The Reproductive and Neural Toxicities of Acrylamide and Three Analogues in Swiss Mice, Evaluated Using the Continuous Breeding Protocol

Chapin, Robert E.; Fail, Patricia A.; George, Julia D.; Grizzle, Thomas B.; Jj, Heindel; Harry, G.J.; Collins, BJ; Teague, J.Lynn

doi:10.1006/faat.1995.1104

Cited by 53 publications

(24 citation statements)

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“…Based upon the concordance of tumour sites between AA and GA, it can be concluded that carcinogenic activity of AA is due to its metabolic conversion to GA. (2012). These previous evaluations referred to several studies reporting on the reproductive and developmental toxicity of orally administered AA Sakamoto and Hashimoto, 1986;Smith et al, 1986;Working et al, 1987;Sublet et al, 1989;Chapin et al, 1995;Tyl et al, 2000a,b). AA did not significantly affect mating performance in female rats, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…A similar pattern of effects was noted for the second exposure period. Chapin et al (1995) The NTP conducted a 13-week study (drinking water and diet) and a 2-year study (drinking water) in B6C3F 1 mice administered AA (NTP, 2012). In the 13-week range finding study, groups of eight male and eight female mice were treated with AA at a concentration of 0, 0.14, 0.35, 0.70, 1.41 or 3.52 mM in drinking-water (0, 10, 25, 50, 100 or 250 mg/L equivalent to 0, 3.2, 6.9, 13.3, 32.8 and 70.0 mg/kg b.w.…”

Section: Repeated Dose Toxicitymentioning

confidence: 99%

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Scientific Opinion on acrylamide in food

Publication¹

2015

EFS2

331

170

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EFSA was asked to deliver a scientific opinion on acrylamide (AA) in food. AA has widespread uses as an industrial chemical. It is also formed when certain foods are prepared at temperatures above 120 °C and low moisture, especially in foods containing asparagine and reducing sugars. The CONTAM Panel evaluated 43 419 analytical results from food commodities. AA was found at the highest levels in solid coffee substitutes and coffee, and in potato fried products. Mean and 95th percentile dietary AA exposures across surveys and age groups were estimated at 0.4 to 1.9 µg/kg body weight (b.w.) per day and 0.6 to 3.4 µg/kg b.w. per day, respectively. The main contributor to total dietary exposure was generally the category 'Potato fried products (except potato crisps and snacks)'. Preferences in home-cooking can have a substantial impact on human dietary AA exposure. Upon oral intake, AA is absorbed from the gastrointestinal tract and distributed to all organs. AA is extensively metabolised, mostly by conjugation with glutathione but also by epoxidation to glycidamide (GA). Formation of GA is considered to represent the route underlying the genotoxicity and carcinogenicity of AA. Neurotoxicity, adverse effects on male reproduction, developmental toxicity and carcinogenicity were identified as possible critical endpoints for AA toxicity from experimental animal studies. The data from human studies were inadequate for dose-response assessment. The CONTAM Panel selected BMDL 10 values of 0.43 mg/kg b.w. per day for peripheral neuropathy in rats and of 0.17 mg/kg b.w. per day for neoplastic effects in mice. The Panel concluded that the current levels of dietary exposure to AA are not of concern with respect to non-neoplastic effects. However, although the epidemiological associations have not demonstrated AA to be a human carcinogen, the margins of exposure (MOEs) indicate a concern for neoplastic effects based on animal evidence. © European Food SUMMARYFollowing a request from the European Commission, the Panel on Contaminants in the Food Chain (CONTAM Panel) was asked to deliver a scientific opinion on acrylamide (AA) in food. The Panel developed the draft scientific opinion which underwent a public consultation from 1 July 2014 to 15 September 2014. The comments received and how they were taken into account when finalising the scientific opinion were published in an EFSA Technical Report (EFSA, 2015).AA is a low molecular weight, highly water soluble, organic compound. It is used inter alia as an industrial chemical and in the production of polyacrylamides. Heightened concerns about exposure to AA arose in 2002 when it was discovered that it forms when certain foods are prepared at temperatures usually above 120 °C and low moisture. It forms, at least in part, due to a Maillard reaction between certain amino acids, such as asparagine, and reducing sugars. However, several other pathways and precursors have also been proposed to contribute to AA formation. AA forms in numerous baked or fried carbohydrate-rich f...

