Phthalates are esters of phthalic acid which are used in cosmetics and other daily personal care products. They are also used in polyvinyl chloride (PVC) plastics to increase durability and ...plasticity. Phthalates are not present in plastics by covalent bonds and thus can easily leach into the environment and enter the human body by dermal absorption, ingestion, or inhalation. Several
and
studies suggest that phthalates can act as endocrine disruptors and cause moderate reproductive and developmental toxicities. Furthermore, phthalates can pass through the placental barrier and affect the developing fetus. Thus, phthalates have ubiquitous presence in food and environment with potential adverse health effects in humans. This review focusses on studies conducted in the field of toxicogenomics of phthalates and discusses possible transgenerational and multigenerational effects caused by phthalate exposure during any point of the life-cycle.
The Frontiers Media family has over 200 journals, which are each headed by usually one Field Chief Editor, and several specialty sections, which are each headed by one or more Specialty Chief ...Editors. The year 2021 was the 10th anniversary of the founding of the Frontiers in Genetics journal and the Frontiers in Toxicogenomics specialty section of this journal. In 2021, we also announce one of the newest of the Frontiers journals–Frontiers in Toxicology which is part of the Frontiers Media family of journals but independent of Frontiers in Genetics. The Specialty Chief Editor of Toxicogenomics, and one of 26 Specialty Chief Editors of Frontiers in Genetics, is Dr. Ruden. As of 2021, Toxicogenomics has published over 138 articles and has over 370 Editors including 90 Associate Editors and 280 Review Editors. The Frontiers in Genetics impact factor was initially approximately 2.5 when it was first listed in PubMed in 2015 and has risen steadily to its current value of 4.8, which is typical for the majority of the over 200 Frontiers journals that have established impact factors. In this overview of the first decade of Toxicogenomics section, we discuss the top 5 articles with the highest Scopus citations, which were all written in the first few years of the journal. The article with the highest number of citations, with 353 Scopus over 600 Google Scholar citations, and the highest average number of citations (67) that steadily increased from 10 citations in 2013 to 119 citations in 2021, was written in 2012 by Dr. Ruden’s laboratory and titled, “Using
Drosophila melanogaster
as a model for genotoxic chemical mutational studies with a new program, SnpSift.” The five most influential authors who published in the journal in the past 10 years based on Scopus citations of a particular paper are Dr. Ruden’s laboratory, with 353 Scopus citations for the SnpSift paper mentioned above; Drs. Brock Christensen and Carmen J. Marsit, with 86 Scopus citations for their review, “Epigenomics in environmental health”; Dr. Michael Aschner and colleagues, with 61 Scopus citations for their paper “Genetic factors and manganese-induced neurotoxicity”; and Dr. Sandra C. dos Santos and colleagues, with 59 Scopus citations for their paper, “Yeast toxicogenomics: genome-wide responses to chemical stresses with impact in environmental health, pharmacology, and biotechnology.” While the top 5 papers were published in the early years of the journal, we will also discuss a more recent article published in 2018 on a comparison of RNA-seq and microarray methods by Dr. Michael Liguori’s laboratory, “Comparison of RNA-Seq and Microarray Gene Expression Platforms for the Toxicogenomic Evaluation of Liver From Short-Term Rat Toxicity Studies”, that far exceeds the number of downloads and views of all the other articles published in the first 10 years of the journal and will likely be a top cited paper in the second decade highlights of this journal. Finally, we discuss where the Toxicogenomics specialty section will go to advance the field of toxicogenomics, and more generally, toxicology, in the future.
