Aristolochic Acid-Induced Genotoxicity and Toxicogenomic Changes in Rodents

Aristolochic acid(AA)is a group of structurally related nitrophenanthrene carboxylic acids found in many plants that are widely used by many cultures as traditional herbal medicines.AA is a causative agent for Chinese herbs nephropathy,a term replaced later by AA nephropathy.Evidence indicates that AA is nephrotoxic,genotoxic,and carcinogenic in humans;and it also induces tumors in the forestomach,kidney,renal pelvis,urinary bladder,and lung of rats and mice.Therefore,plants containing AA have been classified as carcinogenic to humans(Group 1)bytheInternational AgencyforResearchonCancer.In our laboratories,we have conducted a series of genotoxicity and toxicogenomic studies in the rats exposed to AA of 0.1–10 mg/kg for 12 weeks.Our results demonstrated that AA treatments induced DNA adducts and mutations in the kidney,liver,and spleen of rats,as well as significant alteration of gene expression in both its target and nontarget tissues.AA treatments altered mutagenesis-or carcinogenesis-related microRNA expression in rat kidney and resulted in significant changes in protein expression profiling.We also applied benchmark dose(BMD)modeling to the 3-month AA-induced genotoxicity data.The obtained BMDL10(the lower 95%confidence interval of the BMD10 that is a 10%increase over the background level)for AA-induced mutations in the kidney of rats was about 7μg/kg body weight per day.This review constitutes an overview of our investigations on AA-induced genotoxicity and toxicogenomic changes including gene expression,microRNA expression,and proteomics;and presents updated information focused on AA-induced genotoxicity in rodents.

Relationship between head and neck cancer therapy and some genetic endpoints

Head and neck cancer(HNC) is the sixth most common human malignancy worldwide. The main forms of treat ment for HNC are surgery, radiotherapy(RT) and che motherapy(CT). However, the choice of therapy de pends on the tumor staging and approaches, which are aimed at organ preservation. Because of systemic RT and CT genotoxicity, one of the important side effects is a secondary cancer that can result from the activity of radiation and antineoplastic drugs on healthy cells Ionizing radiation can affect the DNA, causing single and double-strand breaks, DNA-protein crosslinks and oxidative damage. The severity of radiotoxicity can be directly associated with the radiation dosimetry and the dose-volume differences. Regarding CT, cisplatin is stil the standard protocol for the treatment of squamous cell carcinoma, the most common cancer located in theoral cavity. However, simultaneous treatment with cisplatin, bleomycin and 5-fluorouracil or treatment with paclitaxel and cisplatin are also used. These drugs can interact with the DNA, causing DNA crosslinks, double and single-strand breaks and changes in gene expression. Currently, the late effects of therapy have become a recurring problem, mainly due to the increased survival of HNC patients. Herein, we present an update of the systemic activity of RT and CT for HNC, with a focus on their toxicogenetic and toxicogenomic effects.

Sequencing XMET genes to promote genotype-guided risk assessment and precision medicine

High-throughput next generation sequencing (NGS) is a shotgun approach applied in a parallel fashion by which the genome is fragmented and sequenced through small pieces and then analyzed either by aligning to a known reference genome or by de novo assembly without reference genome.This technology has led researchers to conduct an explosion of sequencing related projects in multidisciplinary fields of science.However,due to the limitations of sequencing-based chemistry,length of sequencing reads and the complexity of genes,it is difficult to determine the sequences of some portions of the human genome,leaving gaps in genomic data that frustrate further analysis.Particularly,some complex genes are difficult to be accurately sequenced or mapped because they contain high GC-content and/or low complexity regions,and complicated pseudogenes,such as the genes encoding xenobiotic metabolizing enzymes and transporters (XMETs).The genetic variants in XMET genes are critical to predicate interindividual variability in drug efficacy,drug safety and susceptibility to environmental toxicity.We summarized and discussed challenges,wet-lab methods,and bioinformatics algorithms in sequencing "complex" XMET genes,which may provide insightful information in the application of NGS technology for implementation in toxicogenomics and pharmacogenomics.