Level of nutrient intake affects mammary gland gene expression profiles in preweaned Holstein heifers

Bovine mammary parenchyma (PAR) and fat pad (MFP) development are responsive to preweaning level of nutrient intake. We studied transcriptome alterations in PAR and MFP from Holstein heifer calves (n=6/treatment) fed different nutrient intakes from birth to ca. 65 d age. Conventional nutrient intake received 441 g of dry matter (DM)/d of a control milk replacer (MR) [CON; 20% crude protein (CP), 20% fat, DM basis]. Calves in the accelerated nutrition groups received 951 g/d of high-protein/low-fat MR (HPLF; 28% CP, 20% fat, DM basis), 951 g/d of high-protein/high-fat MR (HPHF; 28% CP, 28% fat, DM basis), or 1,431 g/d of HPHF (HPHF+) MR. Out of 13,000 genes evaluated, over 1,500 differentially expressed genes (DEG) were affected (false discovery rate <0.10) by level of nutrient intake in PAR or MFP. Feeding HPLF versus CON resulted in the most dramatic changes in gene expression, with 278 and 588 DEG having ≥1.5-fold change in PAR and MFP. In PAR, the most-altered molecular functions were associated with metabolism of the cell (molecular transport and lipid metabolism) with most of the genes downregulated in HPLF versus CON. In MFP, DEG also were primarily associated with metabolism but changes also occurred in genes linked to cell morphology, cell-to-cell signaling, and immune response. Compared with CON, feeding HPHF or HPHF+ did not result in substantial additional effects on DEG beyond those observed with HPLF. The pentose phosphate, mitochondrial dysfunction, and ubiquinone biosynthesis pathways were among the most enriched due to HPLF versus CON in PAR and were inhibited, whereas glycosphingolipid biosynthesis, arachidonic acid metabolism, and eicosanoid synthesis pathways were among the most enriched due to HPLF versus CON in MFP and were inhibited. These responses suggest that, in PAR, doubling nutrient intake from standard feeding rates inhibited energy metabolism and activity of oxidative pathways that partly serve to protect cells against oxidative stress. The MFP in those heifers appeared to decrease production of lipid-derived metabolites that may play roles in signaling pathways within the adipocyte. Overall, results indicated that prepubertal/preweaned mammary transcriptome is responsive to long-term enhanced nutrient supply to achieve greater growth rates before weaning. The biological significance of these results to future milk production remains to be elucidated.