Developmental Programming: Prenatal Testosterone Excess on Liver and Muscle Coding and Noncoding RNA in Female Sheep

Area of Science:

• Endocrinology and Metabolism
• Genomics and Transcriptomics
• Developmental Biology

Background:

• Prenatal exposure to excess testosterone (T) in female sheep leads to insulin resistance, ectopic lipid accumulation, and disrupted insulin signaling in liver and muscle.
• Understanding the underlying transcriptional changes is crucial for identifying the mechanisms of these metabolic disruptions.

Purpose of the Study:

• To investigate genome-wide transcriptional and noncoding RNA expression changes in liver and muscle of adult female sheep exposed to excess prenatal testosterone.
• To identify potential biomarkers and pathways involved in prenatal T excess-induced metabolic dysfunction.

Main Methods:

• Comparison of messenger RNA (mRNA) and noncoding RNA (ncRNA) expression profiles in liver and muscle tissues from prenatal T-treated and control female sheep using genome-wide expression analysis.
• Analysis of differential gene expression, pathway enrichment, and correlation between ncRNAs and specific genes.
• Identification of potential biomarkers using orthogonal projections to latent structures discriminant analysis (O2PLS-DA).

Main Results:

• Prenatal T exposure induced differential mRNA expression in liver and muscle, with significant downregulation of mitochondrial pathway genes in both tissues.
• Hepatic lipid catabolism and peroxisome proliferator-activated receptor (PPAR) signaling pathways were downregulated.
• Muscle tissue showed modulated noncoding RNA metabolic processes and downregulation of specific long noncoding RNAs (lncRNAs).
• Specific mRNAs and microRNAs (miRNAs) were identified as potential biomarkers for prenatal T excess in both liver and muscle.

Conclusions:

• Gestational excess testosterone exposure programs tissue-specific metabolic dysfunctions, including downregulation of mitochondrial and lipid catabolism pathways in the liver and dysregulation of mitochondrial and ncRNA pathways in muscle.
• These transcriptional changes contribute to the lipotoxic and insulin-resistant phenotype observed in adulthood.
• Noncoding RNA-modulated transcriptional changes play a significant role in the long-term metabolic consequences of prenatal T excess.