Placental contribution to nutritional programming of health and diseases: epigenetics and sexual dimorphism

Abstract

The recent and rapid worldwide increase in non-communicable diseases challenges the assumption that genetic factors are the primary contributors to such diseases. A new concept of the 'developmental origins of health and disease' (DOHaD) is at stake and therefore requires a paradigm shift. Maternal obesity and malnutrition predispose offspring to develop 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. The placenta is a programming agent of adult health and disease. Adaptations of placental phenotype in response to maternal diet and metabolic status alter fetal nutrient supply. This implies important epigenetic changes that are, however, still poorly documented in DOHaD studies, particularly concerning overnutrition. The aim of this review is to discuss the emerging knowledge on the relationships between the effect of maternal nutrition or metabolic status on placental function and the risk of diseases later in life, with a specific focus on epigenetic mechanisms and sexual dimorphism. Explaining the sex-specific causal variables and how males versus females respond and adapt to environmental perturbations should help physicians and patients to anticipate disease susceptibility.KEY WORDS: DOHaD, Fetal programming, Placenta, Sex, Nutrition, Obesity, Maternal environment, Gestation Introduction: developmental origins of health and diseaseThe recent and rapid worldwide increase in non-communicable diseases (NCDs) challenges the assumption that genetic factors are the primary contributors to such diseases (McAllister et al., 2009). The 'developmental origins of health and disease' (DOHaD) paradigm states that the environment during the periconception, gestation and lactation periods shapes the developing individuals, leading, in the case of a deleterious environment, to a predisposition to adult-onset diseases. This theory was popularised by D. J. Barker in the early 1990s (Barker, 1990) but the question had already been raised in earlier studies. In the 1960s and 1970s, different experiments on diverse mammalian species (rat, mouse, guinea pig, pig, etc.) showed that a reduction of maternal calorie or protein intake during pregnancy and lactation affects the growth capacity and cognitive ability of the offspring (reviewed in Roeder and Chow, 1972;McCance, 1976). Later, this concept was extended to phenotype in general, with a strong implication for quantitative traits in agriculture. An increasing number of studies pointed to the fact that maternal environment in cattle was an important parameter to fully express the genetically highly selected potential of the animals (Wallace et al., 2010; Jammes et al., 2011;Tanghe et al., 2014).Male and female susceptibility to NCDs is well described. It appears that in the DOHaD context, the same environmental exposure may affect the long-term health of the offspring with a discrepancy between males and females in terms of the timing, onset ...

The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

“…Intrauterine conditions, especially perturbations in nutrient availability and metabolism, have dramatic effects on epigenetic machinery (Tarrade et al, 2015). For example, maternally derived micronutrients such as folate and choline serve as substrates for DNA methyltransferases (DNMT) and their deficiency decreases placental DNA methylation (Kim et al, 2009).…”

Dynamics of epigenetic phenomena: intergenerational and intragenerational phenotype ‘washout’

“…Significantly, some X-linked genes can escape inactivation by methylation, and such genes are thus more expressed in females (Basu and Zhang, 2011). Y chromosome genes are typically widely expressed through life and in many tissues (Gabory et al, 2015). CpG methylation of the promoter regions for these regions could suppress male phenotypic traits.…”

“…In mammals, some 60-80% of the DNA is methylated in adulthood (Gallou-Kabani et al, 2010;Smith and Meissner, 2013), but in many invertebrates the degree of methylation falls to <3% and may even be difficult to detect, as in the fruit fly Drosophila (Hunt et al, 2013;Schoofs et al, 2015;Weiner and Toth, 2012). Within an individual, DNA methylation changes during embryonic development, maturation and aging/senescence (Ficz, 2015;Gabory et al, 2015;Rodríguez-Rodero et al, 2010;Smith and Meissner, 2013;van Otterdijk et al, 2013). Indeed, in some species, the relationship between CpG methylation and age is so tightly correlated as to lead to the concept of an 'epigenetic clock' based on 'DNA methylation age' (Gršković et al, 2013;Horvath, 2013;Teschendorff et al, 2013).…”

“…Furthermore, at least in mammalian germ cells and zygotes there is a period of 'methylation erasure' for DNA, followed by de novo remethylation after the blastocyst stage and beyond in the embryo, thought to be dictated in part by the environment (Ficz, 2015;Horvath, 2013;Ooi and Bestor, 2008;Wu and Zhang, 2010). In addition to interindividual differences in DNA methylation, specific regions of DNA are more methylated than others (Schär and Fritsch, 2011;Smith and Meissner, 2013), which leads to large differences in DNA methylation of genes responsible for specific tissue types within an organ, such as the placenta (Gabory et al, 2015). It is not at all clear what the drivers are for such intra-individual and inter-organ changes in DNA methylation.…”

“…This decay may also explain loss of morphological modifications as developmental time progresses for each brood. Certainly, progressive intragenerational changes in DNA methylation have been quantified in ants, mice, ground squirrels, cichlid fishes and many other organisms including humans (Alvarado et al, 2014a;Alvarado et al, 2014b;Bollati et al, 2009;Gabory et al, 2015). This hypothesis of a simple time-dependent decline in DNA methylation (or other mechanism) can be readily tested in an animal producing multiple broods over time, such as Daphnia, by delaying the production of the first brood until the normal timing of the third brood, and determining whether the phenotypic modification is present, or has not stood the passage of time.…”