Chapin R E, Fail P A, George J D, Grizzle T B, Heindel J J, Harry G J, Collins B J, Teague J
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Fundam Appl Toxicol. 1995 Aug;27(1):9-24. doi: 10.1006/faat.1995.1104.
Acrylamide is a known genetic, reproductive, and neural toxicant, although it is not known if one effect is predominant. The toxicities of several structural analogues of acrylamide have been incompletely characterized, and the relative sensitivity of the second generation is not known. The present studies were designed to explore the relationship between neurotoxicity and reproductive toxicity, to further characterize the toxicities of three acrylamide analogues, and to evaluate the relative sensitivity of a second generation to these compounds. For the F0 generation, male and female Swiss CD-1 mice were provided drinking water containing acrylamide (ACR; 3, 10, 30 ppm), N,N'-methylenebisacrylamide (MBA; 10, 30, 60 ppm), N-(hydroxymethyl)acrylamide (HMA; 60, 180, 360 ppm), or methacrylamide (MACR; 24, 80, 240 ppm) during and after a 14-week cohabitation. The last litter was reared and dosed after weaning until mating at 74 +/- 10 days of age with the same level of compound given to the parents Neurotoxicity was assessed at several times in both generations by measuring forelimb and hindlimb grip strength. In the F0 generation, ACR caused an 11% decrease in pup number without measurable neurotoxicity; female fertility was not affected. Although both generations consumed the same amount of ACR, there were larger changes in the fertility-related endpoints in the F1 mice than in the F0's, with no concomitant change in organ weights or sperm parameters. In F0 mice, MBA reduced the number of live pups and their adjusted weight, with no neurotoxicity and no change in F0 female reproduction. MBA caused greater adverse effects in the second generation, concomitant with increased consumption. In the F0 generation, HMA caused the largest decrease in pup number during cohabitation (26%) together with a small effect on grip strength. Female reproduction was not affected. The second generation consumed more HMA and showed slightly greater toxic effects. In both generations, MACR was negative for both neurotoxicity and reproductive toxicity. Dominant-lethal studies showed that the fertility effects for ACR, MBA, and HMA could be explained by a male-mediated increase in postimplantation loss. These studies found that dominant lethality occurred without structural effects on the reproductive system in the presence of only minor effects on grip strength and without detectable neural histopathology. Female reproduction was not significantly affected by these compounds at the doses used. Thus, these data confirm the male as the affected gender and that the reproductive toxicity was greater than motoneuron toxicity when measured as grip strength.
丙烯酰胺是一种已知的遗传、生殖和神经毒物，尽管尚不清楚哪种影响占主导。几种丙烯酰胺结构类似物的毒性尚未完全明确，第二代对其相对敏感性也未知。本研究旨在探讨神经毒性与生殖毒性之间的关系，进一步明确三种丙烯酰胺类似物的毒性，并评估第二代对这些化合物的相对敏感性。对于F0代，在14周的同居期间及之后，给雄性和雌性瑞士CD-1小鼠提供含有丙烯酰胺（ACR；3、10、30 ppm）、N,N'-亚甲基双丙烯酰胺（MBA；10、30、60 ppm）、N-（羟甲基）丙烯酰胺（HMA；60、180、360 ppm）或甲基丙烯酰胺（MACR；24、80、240 ppm）的饮用水。最后一窝幼崽在断奶后饲养并给予与亲代相同剂量的化合物，直至74±10日龄交配。通过测量前肢和后肢握力，在两代小鼠的多个时间点评估神经毒性。在F0代中，ACR使幼崽数量减少11%，但无明显神经毒性；雌性生育能力未受影响。尽管两代小鼠摄入的ACR量相同，但F1代小鼠与生育相关的终点变化比F0代更大，而器官重量和精子参数无相应变化。在F0代小鼠中，MBA减少了活产幼崽数量及其调整后的体重，无神经毒性，F0代雌性生殖无变化。MBA在第二代造成了更大的不良影响，且随着摄入量增加而加重。在F0代中，HMA在同居期间使幼崽数量减少最多（26%），对握力有轻微影响。雌性生殖未受影响。第二代摄入的HMA更多，毒性作用略大。在两代小鼠中，MACR对神经毒性和生殖毒性均呈阴性。显性致死研究表明，ACR、MBA和HMA对生育能力的影响可通过雄性介导的植入后损失增加来解释。这些研究发现，在仅对握力有轻微影响且无明显神经组织病理学改变的情况下，显性致死发生时生殖系统无结构变化。在所使用的剂量下，这些化合物对雌性生殖无显著影响。因此，这些数据证实雄性为受影响的性别，并且以握力衡量时，生殖毒性大于运动神经元毒性。
