**Background:** The Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project was designed to examine human milk as a complex biological system that interacts with the lactating person's biology, the milk matrix, and the breastfed infant, as well as external environments. Working Group 1 was tasked with addressing the key question: 'What are the parental factors that affect the composition and volume of breastmilk?' The group expanded this to include how mammary gland development affects milk secretion, the infant's input to secretory activation, how disease conditions impact lactation, and how environmental agents affect mammary development and milk secretion.
**Methods:** This is a narrative review synthesizing evidence from multiple sources, including animal models (mice, rats, pigs, non-human primates), human clinical studies, transcriptomic analyses of milk fat globules and milk-derived mammary epithelial cells (MECs), and single-cell RNA-sequencing studies. The authors organized their analysis around five thematic areas: breast development, normal milk secretion physiology, lactating parent-infant interactions, effects of common clinical conditions, and effects of medications, recreational drugs, and environmental pollutants.
**Key Results:** The review presents several major findings. First, breast development proceeds through critical stages from birth through puberty and pregnancy, with estrogen, progesterone, human placental lactogen (hPL), and growth hormone as key drivers. At puberty, increased circulating estrogens and IGF1 stimulate ductal development, while progesterone during the luteal phase stimulates formation of terminal duct lobular units. During pregnancy, estrogen and progesterone drive massive epithelial development, while progesterone also inhibits milk secretion until birth. Second, milk secretion involves five classical pathways in MECs: the Golgi-secretory vesicle pathway (for lactose, casein, α-lactalbumin, lactoferrin, oligosaccharides), the milk fat globule pathway (for lipids), ion transport across membranes, direct vesicular transport of IgA, and secretion of small extracellular vesicles including exosomes. A sixth paracellular pathway operates only during pregnancy, inflammation, and potentially involution. Third, prolactin (PRL) regulates all aspects of milk synthesis and secretion, but its importance in maintaining human lactation is questioned by observations that milk volume remained high (670–896 mL/h) for the first 6 months despite PRL concentrations falling from ~120 ng/mL at 1 month to 59 ng/mL at 6 months. Fourth, the lactating breast utilizes 20%–30% of the body's daily energy production and cardiac output. Fifth, circadian biology significantly influences milk composition—7% of genes in lactating MECs have a circadian pattern of expression, and concentrations of tryptophan, fats, triacylglycerol, cholesterol, iron, melatonin, cortisone, and cortisol in human milk all show circadian patterns. Sixth, regarding clinical conditions, approximately 4% of women have severe hypoplasia or insufficient glandular tissue. Only about 25% of birthing parents in the United States breastfeed exclusively for the recommended 6 months. Obesity and diabetes are associated with significantly lower breastfeeding initiation, continuation, and exclusivity. Differences have been reported in concentrations of leptin, insulin, adiponectin, ghrelin, pro-inflammatory cytokines, microRNAs, and HMOs in breastmilk from women with obesity and diabetes. Seventh, regarding infectious agents, five viruses have clearly been shown to be transmitted in breastmilk: HIV-1, CMV, HTLV-1, dengue virus, and Zika virus. SARS-CoV-2 transmission in breastmilk is rare, but neutralizing antibodies to the virus were present in the breastmilk of a majority of women who had had the disease. Eighth, 60%–100% of women take at least one prescribed or over-the-counter medication in the first year after giving birth. Selective serotonin receptor uptake inhibitors (SSRIs) delay secretory activation in women. Tetrahydrocannabinol and cannabidiol accumulate to significant concentrations in breastmilk relative to those in plasma. At least 2000 environmental pollutants have been identified, with about 60% being endocrine-disrupting chemicals (EDCs), but their effects on milk production are largely undocumented.
**Clinical Implications:** The review identifies critical research gaps that must be addressed to improve breastfeeding outcomes. These include the need for better understanding of normal breast variation from genetic through endocrine to histologic levels; the need for carefully collected measures of cardiovascular function during lactation; the need for next-generation multi-omic approaches to study human milk and lactation; the need to understand how immune factors in milk relate to development of food allergies in breastfed infants; and the critical need to study how medications, recreational drugs, and EDCs affect lactation physiology and parent-infant bonding. The authors emphasize that diversification of study populations to include families of color and lower-income families is critical, as experiences of racial discrimination and economic instability remain severely understudied in relation to lactation.