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1.
Int J Toxicol ; 36(2): 124-132, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28403741

RESUMEN

Acrylamide (AA) at high exposure levels is neurotoxic, induces testicular toxicity, and increases dominant lethal mutations in rats. RNA-sequencing in testes was used to identify differentially expressed genes (DEG), explore AA-induced pathway perturbations that could contribute to AA-induced testicular toxicity and then used to derive a benchmark dose (BMD). Male F344/DuCrl rats were administered 0.0, 0.5, 1.5, 3.0, 6.0, or 12.0 mg AA/kg bw/d in drinking water for 5, 15, or 31 days. The experimental design used exposure levels that spanned and exceeded the exposure levels used in the rat dominant lethal, 2-generation reproductive toxicology, and cancer bioassays. The time of sample collection was based on previous studies that developed gene expression-based BMD. At 12.0 mg/kg, there were 38, 33, and 65 DEG ( P value <.005; fold change >1.5) in the testes after 5, 15, or 31 days of exposure, respectively. At 31 days, there was a dose-dependent increase in the number of DEG, and at 12.0 mg/kg/d the top three functional clusters affected by AA exposure were actin filament organization, response to calcium ion, and regulation of cell proliferation. The BMD lower 95% confidence limit using DEG ranged from 1.8 to 6.8 mg/kg compared to a no-observed-adverse-effect-level of 2.0 mg/kg/d for male reproductive toxicity. These results are consistent with the known effects of AA on calcium signaling and cytoskeletal actin filaments leading to neurotoxicity and suggest that AA can cause rat dominant lethal mutations by these same mechanisms leading to impaired chromosome segregation during cell division.


Asunto(s)
Acrilamida/toxicidad , Señalización del Calcio/efectos de los fármacos , Citoesqueleto/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Testículo/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratas Endogámicas F344 , Testículo/metabolismo
2.
Mutagenesis ; 31(6): 617-626, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27338305

RESUMEN

Acrylamide is used in many industrial processes and is present in a variety of fried and baked foods. In rodent carcinogenicity assays, acrylamide exposure leads to tumour formation at doses lower than those demonstrated to induce genotoxic damage. We evaluated the potential of acrylamide to induce structural DNA damage and gene mutations in rodents using highly sensitive flow cytometric analysis of micronucleus and Pig-a mutant frequencies, respectively. Male F344 rats and B6C3F1 mice were administered acrylamide in drinking water for 30 days at doses spanning and exceeding the range of acrylamide exposure tested in cancer bioassays-top dose of 12.0 and 24.0mg/kg/day in mice and in rats, respectively. A positive control, N-ethyl-N-nitrosourea, was administered at the beginning and end of the study to meet the expression time for the two DNA damage phenotypes. The results of the micronucleus and Pig-a assays were negative and equivocal, respectively, for male rats exposed to acrylamide at the concentrations tested. In contrast, acrylamide induced a dose-dependent increase in micronucleus formation but tested negative in the Pig-a assay in mice. Higher plasma concentrations of glycidamide in mice than rats are hypothesized to explain, at least in part, the differences in the response. Benchmark dose modelling indicates that structural DNA damage as opposed to point mutations is most relevant to the genotoxic mode of action of acrylamide-induced carcinogenicity. Moreover, the lack of genotoxicity detected at <6.0mg/kg/day is consistent with the notion that non-genotoxic mechanisms contribute to acrylamide-induced carcinogenicity in rodents.


Asunto(s)
Acrilamida/toxicidad , Daño del ADN , Micronúcleos con Defecto Cromosómico/inducido químicamente , Mutación , Acrilamida/farmacología , Animales , ADN/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Pruebas de Mutagenicidad , Ratas , Ratas Endogámicas F344
3.
J Agric Food Chem ; 56(15): 6024-30, 2008 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-18624434

RESUMEN

Acrylamide is a toxic substance that induces a variety of cellular responses including neurotoxicity, male reproductive toxicity, tumorigenicity, clastogenicity, and DNA alkylation. Evidence is provided that inhibition of the microtubule motor protein kinesin is responsible for acrylamide-induced clastogenicity and aneuploidy. Two kinesin motors, KIFC5A and KRP2, which are responsible for spindle assembly and disassembly of kinetochore MT, respectively, are inhibited by acrylamide. The inhibitory concentration for a response is below the levels shown to adversely affect the cytogenetic parameters. The relative contribution of these inhibitions compared to DNA alkylation is considered. The implications of inhibition of these kinesins as the site of action of acrylamide with regard to risk assessment are substantial as this event will have a threshold and a safe level of acrylamide can be determined.


Asunto(s)
Acrilamida/farmacología , Cinesinas/antagonistas & inhibidores , Mutágenos/farmacología , Testículo/enzimología , Acrilamida/administración & dosificación , Alquilación , Animales , ADN/química , Aductos de ADN/análisis , Daño del ADN/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Cinesinas/metabolismo , Masculino , Mutágenos/administración & dosificación , Ratas , Medición de Riesgo
4.
Biodegradation ; 13(4): 221-7, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12521286

RESUMEN

The influence of ultraviolet photolysis as a pretreatment to the aerobic and anaerobic biological mineralization of a 14C-polyacrylamide was assessed using a series of radiorespirometry bioassays. The polyacrylamide studied was non-ionic with molecular weights ranging between 100,000 and 1 million. Aerobic and anaerobic biomineralization of the unphotolysed (raw) polyacrylamide was found to be only 0.60% and 0.70%, respectively, after 6 weeks of incubation, and hence indicative of the natural recalcitrance of polyacrylamide to microbial degradation. The effectiveness of UV irradiation in the physical breakdown of the polyacrylamide chain into oligomers was demonstrated by the shift in the molecular weight distribution and the positive correlation between the time of irradiation and the degree of its biological mineralization. The molecular weight fraction below 3 kD, which represents only 2% of the raw polyacrylamide, was increased to 41, 60 and 80% after 12, 24 and 48 hours of photolysis, respectively. This in turn, yielded, after 6 weeks of incubation, an aerobic mineralization of 5, 17 and 29% of 150 mg/L polyacrylamide, respectively, and an anaerobic mineralization of 3, 5 and 17%, respectively. Biomass acclimation substantially improved the specific initial rate of biomineralization of the photolysed polyacrylamides, but not the overall percentage of polyacrylamides mineralized.


Asunto(s)
Resinas Acrílicas/química , Minerales/química , Fotólisis , Resinas Acrílicas/efectos de la radiación , Aerobiosis , Anaerobiosis , Biodegradación Ambiental , Bioensayo , Biomasa , Minerales/efectos de la radiación , Peso Molecular , Factores de Tiempo , Rayos Ultravioleta , Microbiología del Agua
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