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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\u201313 wks) and aging (43\u201350 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.<\/jats:p>","DOI":"10.3390\/cells12010076","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T07:30:06Z","timestamp":1672126206000},"page":"76","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Advanced Maternal Age Differentially Affects Embryonic Tissues with the Most Severe Impact on the Developing Brain"],"prefix":"10.3390","volume":"12","author":[{"given":"Caroline","family":"Kokorudz","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada"},{"name":"Alberta Children\u2019s Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany N.","family":"Radford","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada"},{"name":"Alberta Children\u2019s Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9441-5044","authenticated-orcid":false,"given":"Wendy","family":"Dean","sequence":"additional","affiliation":[{"name":"Alberta Children\u2019s Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada"},{"name":"Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3332-6958","authenticated-orcid":false,"given":"Myriam","family":"Hemberger","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada"},{"name":"Alberta Children\u2019s Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1093\/humrep\/15.11.2433","article-title":"The risks associated with pregnancy in women aged 35 years or older","volume":"15","author":"Jolly","year":"2000","journal-title":"Hum. 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