SWATH-MS quantitative proteomic investigation of intrauterine growth restriction in a porcine model reveals sex differences in hippocampus development

Intrauterine growth restriction (IUGR) is characterized by reduced growth and weight of the foetus, mainly due to the lack of nutrients and oxygen. Animals affected by IUGR show changes in specific brain areas and several neuronal processes. Female offspring affected by IUGR show increased survival and development compared to males. The objective of this study was to analyse changes in the hippocampus proteome in male and female piglets affected by IUGR. Seven pregnant Iberian sows were fed from Day 35 of pregnancy onwards at 50% of their requirements. At Day 100 of pregnancy, foetuses were obtained and classified by sex and weight, as mild IUGR (Normal Body Weight) versus severe IUGR (Low Body Weight). Hippocampi were dissected and the proteomes analysed by SWATH-MS DIA. In this study, 1497 proteins were identified of which 260 were quantitatively analysed. All differential proteins were more abundant in females versus males and were involved in protein synthesis, neuronal development, metabolism, antiapoptotic signalling and vesicular transport. Our findings support that female foetuses tolerate nutrient limitation better than males, especially under mild IUGR. Under severe IUGR, females still seems to maintain normal lipid metabolism and antiapoptotic signalling, which may be related to the increased female survival. SIGNIFICANCE: In the last years, proteomics have been used to evidence differences related to sex in non-reproductive organs. Intrauterine Growth Restriction (IUGR) can affect female and male offspring differently. Female offspring has stronger protective strategies compared to males, enhancing growth and postnatal survival. Most studies regarding this issue have focused on metabolic organs (i.e. liver). However, the predominance of neurodevelopmental disorders in males suggests that the central nervous system in female offspring adapt better to nutritional stress conditions than that of males. Based on the differential protein expression in hippocampal samples, our work demonstrates that female foetuses indeed adapt better to IUGR than males, especially under mild IUGR conditions. In severe IUGR conditions, differences between males and females were not so evident, but even in this case, the remaining differences suggest increased survival in females than in males.