Developmental programming: Impact of prenatal bisphenol-A exposure on liver and muscle transcriptome of female sheep

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 (0.5 mg/kg/day from days 30 to 90 of gestation; Term: 147 days) female sheep were sequenced. Prenatal BPA-treatment dysregulated: expression of 194 genes (138 down, 56 up) in liver and 112 genes (32 down, 80 up) in muscle (FDR < 0.05 and abs log2FC > 0.5); 155 common gene pathways including mitochondrial-related genes in both tissues; 1415 gene pathways including oxidative stress and lipid biosynthetic process specifically in the liver (FDR < 0.01); 192 gene pathways including RNA biosynthetic processes in muscle (FDR < 0.01); 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 (FDR < 0.1, abs log2FC > 0.5). Multiple ncRNA correlated with LCORL, MED17 and ZNF41 mRNA in liver but none of them in the muscle. Discriminant analysis identified (p < 0.05) PECAM, RDH11, ABCA6, MIR200B, and MIR30B in liver and CAST, NOS1, FASN, 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.