Reduction of ethanol-induced ocular abnormalities in mice through dietary administration of N-acetylcysteine

Abstract

N-acetylcysteine (NAC) is a derivative of the amino acid L-cysteine that previously has been shown to protect against ethanol (EtOH)-induced apoptosis during early development. Ongoing research is demonstrating that NAC is also proving clinically beneficial in reducing oxidative stress-mediated lung, liver and kidney damage, with protection likely resulting from a NACmediated increase in glutathione levels. In the present study, the hypothesis that co-administration of NAC and EtOH via liquid diet on days 7 and 8 of pregnancy in mice would reduce EtOH's teratogenicity was tested. For this work, adult non-pregnant female mice were acclimated to a liquid diet containing EtOH for 16 days, withdrawn from the EtOH, bred and then returned to the liquid diet containing 4.8% EtOH and/or either 0.5 or 1 mg NAC/ml diet on their 7 th and 8 th days of pregnancy. At the concentrations employed, the mice received NAC dosages of approximately 300 or 600 mg/kg/day and achieved peak blood EtOH levels (BEC) that averaged approximately 200 mg/dl. There was no difference in BEC between the EtOH alone and EtOH plus 600 mg/kg NAC group. Following maternal euthanasia, gestational day (GD) 14 fetuses were removed, fixed, weighed and examined for the presence and severity of ocular abnormalities, a readily assessed endpoint that results from GD 7 and 8 EtOH exposures. While the lower dosage of NAC (300 mg/ kg) resulted in a decrease in the incidence of ocular defects in both the left and right eyes, this reduction was not statistically significant. However, doubling the NAC concentration did yield a significant change; as compared to the group treated with EtOH alone, the incidence of ocular abnormalities was diminished by 22%. These results show the potential of an orally administered compound with proven clinical efficacy to reduce EtOH's teratogenic effects and support the premise that oxidative damage plays an important mechanistic role in Fetal Alcohol Spectrum Disorders.

From Research to Practice: An Integrative Framework for the Development of Interventions for Children with Fetal Alcohol Spectrum Disorders

“…As mentioned above, NAP and SAL are also believed to mitigate the teratogenecity of alcohol partly through reducing oxidative stress (Spong, et al 2001). Parnell et al (2010) recently reported that dietary administration of N-acetylcysteine (NAC), which is known to reduce oxidative stress, mitigated alcohol's teratogenecity. Similarly, vitamin E and beta-carotene supplementation have been found to reduce alcohol-induced damage (Mitchell et al 1999).…”

Oxidative Stress, Unfolded Protein Response, and Apoptosis in Developmental Toxicity

“…Fetal alcohol exposure has been shown to lead to an increase in lipid peroxidation in the brain and liver (Chen et al, 1997). There have been several studies documenting the use of antioxidants or ROS-clearing enzymes to decrease the rates of alcohol-induced malformations (Chen et al, 2004; Shirpoor et al, 2009; Patten et al, 2013; Parnell et al, 2010). However, others have noted that the corresponding decrease in oxidative stress and apoptosis may not be sufficient to correct some neurological disorders caused by prenatal alcohol exposure (Marino et al, 2004).…”

Protective Effect of N-acetylcysteine on Liver Damage During Chronic Intrauterine Hypoxia in Fetal Guinea Pig

“…N-acetylcysteine is an antioxidant that crosses the placenta and has previously been shown to inhibit oxidative stress during pregnancy. [56][57][58][59][60] In the current study, the hypoxic fetal guinea pig liver exhibits histopathological damage, increased lipid peroxidation, and DNA fragmentation.…”