Immunotoxicology: A brief history, current status and strategies for future immunotoxicity assessment

Germolec, Dori R.; Luebke, Robert W.; Rooney, Andrew A.; Shipkowski, Kelly A.; Vandebriel, Rob J.; Loveren, Henk Van

doi:10.1016/j.cotox.2017.08.002

Cited by 30 publications

(17 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, it is unknown whether, upon svp knockdown, reduced expression of bacterial recognition proteins (and thereby hampered initial bacterial defense) might lead to the activation of the humoral/IMD immune system at a later time point in the fat body. It is also possible that reduced levels of detoxification enzymes in the absence of svp might result in the accumulation of xenobiotics that activate an immune response, reminiscent of mammalian innate T-cells that recognize and process allergens and other environmental chemicals prior to their presentation to lymphocytes (MINNICOZZI et al 2011;GERMOLEC et al 2017;MAEDA et al 2019). It is also not known at this point whether these changes in immune function and xenobiotic response in the absence of svp occur in adipocytes, oenocytes, or both cell types, or what their functional consequence is to the steps of oogenesis affected by adipocyte/oenocyte Svp activity (WEAVER AND DRUMMOND-BARBOSA 2019).…”

Section: Svp Modulates the Transcription Of Genes Involved In Xenobiomentioning

confidence: 99%

The Nuclear Receptor Seven Up Regulates Genes Involved in Immunity and Xenobiotic Response in the AdultDrosophilaFemale Fat Body

Weaver¹,

Drummond‐Barbosa²

2020

G3 Genes|Genomes|Genetics

View full text Add to dashboard Cite

The physiology of organisms depends on inter-organ communication in response to changes in the environment. Nuclear receptors are broadly expressed transcription factors that respond to circulating molecules to control many biological processes, including immunity, detoxification, and reproduction. Although the tissue-intrinsic roles of nuclear receptors in reproduction have been extensively studied, there is increasing evidence that nuclear receptor signaling in peripheral tissues can also influence oogenesis. We previously showed that the Drosophila nuclear receptor Seven up (Svp) is required in the adult fat body to regulate distinct steps of oogenesis; however, the relevant downstream targets of Svp remain unknown. Here, we took an RNA sequencing approach to identify candidate Svp targets specifically in the adult female fat body that might mediate this response. svp knockdown in the adult female fat body significantly downregulated immune genes involved in the first line of pathogen defense, suggesting a role for Svp in stimulating early immunity. In addition, we found that Svp transcriptionally regulates genes involved in each step of the xenobiotic detoxification response. Based on these findings, we propose a testable model in which Svp functions in the adult female fat body to stimulate early defense against pathogens and facilitate detoxification as part of its mechanisms to promote oogenesis.

show abstract

Section: Svp Modulates the Transcription Of Genes Involved In Xenobiomentioning

confidence: 99%

The Nuclear Receptor Seven Up Regulates Genes Involved in Immunity and Xenobiotic Response in the AdultDrosophilaFemale Fat Body

Weaver¹,

Drummond‐Barbosa²

2020

G3 Genes|Genomes|Genetics

View full text Add to dashboard Cite

show abstract

“…With tens of thousands of chemicals in production globally, frameworks are needed in order to assess them for immunotoxic potential. Current practices for immunotoxicity testing consist of a lowthroughput tiered approach in rodent models (Germolec et al 2017). While Tier I involves screens to assess basic immunologic function after exposure to xenobiotics, Tier II follows in order to provide a meaningful depth of those effects by using multiple immunologic assays for apical endpoints (Germolec et al 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Current practices for immunotoxicity testing consist of a lowthroughput tiered approach in rodent models (Germolec et al 2017). While Tier I involves screens to assess basic immunologic function after exposure to xenobiotics, Tier II follows in order to provide a meaningful depth of those effects by using multiple immunologic assays for apical endpoints (Germolec et al 2017). In fact, the United States Environmental Protection Agency (USEPA) Toxic Substances Control Act Health Effects Guidelines for evaluating immunotoxicity are intended only for use in rodent models, and they do not require functional assessment of myeloid cells in the innate immune system (USEPA 1998).…”

Section: Introductionmentioning

confidence: 99%

In vivoassessment of respiratory burst inhibition by xenobiotic exposure using larval zebrafish

