SAT-048 - Influence of Prolactin on the Early Postpartum Lactating Mammary Transcriptome

Human lactation is established during the first postpartum month and consists of colostral (postpartum days 1-3), transitional (days 4-13) and mature milk (day 14 onwards) phases. Prolactin is the major hormonal driver of lactation. However, its influence on the transcriptomic landscape mediating milk synthesis is unclear. To address this, we evaluated early postpartum longitudinal changes in serum prolactin and mammary prolactin receptor (PRLR) expression, and correlated these with the colostral, transitional and mature milk mammary transcriptomes. N=95 healthy pregnant women intending to breastfeed (aged 27-46 years) were recruited with informed consent. Participants were assessed at 36 weeks’ gestation and during postpartum days 1-28 with serial serum prolactin measurements. Bulk RNA-seq was performed on mammary cell RNA isolated from colostrum, transitional and mature milk samples. An analysis of mean ± SEM serum prolactin showed a 68% increase from 4208±177 mU/L at 36 weeks’ gestation to a peak of 6155±287 mU/L on postpartum day 2 (p < 0.0001) with values thereafter decreasing to 2857±466 mU/L by day 28. Early postpartum serum prolactin, as assessed by area-under-the curve analysis, showed no association with mammary gene expression at any lactation stage. In contrast, mammary PRLR expression, which increased from 135±30 counts per million (CPM) on postpartum day 1 to 399±16 CPM by day 28 (~3-fold increase, p< 0.0001), was associated with altered expression (log2 fold-change >0.5, p< 0.05) of 5192 out of 16,232 different genes (29%) identified in the mammary RNA-seq dataset. Indeed, participants in the highest tertile of PRLR expression had 143 differentially expressed genes (DEGs) during the colostral phase, 5015 DEGs during the transitional milk phase and 847 DEGs during the mature milk phase compared to participants in the lowest tertile. Functional annotation of the top upregulated genes (log2 fold-change >1, p< 0.05) identified genes involved in: synthesizing milk components such as milk proteins and lipids (FASN, SREBF1); lipid droplet biogenesis (PLIN4, PLIN5); maintenance of mammary secretory phenotype (ELF5, GATA3); and tight-junction closure (CLDN8, TJP3), which are critical for initiating milk synthesis. In summary, this temporal mammary transcriptomic analysis demonstrates a novel association between the prolactin-mammary PRLR axis and a broad complement of genes mediating the transition from colostrum to milk production during the early postpartum period.

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