Renal Health Effects in Trichloroethylene and Arsenic Co-Exposed Mice

Development of a rodent model for renal cancer and disease development due to toxicant exposure is complicated by differences in renal handling of toxicants between rodents and humans as well as the tendency of rodents to develop significant background spontaneous renal disease that may mimic pre-neoplastic disease or mask more subtle lesions. Classical toxicological studies often focus on one toxicant in a genetically homogeneous population, despite attempting to model human exposure situations involving genetically heterogeneous populations and exposure to mixtures of toxicants. Given these challenges, it has become clear that toxicological studies must address the effects of genetic variability and the range of sensitivity to toxicity due to this inherent variability. Experimental paradigms that assess and control for as many of the intrinsic and extrinsic factors influencing renal response to toxicant exposure are also needed. In an effort to address these limitations, a mouse model was devised that included genetic heterogeneity, mixtures of toxicants at environmentally relevant concentrations, and diet that reflects a typical western diet to better reflect the exposure conditions of human populations. Despite development of a mouse model that more accurately reflects human environmental toxicant exposure conditions, no primary renal cell tumors were observed in the study. Differences in renal health between exposed and unexposed populations were observed as well as increased evidence of renal disease in male mice compared to females across the entire study population. In the current study TCE exposure did not cause renal cell tumors nor did it increase renal disease when combined with arsenic exposure. Evidence of reduced or equal renal damage from co-exposure was observed in some cases, and we speculate that this is due to a threshold effect of damage from a first toxicant limiting the ability of a second toxicant to cause damage. Additional studies of combined toxicant exposure are needed

Improving Metabolic Health Through Precision Dietetics in Mice

The incidence of diet-induced metabolic disease has soared over the last half-century, despite national efforts to improve health through universal dietary recommendations. Studies comparing dietary patterns of populations with health outcomes have historically provided the basis for healthy diet recommendations. However, evidence that population-level diet responses are reliable indicators of responses across individuals is lacking. This study investigated how genetic differences influence health responses to several popular diets in mice, which are similar to humans in genetic composition and the propensity to develop metabolic disease, but enable precise genetic and environmental control. We designed four human-comparable mouse diets that are representative of those eaten by historical human populations. Across four genetically distinct inbred mouse strains, we compared the American diet’s impact on metabolic health to three alternative diets (Mediterranean, Japanese, and Maasai/ketogenic). Furthermore, we investigated metabolomic and epigenetic alterations associated with diet response. Health effects of the diets were highly dependent on genetic background, demonstrating that individualized diet strategies improve health outcomes in mice. If similar genetic-dependent diet responses exist in humans, then a personalized, or “precision dietetics,” approach to dietary recommendations may yield better health outcomes than the traditional one-size-fits-all approach

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Renal Health Effects in Trichloroethylene and Arsenic Co-Exposed Mice

Development of a rodent model for renal cancer and disease development due to toxicant exposure is complicated by differences in renal handling of toxicants between rodents and humans as well as the tendency of rodents to develop significant background spontaneous renal disease that may mimic pre-neoplastic disease or mask more subtle lesions. Classical toxicological studies often focus on one toxicant in a genetically homogeneous population, despite attempting to model human exposure situations involving genetically heterogeneous populations and exposure to mixtures of toxicants. Given these challenges, it has become clear that toxicological studies must address the effects of genetic variability and the range of sensitivity to toxicity due to this inherent variability. Experimental paradigms that assess and control for as many of the intrinsic and extrinsic factors influencing renal response to toxicant exposure are also needed. In an effort to address these limitations, a mouse model was devised that included genetic heterogeneity, mixtures of toxicants at environmentally relevant concentrations, and diet that reflects a typical western diet to better reflect the exposure conditions of human populations. Despite development of a mouse model that more accurately reflects human environmental toxicant exposure conditions, no primary renal cell tumors were observed in the study. Differences in renal health between exposed and unexposed populations were observed as well as increased evidence of renal disease in male mice compared to females across the entire study population. In the current study TCE exposure did not cause renal cell tumors nor did it increase renal disease when combined with arsenic exposure. Evidence of reduced or equal renal damage from co-exposure was observed in some cases, and we speculate that this is due to a threshold effect of damage from a first toxicant limiting the ability of a second toxicant to cause damage. Additional studies of combined toxicant exposure are needed

Long-Term Combinatorial Exposure to Trichloroethylene and Inorganic Arsenic in Genetically Heterogeneous Mice Results in Renal Tubular Damage and Cancer-Associated Molecular Changes

Trichloroethylene (TCE) and inorganic arsenic (iAs) are environmental contaminants that can target the kidney. Chronic exposure to TCE is associated with increased incidence of renal cell carcinoma, while co-exposure to TCE and iAs likely occurs in exposed human populations, such as those near Superfund sites. In order to better understand the kidney health consequences of TCE and/or iAs exposure, a genetically heterogeneous mouse population derived from FVB/NJ and CAST/EiJ mouse strains and deficient for multidrug resistance genes (Abcb1atm1Bor, Abcb1btm1Bor) was chronically exposed for 52-weeks to varying concentrations of TCE and iAs. Although no exposure group resulted in primary renal cell tumors, kidneys from exposed mice did have significant increases in histologic and biochemical evidence of renal tubular disease with each toxicant alone and with combined exposure, with males having significantly higher levels of damage. Although no added increase in tubular disease was observed with combination exposure compared to single toxicants, molecular changes in kidneys from mice that had the combined exposure were similar to those previous observed in an embryonic stem cell assay for the P81S TCE-induced renal cell carcinoma mutation in the Von Hippel-Lindau syndrome (VHL) gene. While this model more accurately reflects human exposure conditions, development of primary renal tumors observed in humans following chronic TCE exposure was not reproduced even after inclusion of genetic heterogeneity and co-carcinogenic iAs