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Journal of Exposure Science &... Nov 2022Threshold of Toxicological Concern (TTC) approaches are used for chemical safety assessment and risk-based priority setting for data poor chemicals. TTCs are derived...
BACKGROUND
Threshold of Toxicological Concern (TTC) approaches are used for chemical safety assessment and risk-based priority setting for data poor chemicals. TTCs are derived from in vivo No Observed Effect Level (NOEL) datasets involving an external administered dose from a single exposure route, e.g., oral intake rate. Thus, a route-specific TTC can only be compared to a route-specific exposure estimate and such TTCs cannot be used for other exposure scenarios such as aggregate exposures.
OBJECTIVE
Develop and apply a method for deriving internal TTCs (iTTCs) that can be used in chemical assessments for multiple route-specific exposures (e.g., oral, inhalation or dermal) or aggregate exposures.
METHODS
Chemical-specific toxicokinetics (TK) data and models are applied to calculate internal concentrations (whole-body and blood) from the reported administered oral dose NOELs used to derive the Munro TTCs. The new iTTCs are calculated from the 5th percentile of cumulative distributions of internal NOELs and the commonly applied uncertainty factor of 100 to extrapolate animal testing data for applications in human health assessment.
RESULTS
The new iTTCs for whole-body and blood are 0.5 nmol/kg and 0.1 nmol/L, respectively. Because the iTTCs are expressed on a molar basis they are readily converted to chemical mass iTTCs using the molar mass of the chemical of interest. For example, the median molar mass in the dataset is 220 g/mol corresponding to an iTTC of 22 ng/L-blood (22 pg/mL-blood). The iTTCs are considered broadly applicable for many organic chemicals except those that are genotoxic or acetylcholinesterase inhibitors. The new iTTCs can be compared with measured or estimated whole-body or blood exposure concentrations for chemical safety screening and priority-setting.
SIGNIFICANCE
Existing Threshold of Toxicological Concern (TTC) approaches are limited in their applications for route-specific exposure scenarios only and are not suitable for chemical risk and safety assessments under conditions of aggregate exposure. New internal Threshold of Toxicological Concern (iTTC) values are developed to address data gaps in chemical safety estimation for multi-route and aggregate exposures.
Topics: Humans; Toxicokinetics; Cholinesterase Inhibitors; Animals; Toxicity Tests; No-Observed-Adverse-Effect Level; Mutagens; Risk Assessment
PubMed: 36347933
DOI: 10.1038/s41370-022-00494-x -
Molecules (Basel, Switzerland) Jul 2022Meat is a rich source of various nutrients. However, it needs processing before consumption, what in turn generates formation of carcinogenic compounds, i.a., polycyclic... (Review)
Review
Meat is a rich source of various nutrients. However, it needs processing before consumption, what in turn generates formation of carcinogenic compounds, i.a., polycyclic aromatic hydrocarbons (PAH), nitrosamines (NOCs), and the most mutagenic heterocyclic aromatic amines (HAAs). It was widely found that many factors affect the content of carcinogens in processed meat. However, it has recently been discovered that after digestion free HAAs are released, which are not detectable before enzymatic treatment. It was established that the highest percentage of carcinogens is released in the small intestine and that its amount can be increased up to 6.6-fold. The change in free HAAs content in analyzed samples was dependent on many factors such as meat type, doneness, particle size of meat, and the enzyme concentration used for digestion. In turn, introduction of bacteria naturally occurring in the human digestive tract into the model significantly decreases total amount of HAAs. Contrary, the addition of food ingredients rich in polyphenols, fiber, and water (pepper powder, onions, apples) increases free HAAs' release up to 56.06%. Results suggests that in vitro digestion should be an integral step of sample preparation. Artificial digestion introduced before chromatographic analysis will allow to estimate accurately the content of carcinogens in processed meat.
Topics: Amines; Carcinogens; Cooking; Heterocyclic Compounds; Humans; Meat; Mutagens
PubMed: 35889534
DOI: 10.3390/molecules27144665 -
Cellular and Molecular Life Sciences :... Jun 2022Many mortal organisms on this planet have developed the potential to merge all internal as well as external environmental cues to regulate various processes running... (Review)
Review
Many mortal organisms on this planet have developed the potential to merge all internal as well as external environmental cues to regulate various processes running inside organisms and in turn make them adaptive to the environment through the circadian clock. This moving rotator controls processes like activation of hormonal, metabolic, or defense pathways, initiation of flowering at an accurate period, and developmental processes in plants to ensure their stability in the environment. All these processes that are under the control of this rotating wheel can be changed either by external environmental factors or by an unpredictable phenomenon called mutation that can be generated by either physical mutagens, chemical mutagens, or by internal genetic interruption during metabolic processes, which alters normal functionality of organisms like innate immune responses, entrainment of the clock, biomass reduction, chlorophyll formation, and hormonal signaling, despite its fewer positive roles in plants like changing plant type, loss of vernalization treatment to make them survivable in different latitudes, and defense responses during stress. In addition, with mutation, overexpression of gene components sometimes supresses mutation effect and promote normal circadian genes abundance in the cell, while sometimes it affects circadian functionality by generating arrhythmicity and shows that not only mutation but overexpression also effects normal functional activities of plant. Therefore, this review mainly summarizes the role of each circadian clock genes in regulating rhythmicity, and shows that how circadian outputs are controlled by mutations as well as overexpression phenomenon.
