UC Davis

The most common reason for premature breastfeeding cessation is real, or perceived, low milk supply. Maternal stress suppresses milk production, but the mechanism by which stress inhibits lactation has not been defined. The mammalian stress response is mediated in large part by glucocorticoids (GC). It is well-established that excessive endogenous and exogenous GCs transiently suppress milk volume and milk lactose content, without affecting milk fat or protein levels. In vitro studies from the 1980s suggested that the biphasic regulation of alpha-lactalbumin (LALBA) synthesis by GCs is central to the pathophysiology of stress-induced suppression of milk lactose content and milk yield. The LALBA protein is unique to the mammary gland and is required for lactose synthesis and milk production, yet its transcriptional regulation has yet to be defined.

We first sought to define the effect of a synthetic GC (dexamethasone, DEX) on milk yield and composition alongside changes in mammary gene expression in dairy cows. We demonstrated that a single, high dose of DEX administered to lactating dairy cows transiently suppressed milk volume, milk lactose content, milk LALBA content, and LALBA gene expression.

Then, we wanted to determine the reliability and replicability of the murine mammary explant system for the study of GC-mediated regulation of Lalba expression. We defined doses of corticosterone (CORT) and DEX and time intervals at which Lalba expression could be maximally upregulated, inhibited, or suppressed following initial stimulation. We demonstrated for the first time that Lalba expression in mammary explants from midpregnant mice can be suppressed by over 50% in response to high dose of CORT after initial 48 h of stimulation by a low dose of CORT.

The extent to which a decrease in LALBA gene and protein expression contributes to the decline in milk lactose content and milk yield remains to be determined. Future research endeavors should focus on defining the GC-regulated transcriptional landscape at the Lalba promoter using the murine mammary explant system. Determining the mechanism by which GCs modulate LALBA transcription will inform preventative and therapeutic strategies for low milk supply and improve maternal-child health outcomes.