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Developmental Programming: Impact of Prenatal Bisphenol-A Exposure On Liver and Muscle Transcriptome of Female Sheep [ncRNA-Seq]

ABSTRACT: Gestational Bisphenol A (BPA) exposure leads to peripheral insulin resistance, and hepatic and skeletal muscle oxidative stress and lipotoxicity during adulthood in the female sheep offspring. To investigate transcriptional changes underlying the metabolic outcomes, coding and non-coding (nc) RNA in liver and muscle from 21-month-old control and prenatal BPA-treated (0.5mg/kg/day from days 30 to 90 of gestation; Term: 147days) female sheep were sequenced. Prenatal BPA-treatment dysregulated:1) expression of 194 genes (138 down, 56 up) in liver and 112 genes (32 down, 80 up) in muscle; (2) 155 common gene pathways including mitochondrial-related genes in both tissues; 3) 1415 gene pathways including oxidative stress and lipid biosynthetic process specifically in the liver; (4) 192 gene pathways including RNA biosynthetic processes in muscle; (5) 77 lncRNA (49 down, 28 up), 14 microRNAs (6 down, 8 up), 127 snoRNAs (63 down, 64 up) and 55 snRNAs (15 down, 40 up) in the liver while upregulating 6 lncRNA and dysregulating 65 snoRNAs (47 down, 18 up) in muscle. Multiple ncRNA correlated with LCORL, MED17 and ZNF41 in liver but none of them in the muscle. OPLS-DA plots identified mRNAs PECAM, RDH11 and ABCA6, and miRNAs MIR200B and MIR30B in liver and mRNAs CAST, NOS1 and FASN and miRNAs MIR26B and MIR29A in muscle as gene signatures of gestational BPA exposure. These findings provide mechanistic clues into the development and/or maintenance of the oxidative stress and lipid accumulation and potential for development of mitochondrial and fibrotic defects contributing to the prenatal BPA-induced metabolic dysfunctions.

ORGANISM(S): Ovis aries

PROVIDER: GSE190326 | GEO | 2022/07/08

REPOSITORIES: GEO

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Project description:We used the rhesus monkey (Macaca mulatta) as our animal model for the current study with two goals: to characterize the changes in histology and gene expression from early to late gestation (prenatal uterine organogenesis) and to determine if there are effects of prenatal exposure to bisphenol A (BPA) on the developing female uterus. Pregnant rhesus monkeys carrying a female fetus (N=22) were divided into two experimental groups, based on gestational timing: 'early' (N=10) and 'late' (N=12). These groups were then equally sub-divided into control (unexposed) and BPA (exposed) groups (5 Early Control, 5 Early BPA-exposed, 6 Late Control and 6 Late BPA-exposed.) The BPA-exposed monkeys received a deuterated BPA (dBPA, CDN Isotopes, Quebec, Canada) fruit treat on a daily basis, at a dose of 400ug/kg/day). The dosing was aimed at achieving serum levels of BPA detected in adult human biomonitoring studies. The control animals received a vehicle control on a daily basis. The 'early' time period (mid-gestation) referred to gestational days 50-100, approximating the second trimester of human gestation. The fetal monkeys in the 'early' group were delivered via cesarean section on gestation day 100 and euthanized. Samples of maternal and fetal blood and amniotic fluid were obtained. Maternal and fetal weights were also recorded. The 'late' time period referred to gestational days 100-165, approximating the third trimester of human gestation. The fetal monkeys in the 'late' group were delivered vaginally and euthanized. There were five idiopathic stillbirths (2 Control, 3 BPA-exposed) in the late group. Samples of maternal and fetal blood and amniotic fluid were obtained. Maternal and fetal weights were also recorded. After delivery, the fetal uterus was excised and cut sagitally from fundus to cervix; one side was fixed for histological evaluation and the other half was frozen for analysis of gene expression by microarray. The stillbirths were excluded from the microarray.

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Developmental Programming: Impact of Prenatal Bisphenol-A Exposure On Liver and Muscle Transcriptome of Female Sheep [ncRNA-Seq]

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