Antenatal steroids elicited neurodegenerative-associated transcriptional changes in the hippocampus of preterm fetal sheep independent of lung maturation

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dc.coverageDOI: 10.1186/s12916-024-03542-5
dc.creatorCarter, Sean W.D.
dc.creatorFee, Erin L.
dc.creatorUsuda, Haruo
dc.creatorOguz, Gokce
dc.creatorRamasamy, Adaikalavan
dc.creatorAmin, Zubair
dc.creatorAgnihotri, Biswas
dc.creatorWei, Qin
dc.creatorXiawen, Liu
dc.creatorTakahashi, Tsukasa
dc.creatorTakahashi, Yuki
dc.creatorIkeda, Hideyuki
dc.creatorKumagai, Yusaku
dc.creatorSaito, Yuya
dc.creatorSaito, Masatoshi
dc.creatorMattar, Citra
dc.creatorEvans, Mark I.
dc.creatorIllanes, Sebastián E.
dc.creatorJobe, Alan H.
dc.creatorChoolani, Mahesh
dc.creatorKemp, Matthew W.
dc.date2024
dc.date.accessioned2025-11-18T19:55:27Z
dc.date.available2025-11-18T19:55:27Z
dc.description<p>Background: Antenatal steroid therapy for fetal lung maturation is routinely administered to women at risk of preterm delivery. There is strong evidence to demonstrate benefit from antenatal steroids in terms of survival and respiratory disease, notably in infants delivered at or below 32 weeks’ gestation. However, dosing remains unoptimized and lung benefits are highly variable. Current treatment regimens generate high-concentration, pulsatile fetal steroid exposures now associated with increased risk of childhood neurodevelopmental diseases. We hypothesized that damage-associated changes in the fetal hippocampal transcriptome would be independent of preterm lung function. Methods: Date-mated ewes carrying a single fetus at 122 ± 2dGA (term = 150dGA) were randomized into 4 groups: (i) Saline Control Group, 4×2ml maternal saline intramuscular(IM) injections at 12hr intervals (n = 11); or (ii) Dex High Group, 2×12mg maternal IM dexamethasone phosphate injections at 12hr intervals followed by 2×2ml IM saline injections at 12hr intervals (n = 12; representing a clinical regimen used in Singapore); or (iii) Dex Low Group, 4×1.5mg maternal IM dexamethasone phosphate injections 12hr intervals (n = 12); or (iv) Beta-Acetate Group, 1×0.125mg/kg maternal IM betamethasone acetate injection followed by 3×2ml IM sterile normal saline injections 12hr intervals (n = 8). Lambs were surgically delivered 48hr after first maternal injection at 122–125dGA, ventilated for 30min to establish lung function, and euthanised for necropsy and tissue collection. Results: Preterm lambs from the Dex Low and Beta-Acetate Groups had statistically and biologically significant lung function improvements (measured by gas exchange, lung compliance). Compared to the Saline Control Group, hippocampal transcriptomic data identified 879 differentially significant expressed genes (at least 1.5-fold change and FDR &lt; 5%) in the steroid-treated groups. Pulsatile dexamethasone-only exposed groups (Dex High and Dex Low) had three common positively enriched differentially expressed pathways related in part to neurodegeneration (“Prion Disease”, “Alzheimer’s Disease”, “Arachidonic Acid metabolism”). Adverse changes were independent of respiratory function during ventilation. Conclusions: Our data suggests that exposure to antenatal steroid therapy is an independent cause of damage- associated transcriptomic changes in the brain of preterm, fetal sheep. These data highlight an urgent need for careful reconsideration and balancing of how antenatal steroids are used, both for patient selection and dosing regimens.</p>eng
dc.identifierhttps://investigadores.uandes.cl/en/publications/1c7abd6e-3c99-43bd-950d-6f97ed421b17
dc.identifier.urihttps://repositorio.uandes.cl/handle/uandes/59269
dc.languageeng
dc.rightsinfo:eu-repo/semantics/openAccess
dc.sourcevol.22 (2024) nr.1 p.338
dc.subjectBrain injury
dc.subjectFetus
dc.subjectHippocampus
dc.subjectLung maturation
dc.subjectPreterm
dc.subjectSheep
dc.subjectSteroids
dc.titleAntenatal steroids elicited neurodegenerative-associated transcriptional changes in the hippocampus of preterm fetal sheep independent of lung maturationeng
dc.typeArticleeng
dc.typeArtículospa
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