Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics

Abstract

Sex differences occur in most non-communicable diseases, including metabolic diseases, hypertension, cardiovascular disease, psychiatric and neurological disorders and cancer. In many cases, the susceptibility to these diseases begins early in development. The observed differences between the sexes may result from genetic and hormonal differences and from differences in responses to and interactions with environmental factors, including infection, diet, drugs and stress. The placenta plays a key role in fetal growth and development and, as such, affects the fetal programming underlying subsequent adult health and accounts, in part for the developmental origin of health and disease (DOHaD). There is accumulating evidence to demonstrate the sex-specific relationships between diverse environmental influences on placental functions and the risk of disease later in life. As one of the few tissues easily collectable in humans, this organ may therefore be seen as an ideal system for studying how male and female placenta sense nutritional and other stresses, such as endocrine disruptors. Sex-specific regulatory pathways controlling sexually dimorphic characteristics in the various organs and the consequences of lifelong differences in sex hormone expression largely account for such responses. However, sex-specific changes in epigenetic marks are generated early after fertilization, thus before adrenal and gonad differentiation in the absence of sex hormones and in response to environmental conditions. Given the abundance of X-linked genes involved in placentogenesis, and the early unequal gene expression by the sex chromosomes between males and females, the role of X- and Y-chromosome-linked genes, and especially those involved in the peculiar placenta-specific epigenetics processes, giving rise to the unusual placenta epigenetic landscapes deserve particular attention. However, even with recent developments in this field, we still know little about the mechanisms underlying the early sex-specific epigenetic marks resulting in sex-biased gene expression of pathways and networks. As a critical messenger between the maternal environment and the fetus, the placenta may play a key role not only in buffering environmental effects transmitted by the mother but also in expressing and modulating effects due to preconceptional exposure of both the mother and the father to stressful conditions.

The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

“…Such basal placental sex differences likely facilitate sex-specific responses to both normal and pathologic environments. Supporting this, sex differences in placental inflammatory responses, vascular remodeling, and placental size and efficiency have been reported in human pregnancies complicated by asthma, preeclampsia, and malnutrition (Clifton, 2010;Gabory et al, 2013). Such complications are also associated with altered neurodevelopment Walker et al, 2015).…”

“…Importantly, sex-specific reprogramming in response to maternal stress likely arises, owing to sex differences in trophoblasts derived from male (XY) and female (XX) embryos. Sex differences in placental size and gene expression have been identified in normal human and rodent placentas, and sex-specific placental abnormalities predict offspring outcome in pregnancies complicated by maternal asthma and preeclampsia (Buckberry et al, 2014;Clifton, 2010;Gabory et al, 2013;Howerton et al, 2013;Mao et al, 2010;O'Connell et al, 2013;Sood et al, 2006).…”

“…The placenta comprises specialized cells derived from the embryo and thereby expresses the fetal genetic sex (Rossant and Cross, 2001). In uncomplicated pregnancies, sex differences in placental size and gene expression are present throughout gestation (Buckberry et al, 2014;Gabory et al, 2013;Mao et al, 2010;O'Connell et al, 2013;Sood et al, 2006). Such basal placental sex differences likely facilitate sex-specific responses to both normal and pathologic environments.…”

Adverse childhood experiences and physiological wear-and-tear in midlife: Findings from the 1958 British birth cohort

“…The second sensitivity analysis was to ensure that our results using a (Table S5). Recent studies have shown that potential sex/sex differences may exist when analyzing the life course processes of disease development (43)(44)(45). When studying the lasting impact of stress-related diseases, the perception, interpretation, and physiological responses to chronic stress could have a differential impact on men and women (for further details, see SI Materials and Methods).…”

Of the bugs that shape us: maternal obesity, the gut microbiome, and long-term disease risk

“…In rodents, maternal HF diet during pregnancy and lactation induces obesity and hepatic steatosis in the offspring, irrespective of postnatal diet (43) and induces insulin and leptin resistance (44), hypertension (45), and hepatic inflammation in offspring (46). Sex-specific obesity risk and metabolic dysfunction have also been shown and have become a focus for some studies (47). Diet-induced maternal obesity in rodents induces sex-specific effects on placental growth and fetal metabolic phenotype (48), gene expression, and epigenetic regulation (49)-consistent with human data (50).…”