Current opinion in toxicology最新文献

The introduction of biotherapeutics opened a new era of treatment for several inflammatory and cancer diseases, although they are not deprived in toxicity, which can lead to drug interruption. Besides infusion reactions, the occurrence of cytopenia is a major concern regarding treatment with biologicals. Biotherapeutic-related hemotoxicities is a challenging clinical problem, especially because the definition of the culprit pathological mechanism can be very complicated. In fact, some confounders, such as the baseline disease or concomitant therapies, as well as the direct effect on hematopoiesis of biologicals, all contribute to the growing difficulty in understanding the mechanism of hematotoxicity. This review summarizes the knowledge about the immune-mediated mechanisms of anemia, leucopenia, and thrombocytopenia associated with the use of biologicals.

Heavy metal exposure can lead to death and disability. A variety of sources including soil, wastewater, mining activities, industrial waste, sewage wastes, pesticides used in agriculture and automobile exhaust gas contribute to the overall metal burden. The adverse health effects of heavy metals such as lead, arsenic, mercury, and cadmium have become more complicated and challenging for the world owing to the highly complex nature of heavy metal–biological interactions. Although the mechanism of action of metals varies, the only way to help the body struggle with the heavy metal burden is to remove heavy metals from the body and eliminate, or reduce, the possibility of re-exposure. It is thought that the use of biomarkers to detect early damage to the cardiovascular system by exposure to low amounts of heavy metals may be beneficial. Furthermore, the clinical status for the patient can be questioned by determining long-term low levels of exposure to humans for doses empirically used to induce cardiotoxicity.

The nature and type of genome editing tools are rapidly expanding and becoming increasingly incorporated into research efforts aimed at understanding human disease. The majority of research involving genome editing has been driven by medical research, with a limited but increasing number of studies currently published in the field of environmental health and toxicology. The aim of the review is to address this research gap by providing a high-level summary of current genome editing techniques and presenting examples of how some of these techniques have been used toxicologically to evaluate environmental exposure–induced disease. Specific strategies surrounding the evaluation of hazardous chemicals, chemical mechanism of action/adverse outcome pathways, and interindividual response variability are also discussed to aid in the translation of genome editing methods toward toxicological and environmental health research.

Epigenetics refers to the study of mitotically heritable and potentially reversible changes in gene expression unrelated to the DNA sequence itself, influenced by epigenetic marks including chromatin modifications, noncoding RNA (ncRNA), and alterations to DNA itself via methylation and hydroxymethylation. Epigenetics has taken center stage in the study of diseases such as cancer, diabetes, and neurodegeneration; however, its integration into the field of environmental health sciences and toxicology (e.g. toxicoepigenetics) is in its infancy. This review highlights the need to evaluate surrogate and target tissues in the field of toxicoepigenetics as the National Institute of Environmental Health Sciences multiphased Toxicant Exposure and Response by Genomic and Epigenomic Regulators of Transcription consortia make headway and the emergence of ncRNA biomarkers. The review also discusses lead (Pb) as a potential toxicoepigenetic exposure, where prenatal and postnatal Pb exposure is associated with reprogramming of DNA methylation, histone modifications, and microRNA expression, representing potential biomarkers or predictors for Pb-induced health outcomes. Finally, new advances in epigenome editing, highlighting the potential of small ncRNA, will be explored for environmental health sciences research.

Microarray profiling in the context of toxicity testing in animals has been used for years to identify mechanisms of toxicity, derive points of departure using dose–response modeling, and determine human relevance. High-throughput transcriptomic technologies are increasingly being used to screen environmental chemicals in vitro to identify molecular targets and provide mechanistic context for regulatory testing. This review will discuss the use of gene expression biomarkers to make predictions of activity of molecular targets of chemicals that can be linked to adverse outcomes in a number of cellular and tissue contexts. Gene expression biomarkers are built using global gene expression comparisons from cells or tissues exposed to chemicals with known effects on the factor of interest. Incorporating profiles in which the expression of the factor is altered (e.g. in gene-null mice) facilitates the identification of predictive genes. As an example of their use, biomarkers that predict molecular initiating events and key events in liver cancer adverse outcome pathways have been shown to accurately identify chemical–dose combinations in short-term studies that lead to liver cancer in 2-year bioassays. In the near future, batteries of biomarkers that predict modulation of important targets of environmental chemicals could be used to interpret high-throughput transcriptomic screening data.

Adverse outcome pathways (AOPs) are pragmatic tools in toxicology and risk assessment with broad potential. AOPs are designed to provide a clear-cut mechanistic representation of toxicological effects that span over different layers of biological organization. AOPs share a common structure consisting of a molecular initiating event, a series of key events connected by key event relationships and an adverse outcome. AOPs can serve a number of purposes pertinent to safety assessment of chemicals, such as the establishment of quantitative structure–activity relationships, the development of novel in vitro toxicity screening tests, and the elaboration of prioritization strategies. Development of AOPs ideally complies with guidelines issued by the Organization for Economic Cooperation and Development. Omics, in particular transcriptomics, plays a major role in the establishment and application of AOPs by defining key events and by providing biomarkers for toxicity screening, respectively.

Gene–environment interactions impact the adverse health effects of environmental exposure to toxicants. Identification of genetic factors modulating organismal and cellular response to environmental toxicants can inform risk assessment. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)–based genetic perturbation screening has recently emerged as a powerful approach to illuminate complex cellular processes including mechanisms modulating chemical toxicity. Here, we review key studies that demonstrate the utility of CRISPR screens in deciphering the molecular determinants of sensitivity and tolerance to toxic substances. We reflect on key considerations for implementing a CRISPR screen in toxicology. We also discuss computational methods used for analyzing CRISPR screens and strategies for validating screening results. Finally, we highlight potential future directions to address limitations in CRISPR screening approaches as applied to toxicology.

Next-generation sequencing (NGS) represents several powerful platforms that have revolutionized RNA and DNA analysis. The parallel sequencing of millions of DNA molecules can provide mechanistic insights into toxicology and provide new avenues for biomarker discovery with growing relevance for risk assessment. The evolution of NGS technologies has improved over the last decade with increased sensitivity and accuracy to foster new biomarker assays from tissue, blood, and other biofluids. NGS technologies can identify transcriptional changes and genomic targets with base pair precision in response to chemical exposure. Furthermore, there are several exciting movements within the toxicology community that incorporate NGS platforms into new strategies for more rapid toxicological characterizations. These include the Tox21 in vitro high-throughput transcriptomic screening program, development of organotypic spheroids, alternative animal models, mining archival tissues, liquid biopsy, and epigenomics. This review will describe NGS-based technologies, demonstrate how they can be used as tools for target discovery in tissue and blood, and suggest how they might be applied for risk assessment.

Based on increasing use of mechanistic information in risk assessment, Health Canada's (HC) Task Force on Scientific Risk Assessment established a working group to review and report on the application of toxicogenomics across HC's risk assessment bureaus. The aim was to review current applications and needs for toxicogenomics at HC, to document existing challenges and to promote consistent/coherent risk assessments that consider toxicogenomics. Overall, HC foresees a role for toxicogenomics in risk assessment. To date, select bureaus have incorporated toxicogenomic data, primarily in weight of evidence approaches, to support mode of action analysis. Future efforts to foster networks for increasing expertise/capacity around toxicogenomic data interpretation were viewed as valuable endeavours, and continued support of research to advance applications was recommended.