Topics: Circadian Clocks; Circadian Rhythm; Mutagens; Mutation; Plants
PubMed: 35687153
DOI: 10.1007/s00018-022-04368-1 -
Toxicological Sciences : An Official... Jan 2020Heterocyclic aromatic amines (HAAs) are mutagens and potential human carcinogens. Our group and others have demonstrated that HAAs may also produce selective...
Heterocyclic aromatic amines (HAAs) are mutagens and potential human carcinogens. Our group and others have demonstrated that HAAs may also produce selective dopaminergic neurotoxicity, potentially relevant to Parkinson's disease (PD). The goal of this study was to elucidate mechanisms of HAA-induced neurotoxicity through examining a translational biochemical weakness of common PD models. Neuromelanin is a pigmented byproduct of dopamine metabolism that has been debated as being both neurotoxic and neuroprotective in PD. Importantly, neuromelanin is known to bind and potentially release dopaminergic neurotoxicants, including HAAs (eg, β-carbolines such as harmane). Binding of other HAA subclasses (ie, aminoimidazoaazarenes) to neuromelanin has not been investigated, nor has a specific role for neuromelanin in mediating HAA-induced neurotoxicity been examined. Thus, we investigated the role of neuromelanin in modulating HAA-induced neurotoxicity. We characterized melanin from Sepia officinalis and synthetic dopamine melanin, proposed neuromelanin analogs with similar biophysical properties. Using a cell-free assay, we demonstrated strong binding of harmane and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to neuromelanin analogs. To increase cellular neuromelanin, we transfected SH-SY5Y neuroblastoma cells with tyrosinase. Relative to controls, tyrosinase-expressing cells exhibited increased neuromelanin levels, cellular HAA uptake, cell toxicity, and oxidative damage. Given that typical cellular and rodent PD models form far lower neuromelanin levels than humans, there is a critical translational weakness in assessing HAA-neurotoxicity. The primary impacts of these results are identification of a potential mechanism by which HAAs accumulate in catecholaminergic neurons and support for the need to conduct neurotoxicity studies in systems forming neuromelanin.
Topics: Amines; Animals; Carcinogens; Dopamine; Dopaminergic Neurons; Humans; Imidazoles; Melanins; Mutagens; Neurotoxicity Syndromes
PubMed: 31562763
DOI: 10.1093/toxsci/kfz210 -
International Journal of Molecular... May 2023Soybean ( (L.) Merr.) is a nutritious crop that can provide both oil and protein. A variety of mutagenesis methods have been proposed to obtain better soybean germplasm...
Soybean ( (L.) Merr.) is a nutritious crop that can provide both oil and protein. A variety of mutagenesis methods have been proposed to obtain better soybean germplasm resources. Among the different types of physical mutagens, carbon-ion beams are considered to be highly efficient with high linear energy transfer (LET), and gamma rays have also been widely used for mutation breeding. However, systematic knowledge of the mutagenic effects of these two mutagens during development and on phenotypic and genomic mutations has not yet been elucidated in soybean. To this end, dry seeds of Williams 82 soybean were irradiated with a carbon-ion beam and gamma rays. The biological effects of the M generation included changes in survival rate, yield and fertility. Compared with gamma rays, the relative biological effectiveness (RBE) of the carbon-ion beams was between 2.5 and 3.0. Furthermore, the optimal dose for soybean was determined to be 101 Gy to 115 Gy when using the carbon-ion beam, and it was 263 Gy to 343 Gy when using gamma rays. A total of 325 screened mutant families were detected from out of 2000 M families using the carbon-ion beam, and 336 screened mutant families were found using gamma rays. Regarding the screened phenotypic M mutations, the proportion of low-frequency phenotypic mutations was 23.4% when using a carbon ion beam, and the proportion was 9.8% when using gamma rays. Low-frequency phenotypic mutations were easily obtained with the carbon-ion beam. After screening the mutations from the M generation, their stability was verified, and the genome mutation spectrum of M was systemically profiled. A variety of mutations, including single-base substitutions (SBSs), insertion-deletion mutations (INDELs), multinucleotide variants (MNVs) and structural variants (SVs) were detected with both carbon-ion beam irradiation and gamma-ray irradiation. Overall, 1988 homozygous mutations and 9695 homozygous + heterozygous genotype mutations were detected when using the carbon-ion beam. Additionally, 5279 homozygous mutations and 14,243 homozygous + heterozygous genotype mutations