Phelps

Fletcher

Rodríguez-Nunez

et al. 2020

Journal of Immunotoxicology

View full text Add to dashboard Cite

Currently, assessment of the potential immunotoxicity of a given agent involves a tiered approach for hazard identification and mechanistic studies, including observational studies, evaluation of immune function, and measurement of susceptibility to infectious and neoplastic diseases. These studies generally use costly low-throughput mammalian models. Zebrafish, however, offer an excellent alternative due to their rapid development, ease of maintenance, and homology to mammalian immune system function and development. Larval zebrafish also are a convenient model to study the innate immune system with no interference from the adaptive immune system. In this study, a respiratory burst assay (RBA) was utilized to measure reactive oxygen species (ROS) production after developmental xenobiotic exposure. Embryos were exposed to non-teratogenic doses of chemicals and at 96 h post-fertilization, the ability to produce ROS was measured. Using the RBA, 12 compounds with varying immune-suppressive properties were screened. Seven compounds neither suppressed nor enhanced the respiratory burst; five reproducibly suppressed global ROS production, but with varying potencies: benzo[a]pyrene, 17b-estradiol, lead acetate, methoxychlor, and phenanthrene. These five compounds have all previously been reported as immunosuppressive in mammalian innate immunity assays. To evaluate whether the suppression of ROS by these compounds was a result of decreased immune cell numbers, flow cytometry with transgenic zebrafish larvae was used to count the numbers of neutrophils and macrophages after chemical exposure. With this assay, benzo[a]pyrene was found to be the only chemical that induced a change in the number of immune cells by increasing macrophage but not neutrophil numbers. Taken together, this work demonstrates the utility of zebrafish larvae as a vertebrate model for identifying compounds that impact innate immune function at non-teratogenic levels and validates measuring ROS production and phagocyte numbers as metrics for monitoring how xenobiotic exposure alters the innate immune system.

show abstract

“…The awareness of the consequences of altered immune function is the most likely outcome of inadvertent exposure. The human health implications of studies in which chemical exposure reduced resistance to infection drove an early focus on immunosuppression within the toxicology community [12].…”

Section: Introductionmentioning

confidence: 99%

Novel Acaricidal Drug Fluazuron Causes Immunotoxicity via Selective Depletion of Lymphocytes T CD8

Ribeiro

Soares

Chaves

et al. 2019

Evidence-Based Complementary and Alternative Medicine

View full text Add to dashboard Cite

Fluazuron is one of the newest veterinary antitick medicines. Belonging to the benzoylphenylureas group, its mechanism of action acts by the interference of the formation of the chitin of the tick, which is responsible for the hardening of its exoskeletons. In addition to taking care of the health of the animal so that it receives the medication in the doses and the correct form, it is important to analyze the safety of the operator. Reduced resistance to infectious disease was a well-documented consequence of primary and acquired immunodeficiencies, but a novel finding following xenobiotic exposure. The awareness of the consequences of altered immune function is the most likely outcome of inadvertent exposure. The human health implications of studies in which chemical exposure reduced resistance to infection drove an early focus on immunosuppression within the toxicology community. The main objective is to perform the evaluation by computational platforms and in cell culture, searching for data that can serve as a foundation for a better understanding of the toxic effects involved with the accidental contamination of Fluazuron and, thus, to assist the medical community and users to understand the risks inherent in its use. As far as we can determine in the literature, our work has unmistakably demonstrated that the Fluazuron can cause genotoxicity by probable chromatin rearrangement and immunodepleting by specific reduction of the CD8 T lymphocyte subpopulation, mediated by the decrease in gamma interferon production. Although the use of Fluazuron is a necessity for tick control and for cattle management, we must bear in mind that the imminent risks to its application exist. Careless use can damage the immune system which in turn carries a gigantic hazard by opening a door to diseases and pathogens and leaving us defenseless.

show abstract

Immunotoxicology: A brief history, current status and strategies for future immunotoxicity assessment

Cited by 30 publications

References 36 publications

The Nuclear Receptor Seven Up Regulates Genes Involved in Immunity and Xenobiotic Response in the AdultDrosophilaFemale Fat Body

The Nuclear Receptor Seven Up Regulates Genes Involved in Immunity and Xenobiotic Response in the AdultDrosophilaFemale Fat Body

In vivoassessment of respiratory burst inhibition by xenobiotic exposure using larval zebrafish

Novel Acaricidal Drug Fluazuron Causes Immunotoxicity via Selective Depletion of Lymphocytes T CD8

Contact Info

Product

Resources

About