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Cited by 345Birth, Development, and HealthGenetic and Clinical Aspects of Sex Determination and Chromosomal AbnormalitiesGenetic Syndromes and Imprinting

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

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Gabory, Anne, Roseboom, Tessa J, Moore, Tom, Moore, Lorna G, Junien, Claudine·2013·Biology of Sex Differences
DOI 10.1186/2042-6410-4-5PMC PMC3618244
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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.

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Figure 1 Sex-specific transmission of exposure to environment to subsequent generations. Environmental factors - including nutrition, psychosocial stress, toxins, endocrine disruptors, tobacco, alcohol, microbiota – impact individual (F0) epigenetic landscapes hence gene pathways and networks in ways that differ between the sexes. For example maternal and paternal preconceptional exposures can modify gamete quality and be transmitted to the subsequent (F1) generation. Additionally consequences of maternal F0 exposure during pregnancy (stress, metabolism, diet, hormonal changes…) can be transmitted from the maternal to the fetal compartment via the placenta in a sex-specific manner and affect F1 tissue development. Programming of somatic tissues can lead to changes in long-term health outcomes in the first generation. Moreover, primordial germ cells, which develop and undergo reprogramming during fetal development, can also be affected by F0 maternal environment and contribute genetic and epigenetic information to the F2 generation. Maternal and paternal lineages affect the transmission of such influences differently. In particular, multigenerational exposure on the maternal lineage can be seen in the F0, F1 and F2 generations, and transgenerational phenotype would be observed in F3, whereas on the paternal lineage multigenerational exposure concerns F0 and F1, and transgenerational phenotype in F2 and F3 generations.
Figure 1 Sex-specific transmission of exposure to environment to subsequent generations. Environmental factors - including nutrition, psychosocial stress, toxins, endocrine disruptors, tobacco, alcohol, microbiota – impact individual (F0) epigenetic landscapes hence gene pathways and networks in ways that differ between the sexes. For example maternal and paternal preconceptional exposures can modify gamete quality and be transmitted to the subsequent (F1) generation. Additionally consequences of maternal F0 exposure during pregnancy (stress, metabolism, diet, hormonal changes…) can be transmitted from the maternal to the fetal compartment via the placenta in a sex-specific manner and affect F1 tissue development. Programming of somatic tissues can lead to changes in long-term health outcomes in the first generation. Moreover, primordial germ cells, which develop and undergo reprogramming during fetal development, can also be affected by F0 maternal environment and contribute genetic and epigenetic information to the F2 generation. Maternal and paternal lineages affect the transmission of such influences differently. In particular, multigenerational exposure on the maternal lineage can be seen in the F0, F1 and F2 generations, and transgenerational phenotype would be observed in F3, whereas on the paternal lineage multigenerational exposure concerns F0 and F1, and transgenerational phenotype in F2 and F3 generations.CC BY · PubMed Central
Figure 2 Sex specific expression of the X/Y paralogues Kdm5c and Kdm5d. Three PCR primer pairs have been designed for recognizing specifically either Kdm5c or Kdm5d cDNA and for recognizing both Kdm5c/5d cDNA. Their expression was studied in male and female placentas in pregnant female mice fed either a control diet (CD) or a high-fat diet (HFD) from E0.5 to sacrifice at E15.5 stage. Kdm5c expression is higher in females (pink bars) than males (blue bars), and Kdm5d is expressed only in males, regardless of maternal diet. The Kdm5c/5d PCR shows that the combined expression of Kdm5d and Kdm5c expression in males is not of equivalent magnitude as the expression of Kdm5c from both alleles in females.
Figure 2 Sex specific expression of the X/Y paralogues Kdm5c and Kdm5d. Three PCR primer pairs have been designed for recognizing specifically either Kdm5c or Kdm5d cDNA and for recognizing both Kdm5c/5d cDNA. Their expression was studied in male and female placentas in pregnant female mice fed either a control diet (CD) or a high-fat diet (HFD) from E0.5 to sacrifice at E15.5 stage. Kdm5c expression is higher in females (pink bars) than males (blue bars), and Kdm5d is expressed only in males, regardless of maternal diet. The Kdm5c/5d PCR shows that the combined expression of Kdm5d and Kdm5c expression in males is not of equivalent magnitude as the expression of Kdm5c from both alleles in females.CC BY · PubMed Central

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  1. Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJ: Boys live dangerously in the womb. Am J Hum Biol 2009, 22: 330–335. · DOI · Paper page

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Metadata

Authors
Gabory, A., Roseboom, T. J., Moore, T., Moore, L. G., & Junien, C.
Affiliations
  • Biologie de la Reproduction, Environnement, Epigénétique et Développement (FR)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • University College Cork (IE)
  • University of Colorado Denver (US)
  • Université de Versailles Saint-Quentin-en-Yvelines (FR)
Corresponding author
Junien, Claudine
ORCID
Venue
Biology of Sex Differences
Publisher
Springer Science and Business Media LLC
Published
2013-03-21
Volume
4
Issue
1
Pages
5-5
ISSN
2042-6410 (ISSN-L)
DOI
10.1186/2042-6410-4-5
PMC
PMC3618244
OpenAlex
W2150272037
Cited by
344
References
163
Citations by year
2026: 17 · 2025: 24 · 2024: 26 · 2023: 19 · 2022: 26 · 2021: 37 · 2020: 31 · 2019: 23 · 2018: 32 · 2017: 24 · 2016: 23 · 2015: 32 · 2014: 21 · 2013: 9
FWCI
26.45
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Biology of Sex Differences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion)
  • Arrow@dit (Dublin Institute of Technology) (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • Cork Open Research Archive (University College Cork, Ireland) (submittedVersion, cc-by)
  • Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion)
Funders
  • Science Foundation Ireland
  • Agence Nationale de la Recherche
  • National Institutes of Health (079647)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
Keywords
placenta, sexual dimorphism, sex differences in disease, sex chromosomes, X-linked genes, Y chromosome, epigenetics, developmental origins of health and disease, fetal programming, sex-specific gene expression, endocrine disruptors, sex hormones, non-communicable diseases, maternal environment

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