Validation of research trajectory 1 of an Exposome framework: Exposure to benzo(a)pyrene confers enhanced susceptibility to bacterial infection

Abstract

The exposome provides a framework for understanding elucidation of an uncharacterized molecular mechanism conferring enhanced susceptibility of macrophage membranes to bacterial infection after exposure to the environmental contaminant benzo(a)pyrene, [B(a)P]. The fundamental requirement in activation of macrophage effector functions is the binding of immunoglobulins to Fc receptors. FcγRIIa (CD32a), a member of the Fc family of immunoreceptors with low affinity for immunoglobulin G, has been reported to bind preferentially to IgG within lipid rafts. Previous research suggested that exposure to B(a)P suppressed macrophage effector functions but the molecular mechanisms remained elusive. The goal of this study was to elucidate the mechanism(s) of B(a)P-exposure induced suppression of macrophage function by examining the resultant effects of exposure-induced insult on CD32-lipid raft interactions in the regulation of IgG binding to CD32. The results demonstrate that exposure of macrophages to B(a)P alters their lipid raft integrity by decreasing membrane cholesterol 25% while increasing CD32 into non-lipid raft fractions. This robust diminution in membrane cholesterol and 30% exclusion of CD32 from lipid rafts causes a significant reduction in CD32-mediated IgG binding to suppress essential macrophage effector functions. Such exposures across the lifespan would have the potential to induce an immunosuppressive endophenotypes in vulnerable populations.

Chemoprevention of Colorectal Cancer by Anthocyanidins and Mitigation of Metabolic Shifts Induced by Dysbiosis of the Gut Microbiome

“…BPDE has also been found to target p53 thereby altering the tumor suppression of cells which may ultimately lead to cancer (7). Interestingly, research that measures all of the exposures of an individual in a lifetime and how those exposures relate to health, referred to as "exposome," has found that exposure to B[a]P leads to the enhanced susceptibility of macrophage membranes to bacterial infection and ultimately may lead to immunosuppression (8). Although one of the first carcinogens to be studied, B[a]P remains a continued threat due to its widespread presence in the environment.…”

Application of the Public Health Exposome Framework to Estimate Phenotypes of Resilience in a Model Ohio African-American Women’s Cohort

“…While this is particularly evident in environmentally compromised neighborhoods, globally, very little is known as to how chemical and non-chemical exposures from the natural, built, and social environment, coupled with individual behavioral and inherent characteristics, propagate the effects of PM 2.5 on the lifetime progression of disparate cardio-metabolic health outcomes in longitudinal cohorts around the globe. In the future, the Public Health Exposome framework [6,7,13,29] will advance understanding of associations between a combination of chemical and non-chemical stressor exposures, personal characteristics, and CMD risk in the cohorts of African-American women.…”

“…The Public Health Exposome framework will allow for the development of cumulative risk models that Values must be interpreted carefully estimate the role of which exposure(s) to multiple, chemical (PM 2.5 ), and non-chemical (sub-standard housing, violence, neighborhood deprivation) stressors over the life course produce endo-phenotypes that modify the incidence of adverse health events, or alternatively resilience, at the population level. This approach holds great promise for increasing our understanding of exposure mechanisms and pathways associated with adverse health outcomes and for identifying the effects of different levels of exposure at critical life stages [6,13]. It serves as a template for targeting clinical, program, and policy initiatives that address the needs and circumstances of vulnerable populations and neighborhoods.…”

Comparing the effects of an exposure to a polycyclic aromatic hydrocarbon mixture versus individual polycyclic aromatic hydrocarbons during monocyte to macrophage differentiation: Mixture exposure results in altered immune metrics

“…During differentiation, PAH exposures of 10‐μM B[ a ]P (Sigma‐Aldrich), 10‐μM benz[ a ]anthracene (B[ a ]A, Sigma‐Aldrich), or a combination of six PAHs (6‐MIX) were added to cell media. To maximize the relevance of the cell line model exposure results, the dose of the PAH exposure was chosen to allow direct comparisons to previously published studies performed using primary human monocytes (Laupeze et al, 2002; van Grevenynghe et al, 2003), human primary T cells (Davila et al, 1996), or human PBMC (Clark et al, 2016; Romero et al, 1997). This dose also allows comparison with other cell lines such as Daudi human B cells (Mounho & Burchiel, 1998), human epithelial cells (Courter et al, 2007), human fibroblasts (Plant et al, 1985), and other human monocyte lines, including THP‐1 (Wan et al, 2006).…”