Hormones, Intrauterine Health and Programming

Abstract

There is mounting evidence that the placenta can be considered as a programming agent of adult health and diseases. Placental weight and shape at term are correlated with the development of metabolic diseases in adulthood in humans. Maternal obesity and malnutrition predispose the offspring to developing metabolic syndrome, a vicious cycle leading to transmission to subsequent generation(s), with differences in response and susceptibility according to the sex of the individual. Adaptations in placental phenotype in response to maternal diet and body composition alter fetal nutrient provision. This finding implies important epigenetic changes. However, the epigenetics of placental development in studies of developmental origins of health and disease (DOHaD) is still poorly documented, particularly concerning overnutrition. We used histology, microarray analyses and epigenetic techniques to investigate the effects of a high fat diet (HFD) or low protein diet on mouse placental development, respectively. We showed for the first time that not only the gene sets but also their biological functions affected by the HFD differed markedly between the two sexes. Remarkably, genes of the epige-netic machinery as well as global DNA methylation level showed sexual dimorphism. Imprinted gene expression was altered, with locus-specific changes in DNA methylation. Thus, these findings demonstrate a striking sexual dimorphism of programming trajectories in response to the same environmental challenge, implicating sex chromosome genes, not just hormones. Explaining the sex-specific causal variables and how males versus females respond and adapt, and to what extent, to environmental perturbations should help physicians and patients anticipate disease susceptibility.