1 biomarkers over a period of 72 h. UPSN decreased AFM1 excretion by 88-97%, indicating highly effective binding. FB1 excretion was reduced, to a lesser extent, ranging from 45% to 85%. When in combination, both AFB1 and FB1 binding occurred, but capacity was decreased by almost half. In the absence of UPSN, the combined AFB1 and FB1 treatment decreased the urinary biomarkers by 67% and 45% respectively, but increased levels of AFB1 -albumin, presumably by modulating its cytochrome metabolism. UPSN significantly reduced bioavailability of both AFB1 and FB1 when in combination; suggesting that it can be utilized to reduce levels below their respective thresholds for affecting adverse biological effects., (Copyright © 2013 John Wiley & Sons, Ltd.)