Advanced Maternal Age Differentially Affects Embryonic Tissues with the Most Severe Impact on the Developing Brain

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 1; p. 76
• Main Authors: Kokorudz, Caroline, Radford, Bethany N, Dean, Wendy, Hemberger, Myriam
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24.12.2022; MDPI
• Subjects: advanced maternal age; Age; Aging; Animals; Antigens; Brain; Congenital diseases; Embryonic development; Embryos; Female; Females; Fetuses; Genes; Genomes; Health aspects; Health sciences; Heart; Maternal Age; Mice; Mother and infant; Neurodevelopment; Placenta; Placenta - metabolism; Placentation; Preeclampsia; Pregnancy; Pregnancy complications; Premature birth; RNA-seq; Stem cell transplantation; Stem cells; Transcriptomes; Transcriptomics; Trophoblasts - metabolism; Uterus; Canada; United States > US; facial prominences; RNA-seq; embryonic development; transcriptomics; placenta; uterine stroma; brain; advanced maternal age; trophoblast stem cells; heart
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12010076

Advanced maternal age (AMA) poses the single greatest risk to a successful pregnancy. Apart from the impact of AMA on oocyte fitness, aged female mice often display defects in normal placentation. Placental defects in turn are tightly correlated with brain and cardiovascular abnormalities. It therefore follows that placenta, brain and heart development may be particularly susceptible to the impact of AMA. In the current study, we compared global transcriptomes of placentas, brains, hearts, and facial prominences from mid-gestation mouse conceptuses developed in young control (7-13 wks) and aging (43-50 wks) females. We find that AMA increases transcriptional heterogeneity in all tissues, but particularly in fetal brain. Importantly, even overtly normally developed embryos from older females display dramatic expression changes in neurodevelopmental genes. These transcriptomic alterations in the brain are likely induced by defects in placental development. Using trophoblast stem cells (TSCs) as a model, we show that exposure to aging uterine stromal cell-conditioned medium interferes with normal TSC proliferation and causes precocious differentiation, recapitulating many of the defects observed in placentas from aged females. These data highlight the increased risk of AMA on reproductive outcome, with neurodevelopment being the most sensitive to such early perturbations and with potential for lifelong impact.