were detected when using gamma rays. The carbon-ion beam, which resulted in low levels of background mutations, has the potential to alleviate the problems caused by linkage drag in soybean mutation breeding. Regarding the genomic mutations, when using the carbon-ion beam, the proportion of homozygous-genotype SVs was 0.45%, and that of homozygous + heterozygous-genotype SVs was 6.27%; meanwhile, the proportions were 0.04% and 4.04% when using gamma rays. A higher proportion of SVs were detected when using the carbon ion beam. The gene effects of missense mutations were greater under carbon-ion beam irradiation, and the gene effects of nonsense mutations were greater under gamma-ray irradiation, which meant that the changes in the amino acid sequences were different between the carbon-ion beam and gamma rays. Taken together, our results demonstrate that both carbon-ion beam and gamma rays are effective techniques for rapid mutation breeding in soybean. If one would like to obtain mutations with a low-frequency phenotype, low levels of background genomic mutations and mutations with a higher proportion of SVs, carbon-ion beams are the best choice.
Topics: Glycine max; Mutation; Gamma Rays; Ions; Phenotype; Mutagens; Carbon; Genomics
PubMed: 37240171
DOI: 10.3390/ijms24108825 -
G3 (Bethesda, Md.) Mar 2023Metal nanoparticles, especially silver, have been used in various medical scenarios, due to their excellent antimicrobial effects. Recent studies have shown that AgNPs...
Metal nanoparticles, especially silver, have been used in various medical scenarios, due to their excellent antimicrobial effects. Recent studies have shown that AgNPs do not exert mutagenic effects on target bacteria, but the degree to which they compromise eukaryotic genomes remains unclear. To study this, we evaluated the mutagenic effects of AgNPs on the fission yeast Schizosaccharomyces pombe ATCC-16979, of which ∼23% genes are homologous to human ones, at single-nucleotide resolution, and whole-genome scale by running 283 mutation accumulation lines for ∼260,000 cell divisions in total. We also explored the action and mutagenesis mechanisms using differential gene-expression analysis based on RNAseq. Upon AgNPs treatment, the genomic base-substitution mutation rate of S. pombe at four-fold degenerate sites increased by 3.46×, and small indels were prone to occur in genomic regions that are not simple sequence repeats. The G:C → T:A transversion rate was also significantly increased, likely mostly from oxidative damage. Thus, in addition to their antimicrobial potency, AgNPs might pose slight genotoxicity threats to eukaryotic and possibly human genomes, though at a low magnitude.
Topics: Humans; Silver; Eukaryota; Metal Nanoparticles; Mutagenesis; Mutagens; Schizosaccharomyces; Anti-Infective Agents
PubMed: 36635051
DOI: 10.1093/g3journal/jkad008 -
Nucleic Acids Research Jul 2022Acetaldehyde (AA), a by-product of ethanol metabolism, is acutely toxic due to its ability to react with various biological molecules including DNA and proteins, which...
Acetaldehyde (AA), a by-product of ethanol metabolism, is acutely toxic due to its ability to react with various biological molecules including DNA and proteins, which can greatly impede key processes such as replication and transcription and lead to DNA damage. As such AA is classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC). Previous in vitro studies have shown that AA generates bulky adducts on DNA, with signature guanine-centered (GG→TT) mutations. However, due to its weak mutagenicity, short chemical half-life, and the absence of powerful genetic assays, there is considerable variability in reporting the mutagenic effects of AA in vivo. Here, we used an established yeast genetic reporter system and demonstrate that AA treatment is highly mutagenic to cells and leads to strand-biased mutations on guanines (G→T) at a high frequency on single stranded DNA (ssDNA). We further demonstrate that AA-derived mutations occur through lesion bypass on ssDNA by the translesion polymerase Polζ. Finally, we describe a unique mutation signature for AA, which we then identify in several whole-genome and -exome sequenced cancers, particularly those associated with alcohol consumption. Our study proposes a key mechanism underlying carcinogenesis by acetaldehyde-mutagenesis of single-stranded DNA.
Topics: Acetaldehyde; DNA; DNA Adducts; DNA Damage; DNA Replication; DNA, Single-Stranded; Guanine; Mutagenesis; Mutagens; Mutation
PubMed: 35776120
DOI: 10.1093/nar/gkac570 -
Cells Apr 2022The nuclear membrane defines the boundaries that confine, protect and shape the genome. As such, its blebbing, ruptures and deformations are known to compromise the...