The Frontiers Media family has over 200 journals, which are each headed by usually one Field Chief Editor, and several thousand specialty sections, which are each headed by one or more Specialty ...Chief Editors. The year 2021 was the 10th anniversary of the founding of the Frontiers in Genetics journal and the Frontiers in Toxicogenomics specialty section of this journal. In 2021, we also announce one of the newest of the Frontiers journals-Frontiers in Toxicology which is part of the Frontiers Media family of journals but independent of Frontiers in Genetics. Dr. Ruden is the founding, and currently sole, Specialty Chief Editor of Frontiers in Toxicogenomics and one of 9 Specialty Chief Editors of Frontiers in Toxicology. As of 2021, Frontiers in Toxicogenomics has published over 138 articles and has over 370 Editors including 90 Associate Editors and 280 Review Editors. The Frontiers in Genetics impact factor was initially approximately 2.5 when it was first listed in PubMed in 2015 and has risen steadily to its current value of 4.8, which is typical for the majority of the over 200 Frontiers journals that have established impact factors. In this overview of the first decade of Frontiers in Toxicogenomics, we discuss the top 5 articles with the highest Scopus citations, which were all written in the first few years of the journal. The article with the highest number of citations, with 353 Scopus over 600 Google Scholar citations, and the highest average number of citations (67) that steadily increased from 10 citations in 2013 to 119 citations in 2021, was written in 2012 by Dr. Ruden's laboratory and titled, "Using
as a model for genotoxic chemical mutational studies with a new program, SnpSift." The five most influential authors who published in the journal in the past 10 years based on Scopus citations of a particular paper are Dr. Ruden's laboratory, with 353 Scopus citations for the SnpSift paper mentioned above; Drs. Brock Christensen and Carmen J. Marsit, with 86 Scopus citations for their review, "Epigenomics in environmental health"; Dr. Michael Aschner and colleagues, with 61 Scopus citations for their paper "Genetic factors and manganese-induced neurotoxicity"; and Dr. Sandra C. dos Santos and colleagues, with 59 Scopus citations for their paper, "Yeast toxicogenomics: genome-wide responses to chemical stresses with impact in environmental health, pharmacology, and biotechnology." While the top 5 papers were published in the early years of the journal, we will also discuss a more recent article published in 2018 on a comparison of RNA-seq and microarray methods by Dr. Michael Liguori's laboratory, "Comparison of RNA-Seq and Microarray Gene Expression Platforms for the Toxicogenomic Evaluation of Liver From Short-Term Rat Toxicity Studies," that far exceeds the number of downloads and views of all the other articles published in the first 10 years of the journal and will likely be a top cited paper in the second decade highlights of this journal. Finally, we discuss where the Frontiers in Toxicogenomics specialty journal and the Frontiers in Toxicology journal will go to advance the field of toxicogenomics, and more generally, toxicology, in the future.
Hsp90 is a chaperone protein that interacts with client proteins that are known to be in the cell cycle, signaling and chromatin-remodeling pathways. Hsp90 inhibitors act additively or ...synergistically with many other drugs in the treatment of both solid tumors and leukemias in murine tumor models and humans. Hsp90 inhibitors potentiate the actions of anti-cancer drugs that target Hsp90 client proteins, including trastuzumab (Herceptin™) which targets Her2/Erb2B, as Hsp90 inhibition elicits the drug effects in cancer cell lines that are otherwise resistant to the drug. A phase II study of the Hsp90 inhibitor 17-AAG and trastuzumab showed that this combination therapy has anticancer activity in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. In this review, we discuss the results of Hsp90 inhibitors in combination with trastuzumab and other cancer drugs. We also discuss recent results from yeast focused on the genetics of drug resistance when Hsp90 is inhibited and the implications that this might have in understanding the effects of genetic variation in treating cancer in humans.
This study explores the use of human embryonic stem cells (hESCs) for assessing nanotoxicology, specifically, the effect of gold nanoparticles (AuNPs) of different core sizes (1.5, 4, and 14 nm) on ...the viability, pluripotency, neuronal differentiation, and DNA methylation of hESCs. The hESCs exposed to 1.5 nm thiolate‐capped AuNPs exhibit loss of cohesiveness and detachment suggesting ongoing cell death at concentrations as low as 0.1 μg mL−1. The cells exposed to 1.5 nm AuNPs at this concentration do not form embryoid bodies but rather disintegrate into single cells within 48 h. Cell death caused by 1.5 nm AuNPs also occur in hESC‐derived neural progenitor cells. None of the other nanoparticles exhibit toxic effects on the hESCs at concentrations as high as 10 μg mL−1 during a 19 d neural differentiation period. Thiolate‐capped 4 nm AuNPs at 10 μg mL−1 cause a dramatic decrease in global DNA methylation (5 mC) and a corresponding increase in global DNA hydroxymethylation (5 hmC) of the hESC's DNA in only 24 h. This work identifies a type of AuNPs highly toxic to hESCs and demonstrates the potential of hESCs in predicting nanotoxicity and characterizing their ability to alter the DNA methylation and hydroxymethylation patterns in the cells.
The differentiation of human embryonic stem cells (hESCs) into neurons is used to assess the morphological and epigenetic effects of exposure to gold nanoparticles (AuNPs). Ultrasmall AuNPs are highly toxic to hESCs and their neural derivatives. This work demonstrates the potentials of stem cells in predicting nanotoxicity and will help to define the health risks of nanoparticles.
•Chronic lead exposure induces cochlear oxidative stress.•Chronic lead exposure shifts hearing threshold levels.•Lead co-exposure potentiates noise-induced hearing loss.
