Sex-Specific Placental Responses in Fetal Development

Abstract

The placenta is an ephemeral but critical organ for the survival of all eutherian mammals and marsupials. It is the primary messenger system between the mother and fetus, where communicational signals, nutrients, waste, gases, and extrinsic factors are exchanged. Although the placenta may buffer the fetus from various environmental insults, placental dysfunction might also contribute to detrimental developmental origins of adult health and disease effects. The placenta of one sex over the other might possess greater ability to respond and buffer against environmental insults. Given the potential role of the placenta in effecting the lifetime health of the offspring, it is not surprising that there has been a resurging interest in this organ, including the Human Placental Project launched by the National Institutes of Child Health and Human Development. In this review, we will compare embryological development of the laboratory mouse and human chorioallantoic placentae. Next, evidence that various species, including humans, exhibit normal sex-dependent structural and functional placental differences will be examined followed by how in utero environmental changes (nutritional state, stress, and exposure to environmental chemicals) might interact with fetal sex to affect this organ. Recent data also suggest that paternal state impacts placental function in a sex-dependent manner. The research to date linking placental maladaptive responses and later developmental origins of adult health and disease effects will be explored. Finally, we will focus on how sex chromosomes and epimutations may contribute to sex-dependent differences in placental function, the unanswered questions, and future directions that warrant further consideration.

Effects of Prenatal Exposure to Endocrine Disruptors and Toxic Metals on The Fetal Epigenome

“…Finally, if germ cells are exposed to toxic metals and/or endocrine disruptors and undergo epigenomic reprogramming, multi-and transgenerational effects may be noted following prenatal exposure in the F1. Effects of prenatal exposure to endocrine disruptors & toxic metals on the fetal epigenome Review mental differences between placentas derived from male or female fetuses may result in sexually dimorphic responses to environmental exposures [132]. It has recently been shown that gene-specific methylation differs between male and female placentas and these genes are enriched for immune function, transport of substances across the placenta, and transcription factors [133].…”

“…Specifically, male placentas have enriched expression of genes related to inflammation and immune functioning, while female placentas have enriched expression of immune-regulating genes [134,135]. These immunologic differences between male and female fetuses may result in greater vulnerability in male fetuses when faced with adverse environmental exposures in utero [132]. Additionally, differences in the expression of glucocorticoid receptors have been observed based on fetal sex, which may result in differential fetal susceptibility to the maternal stress and/or immune response following exposure to environmental contaminants [136,137].…”

SExual Epigenetic Dimorphism in The Human Placenta: Implications for Susceptibility During The Prenatal Period

“…In support of this hypothesis, physiologic differences between male and female placentas have been observed [19]. For example, placentas derived from pregnancies of males and females display variation in the abundance and type of glucocorticoid transporter proteins, the expression of hormones and the production of immune-related proteins including cytokines [12,[19][20][21]. In addition, sex-based differences in response to prenatal stressors have been observed at the levels of the placental proteome, transcriptome and epigenome [3,7,14,20,[22][23][24][25][26][27].…”

“…We hypothesize that sex-dependent health outcomes in infants may be associated with sexual dimorphism of the placenta. In support of this hypothesis, physiologic differences between male and female placentas have been observed [19]. For example, placentas derived from pregnancies of males and females display variation in the abundance and type of glucocorticoid transporter proteins, the expression of hormones and the production of immune-related proteins including cytokines [12,[19][20][21].…”

The Effects of Maternal Periconceptional Ethanol Exposure on the Development of the Pre-Implantation Embryo, Placenta, and the Influence of the Uterine Environment

“…Alternatively, upregulation or maintenance of labyrinth growth may aid in maintaining nutrient transfer to help ensure fetal survival. Changes to the labyrinthine vasculature are also likely to contribute to the observed sex specific alterations in gene expression of glucose and nutrient transporters, glucocorticoid responsive genes, growth factors, as well as inflammatory responses, see reviews by Clifton (2010) and Rosenfeld (2015). Further research into sexual dimorphism of labyrinthine differentiation, vasculogenesis and branching morphogenesis, interhemal membrane thickness, and functional nutrient transport assays may shed light on sex differences in placental efficiency and adaptation to maternal perturbations.…”