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Section: Discussionmentioning

confidence: 99%

Section: Repeated Dose Toxicitymentioning

confidence: 99%

Scientific Opinion on acrylamide in food

Publication¹

2015

EFS2

331

170

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“…Subsequently, in an NTP Reproductive Assessment by Continuous Breeding (RACB) study, the fertility of CD1 mice administered NHMA (highest dose, 360 ppm) in their drinking water was found to be reduced and, after 13 weeks of treatment, increased numbers of resorptions were seen in pregnancies of untreated females mated to treated males, indicating that dominant lethal mutations were induced as a result of chromosome aberrations in male germ cells [Chapin et al, 1995]. This dominant lethal effect was unexpected, since all chemicals previously reported to induce dominant lethal mutations also induced MN in rodent tests [Adler and Ashby, 1989;Waters et al, 1994;Shelby, 1996;Tinwell et al, 2001;Ashby and Tinwell, 2001].…”

Section: Introductionmentioning

confidence: 98%

Mouse bone marrow micronucleus test results do not predict the germ cell mutagenicity of N‐hydroxymethylacrylamide in the mouse dominant lethal assay

Witt

Hughes

Burka

et al. 2003

Environ and Mol Mutagen

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N-Hydroxymethylacrylamide (NHMA), a mouse carcinogen inactive in the Salmonella assay and mouse micronucleus (MN) assay, was tested for reproductive effects in a mouse continuous breeding study. In that study, increased embryonic deaths were observed after 13 weeks exposure of parental animals to NHMA via drinking water (highest dose, 360 ppm); the results indicated the possible induction of chromosome damage in germ cells of treated males. An additional mouse MN test was conducted using a 31-day treatment period to better match the dosing regimen used in the breeding study; the results were negative. Additional studies were conducted to explore the germ cell activity of NHMA. A male mouse dominant lethal study was conducted using a single intraperitoneal injection of 150 mg/kg NHMA; the results were negative. A follow-up study was conducted using fractionated dosing, 50 mg/kg/day for 5 days; again, no increase in dominant lethal mutations was observed. NHMA (180-720 ppm) was then administered to male mice in drinking water for 13 weeks, during which three sets of matings occurred. Two weeks after mating, females were killed and the uterine contents were analyzed. Large, dose-related increases in dominant lethal mutations were observed with increasing length of exposure. The magnitude of the increases stabilized after 8 weeks of treatment. However, the frequency of micronucleated peripheral blood erythrocytes was not elevated in mice treated for 13 weeks with NHMA in drinking water. Thus, NHMA appears to be unique in inducing genetic damage in germ cells but not somatic cells of male mice.

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“…ACR is reported, at a dose of 7–14 mg/kg, to reduce fertility rates, increase resorptions of fetuses, reduce litter size in pregnant females, and cause the formation of abnormal sperm and decrease sperm count in males (Sakamoto and Hashimoto 1986; Chapin et al 1995). ACR-induced histopathological lesions, such as formation of multinucleated giant cells and vacuolation, and numerous apoptotic cells were observed in seminiferous tubules.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis induced by acrylamide is suppressed in a 21.5% fat diet through caspase-3-independent pathway in mice testis

Zhang

Chen

Huang

2009

Toxicology Mechanisms and Methods

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This study investigates the simultaneous effect of acrylamide (ACR) and high-fat-intake on the apoptosis in testis cells, and also the expression and activity of caspase-3. Seventy-two male Kunming mice were divided into two blocks and fed with a high-fat diet (crude fat 21.5%) or basic diet (crude fat 4.4%), respectively; and animals in each diet block were exposed to ACR at the dose of 20 mg/kgbw•d or 40 mg/kgbw•d as ACR treated groups or the normal saline as control. Germ cells prepared from testis were stained with Hoechst dye 33258 and paraffin wax sections from testis were suffered to a TUNEL process. Expression of caspase-3 on protein level was investigated using an immunohistochemical analysis assay. The supernatant of unilateral testes were subjected to a Caspase-3 activity kit to determine the activity of Caspase-3 in testis. The concentration of ACR and glycidamide(GA), epox-ide of ACR, in plasma and testis were detected by LC-ES/MS/MS analysis. Results based on the morphological changes, percentage of apoptotic cells, and integrated optical density (IOD) of positive amethyst staining which indicates the apoptotic DNA fragmentation, show that apoptosis was induced by acrylamide only; however, acr-ylamide-induced apoptosis was weakened by high-fat-intake. The protein expression and activity of Caspase-3 were not induced by ACR or high-fat-intake. Moreover, no significant differences of ACR and GA concentration were found between the high-fat and basic diet groups after exposure of ACR. Results indicate that high-fat-intake reverses the effects on apoptosis induced by ACR; and more possibly, apoptosis is induced by a caspase-3-independent mechanism.

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The Reproductive and Neural Toxicities of Acrylamide and Three Analogues in Swiss Mice, Evaluated Using the Continuous Breeding Protocol

Cited by 53 publications

References 0 publications

Scientific Opinion on acrylamide in food

Scientific Opinion on acrylamide in food

Mouse bone marrow micronucleus test results do not predict the germ cell mutagenicity of N‐hydroxymethylacrylamide in the mouse dominant lethal assay

Apoptosis induced by acrylamide is suppressed in a 21.5% fat diet through caspase-3-independent pathway in mice testis

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