Acquired hearing loss is ...caused by complex interactions of multiple environmental risk factors, such as elevated levels of lead and noise, which are prevalent in urban communities. This study delineates the mechanism underlying lead-induced auditory dysfunction and its potential interaction with noise exposure. Young-adult C57BL/6 mice were exposed to: 1) control conditions; 2) 2 mM lead acetate in drinking water for 28 days; 3) 90 dB broadband noise 2 h/day for two weeks; and 4) both lead and noise. Blood lead levels were measured by inductively coupled plasma mass spectrometry analysis (ICP-MS) lead-induced cochlear oxidative stress signaling was assessed using targeted gene arrays, and the hearing thresholds were assessed by recording auditory brainstem responses. Chronic lead exposure downregulated cochlear Sod1, Gpx1, and Gstk1, which encode critical antioxidant enzymes, and upregulated ApoE, Hspa1a, Ercc2, Prnp, Ccl5, and Sqstm1, which are indicative of cellular apoptosis. Isolated exposure to lead or noise induced 8–12 dB and 11–25 dB shifts in hearing thresholds, respectively. Combined exposure induced 18–30 dB shifts, which was significantly higher than that observed with isolated exposures. This study suggests that chronic exposure to lead induces cochlear oxidative stress and potentiates noise-induced hearing impairment, possibly through parallel pathways.
We report that the DNA methylation profile of a child's neonatal whole blood can be significantly influenced by his or her mother's neonatal blood lead levels (BLL). We recruited 35 mother-infant ...pairs in Detroit and measured the whole blood lead (Pb) levels and DNA methylation levels at over 450,000 loci from current blood and neonatal blood from both the mother and the child. We found that mothers with high neonatal BLL correlate with altered DNA methylation at 564 loci in their children's neonatal blood. Our results suggest that Pb exposure during pregnancy affects the DNA methylation status of the fetal germ cells, which leads to altered DNA methylation in grandchildren's neonatal dried blood spots. This is the first demonstration that an environmental exposure in pregnant mothers can have an epigenetic effect on the DNA methylation pattern in the grandchildren.
Amyotrophic lateral sclerosis (ALS) is a terminal disease involving the progressive degeneration of motor neurons within the motor cortex, brainstem and spinal cord. Most cases are sporadic (sALS) ...with unknown causes suggesting that the etiology of sALS may not be limited to the genotype of patients, but may be influenced by exposure to environmental factors. Alterations in epigenetic modifications are likely to play a role in disease onset and progression in ALS, as aberrant epigenetic patterns may be acquired throughout life. The aim of this study was to identify epigenetic marks associated with sALS. We hypothesize that epigenetic modifications may alter the expression of pathogenesis-related genes leading to the onset and progression of sALS. Using ELISA assays, we observed alterations in global methylation (5 mC) and hydroxymethylation (5 HmC) in postmortem sALS spinal cord but not in whole blood. Loci-specific differentially methylated and expressed genes in sALS spinal cord were identified by genome-wide 5mC and expression profiling using high-throughput microarrays. Concordant direction, hyper- or hypo-5mC with parallel changes in gene expression (under- or over-expression), was observed in 112 genes highly associated with biological functions related to immune and inflammation response. Furthermore, literature-based analysis identified potential associations among the epigenes. Integration of methylomics and transcriptomics data successfully revealed methylation changes in sALS spinal cord. This study represents an initial identification of epigenetic regulatory mechanisms in sALS which may improve our understanding of sALS pathogenesis for the identification of biomarkers and new therapeutic targets.
This paper describes a new program SnpSift for filtering differential DNA sequence variants between two or more experimental genomes after genotoxic chemical exposure. Here, we illustrate how SnpSift ...can be used to identify candidate phenotype-relevant variants including single nucleotide polymorphisms, multiple nucleotide polymorphisms, insertions, and deletions (InDels) in mutant strains isolated from genome-wide chemical mutagenesis of Drosophila melanogaster. First, the genomes of two independently isolated mutant fly strains that are allelic for a novel recessive male-sterile locus generated by genotoxic chemical exposure were sequenced using the Illumina next-generation DNA sequencer to obtain 20- to 29-fold coverage of the euchromatic sequences. The sequencing reads were processed and variants were called using standard bioinformatic tools. Next, SnpEff was used to annotate all sequence variants and their potential mutational effects on associated genes. Then, SnpSift was used to filter and select differential variants that potentially disrupt a common gene in the two allelic mutant strains. The potential causative DNA lesions were partially validated by capillary sequencing of polymerase chain reaction-amplified DNA in the genetic interval as defined by meiotic mapping and deletions that remove defined regions of the chromosome. Of the five candidate genes located in the genetic interval, the Pka-like gene CG12069 was found to carry a separate pre-mature stop codon mutation in each of the two allelic mutants whereas the other four candidate genes within the interval have wild-type sequences. The Pka-like gene is therefore a strong candidate gene for the male-sterile locus. These results demonstrate that combining SnpEff and SnpSift can expedite the identification of candidate phenotype-causative mutations in chemically mutagenized Drosophila strains. This technique can also be used to characterize the variety of mutations generated by genotoxic chemicals.
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