The nuclear membrane defines the boundaries that confine, protect and shape the genome. As such, its blebbing, ruptures and deformations are known to compromise the integrity of genetic material. Yet, drastic transitions of the nuclear membrane such as its invagination towards the nucleoplasm or its capacity to emit nuclear lipid droplets (nLD) have not been evaluated with respect to their impact on genome dynamics. To begin assessing this, in this work we used as a model to ask whether a selection of genotoxins can trigger the formation of nLD. We report that nLD formation is not a general feature of all genotoxins, but of those engendering replication stress. Exacerbation of endogenous replication stress by genetic tools also elicited nLD formation. When exploring the lipid features of the nuclear membrane at the base of this emission, we revealed a link with the unsaturation profile of its phospholipids and, for the first time, of its sterol content. We propose that stressed replication forks may stimulate nLD birth by anchoring to the inner nuclear membrane, provided that the lipid context is adequate. Further, we point to a transcriptional feed-back process that counteracts the membrane's proneness to emit nLD. With nLD representing platforms onto which genome-modifying reactions can occur, our findings highlight them as important players in the response to replication stress.
Topics: Cell Nucleus; Lipid Droplets; Lipid Metabolism; Mutagens; Phospholipids; Saccharomyces cerevisiae
PubMed: 35563696
DOI: 10.3390/cells11091390 -
Mutation Research. Genetic Toxicology... 2022CYP1B1 activates many chemical carcinogens into potent genotoxins, and allelic variants are risk factors in lung, breast, and prostate cancer. However, few eukaryotic...
CYP1B1 activates many chemical carcinogens into potent genotoxins, and allelic variants are risk factors in lung, breast, and prostate cancer. However, few eukaryotic genetic instability endpoints have been directly measured for CYP1B1-activated metabolites. In this study, we expressed human CYP1B1 in yeast strains that measure DNA damage-associated toxicity and frequencies of chromosomal translocations. DNA damage-associated toxicity was measured in a rad4 rad51 strain, defective in both DNA excision and recombinational repair. Frequencies of chromosomal translocations were measured in diploid yeast strains containing two his3 fragments. These strains were exposed to benzo[a]pyrene-7,8-dihydrodiol (BaP-DHD), aflatoxin B (AFB), and the heterocyclic aromatic amines, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). We observed that AFB, BaP-DHD, IQ, and MeIQx conferred toxicity in the DNA repair mutant expressing CYP1B1. Translocation frequencies increased eight-fold and three-fold after exposure to 50 μM AFB and 33 μM BaP-DHD respectively. A DNA damage response was observed after AFB exposure, as measured by the induction of the small subunit of ribonucleotide reductase, Rnr3. While CYP1B1-mediated activation of BaP-DHD and heterocyclic aromatic amines was expected, activation of AFB to become a potent recombinagen was not expected. These studies demonstrate that chromosomal rearrangement is a useful genotoxic endpoint for CYP1B1-mediated carcinogen activation.
Topics: Amines; Carcinogens; Cytochrome P-450 CYP1B1; DNA-Binding Proteins; Humans; Male; Mutagens; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Translocation, Genetic
PubMed: 35151423
DOI: 10.1016/j.mrgentox.2022.503440 -
Scientific Reports Jun 2023Ionizing radiation is known to be DNA damaging and mutagenic, however less is known about which mutational footprints result from exposures of human cells to different...
Ionizing radiation is known to be DNA damaging and mutagenic, however less is known about which mutational footprints result from exposures of human cells to different types of radiation. We were interested in the mutagenic effects of particle radiation exposures on genomes of various human cell types, in order to gauge the genotoxic risks of galactic cosmic radiation, and of certain types of tumor radiotherapy. To this end, we exposed cultured cell lines from the human blood, breast and lung to fractionated proton and alpha particle (helium nuclei) beams at doses sufficient to considerably affect cell viability. Whole-genome sequencing revealed that mutation rates were not overall markedly increased upon proton and alpha exposures. However, there were modest changes in mutation spectra and distributions, such as the increases in clustered mutations and of certain types of indels and structural variants. The spectrum of mutagenic effects of particle beams may be cell-type and/or genetic background specific. Overall, the mutational effects of repeated exposures to proton and alpha radiation on human cells in culture appear subtle, however further work is warranted to understand effects of long-term exposures on various human tissues.
Topics: Humans; Protons; Alpha Particles; Cosmic Radiation; Radiation, Ionizing; Mutation; Mutagens
PubMed: 37328655
DOI: 10.1038/s41598-023-36845-3