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

Abstract

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 genera tions consumed the same amount of ACR1 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 F 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 neuro toxicity 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.