Prenatal N-acetyl-cysteine administration alleviates the long-term effects of maternal obesity of adolescent male and female mouse offspring

Introduction. High-fat diet (HFD) consumption during pregnancy may act as a prenatal stressor affecting foetal brain developmental and representing an important risk factor for mental health. Indeed, offspring of obese mothers are prenatally over-exposed to increased levels of oxidative stress, hormones and pro-inflammatory cytokines, that all together can dramatically alter the development of neuronal circuits involved in the regulation of behaviour and mood. N-acetyl-cysteine (NAC) is a promising antioxidant compound that has revealed beneficial effects in the treatment of psychopathology. Aim. The aim of this study was to evaluate the general neurodevelopment, the social behaviour and the emotional phenotype of male and female offspring of dams exposed to a HFD (a mouse model of maternal obesity) before and during pregnancy. Furthermore, we tested the efficacy of prenatal NAC administration in preventing the negative effects of maternal HFD. We focused on adolescence, an age of main vulnerability for the onset of psychopathologies. Methods. Female C57BL/6N mice were fed either HFD (energy 5.56 kcal/g, fat 58%, carbohydrate 25.5% and protein 16.4%) or control diet (CD, energy 4.07 kcal/g, fat 10.5%, carbohydrate 73.1% and protein 16.4%) for 13 weeks and, after 5 weeks, were also exposed to NAC (1 g/kg body weight) via drinking water, until delivery. The general neurodevelopment of offspring was assessed through the Homing test at post-natal day (PND) 10; emotionality and social behaviour were assessed during adolescence (PND 35-45) by means of the elevated-plus-maze (EPM) and social interaction tests (SIT). A forced swimming test was used both to evaluate depressive-like behaviour as well as a stressful challenge to measure hypothalamic-pituitary-adrenal (HPA) axis reactivity. Transcriptomic analysis on hippocampus were performed in order to identify mechanisms of action of both HFD and NAC. Data were analysed using parametric analysis of variance (ANOVA) with Prenatal diet (HFD vs. CD), Prenatal treatment (NAC vs. WATER), Sex (females vs. males) as between subjects factors and time blocks as within-subjects repeated measures (i.e. body weight). Post hoc comparisons were performed using the Tukey’s test. Results. NAC was effective in moderating body weight gain in HFD-fed dams (Diet x Treatment x time p=0.0078, post hoc HFD-WATER vs. HFD-NAC p<0.05). Neither HFD or NAC affected neurodevelopment of offspring at PND 10. Prenatal HFD reduced exploratory behaviours in the EPM (main effect of Prenatal diet in frequency of crossings p=0.0001; frequency of head dipping p=0.0292; frequency of wall-rearing p=0.0255) and decreased sociability (Prenatal diet x Prenatal treatment in the duration of sniff the cospecific subject p=0.0002, post hoc CD-WATER vs. HFD-WATER p<0.05) in the SIT in periadolescent offspring. Prenatal NAC administration was effective in preventing social anxiety in offspring of HFD-fed dams (post hoc HFD-WATER vs. HFD NAC p<0.05). HPA axis functionality and brain transcriptomics are currently ongoing for mechanistic insight. Conclusions. Data from this study indicate that the long-term effects of maternal obesity may be mediated by changes in oxidative stress and point to NAC as a potential preventive strategy. ERANET-NEURON-JTC 2018 (Mental Disorders) Project ‘‘EMBED”.