title: Early life ethanol exposure causes long-lasting disturbances in rat mesenchymal stem cells via epigenetic modifications.
abstract: Fetal alcohol syndrome (FAS) is a birth defect due to maternal alcohol consumption during pregnancy. Because mesenchymal stem cells (MSCs) are the main somatic stem cells in adults and may contribute to tissue homeostasis and repair in adulthood, we investigated whether early life ethanol exposure affects MSCs and contributes to the propensity for disease onset in later life. Using a rodent model of FAS, we found that ethanol exposure (5.25g/kg/day) from postnatal days 4 to 9 in rat pups (mimic of human third trimester) caused long-term anomalies in bone marrow-derived MSCs. MSCs isolated from ethanol-exposed animals were prone to neural induction but resistant to osteogenic and adipogenic inductions compared to their age-matched controls. The altered differentiation may contribute to the severe trabecular bone loss seen in ethanol-exposed animals at 3months of age as well as overt growth retardation. Expression of alkaline phosphatase, osteocalcin, aP2, and PPARγ were substantially inhibited, but BDNF was up-regulated in MSCs isolated from ethanol-exposed 3month-old animals. Several signaling pathways were distorted in ethanol-exposed MSCs via altered trimethylation at histone 3 lysine 27. These results demonstrate that early life ethanol exposure can have long-term impacts in rat MSCs by both genetic and epigenetic mechanisms.
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi 621, Taiwan.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Leu
authors.affiliation: Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.affiliation: Division of Neurosurgery, Changhua Christian Hospital, Changhua 500, Taiwan.
authors.forename: Chien-Min
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan.
authors.forename: Kun-Tu
authors.initials: KT
authors.lastname: Yeh
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi 621, Taiwan.
authors.forename: Yu Ming
authors.initials: YM
authors.lastname: Liu
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi 621, Taiwan.
authors.forename: Yen-Hui
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi 621, Taiwan.
authors.forename: Shan-Tsu
authors.initials: ST
authors.lastname: Kuo
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi 621, Taiwan. Electronic address: bioshh@ccu.edu.tw.
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Hsiao
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects*; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000209:etiology / Q000235:genetics; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats
chemical_list: D017931:DNA Primers; D000431:Ethanol
keywords: Bone; Development; Differentiation; Epigenetic modification; Stem cell