Adverse Effects of Coumestrol and Genistein on Mammary Morphogenesis and Future Milk Production Ability of Mammary Epithelial Cells

Abstract

Isoflavones are a class of flavonoids present in legumes and are called phytoestrogens because of their estrogen‐like activity. Endogenous estrogen is well known to regulate mammary gland morphogenesis during pregnancy. Each isoflavone also has different physiological activities. However, it is difficult to investigate the direct effect of each isoflavone in mammary morphogenesis in vivo because isoflavones are metabolized into different isoflavones by enteric bacteria. In this study, investigated are the direct influences of coumestrol, daidzein, and genistein on mammary structure development and future milk production ability of mammary epithelial cells (MECs) using in vitro culture models. Mouse MECs are cultured in Matrigel with basic fibroblast growth factor and epidermal growth factor to induce ductal branching and alveolar formation, respectively. Coumestrol and genistein inhibit ductal branching and alveolar formation by affecting the proliferation and migration of MECs with the induction of apoptosis. Daidzein hardly influences mammary structure development. Furthermore, pretreatment with coumestrol adversely affects the induction of milk production ability of MECs. These results suggest that each isoflavone differentially influences mammary morphogenesis and future milk production by affecting MEC behaviors. These results also suggest that the culture models are effective to study mammary epithelial morphogenesis in vitro.

Polyphenols and Lactation: Molecular Evidence to Support the Use of Botanical Galactagogues

“…Studies in lactating mice and cultured MECs suggests that genistein impairs lactation through the induction of apoptosis and inhibition of ductal branching and alveolar formation by affecting the proliferation and migration of MECs during development. [ 26 ] It also inactivates Stat5a and ERK1/2, thereby decreasing secretion of α‐ and β‐casein and downregulating Csn1 ‐ 3 and Wap expression. In contrast, daidzein, a naturally occurring compound found exclusively in soybeans and other legumes, is the main isoflavone in soy and minimally influences mammary structure development.…”

“…In contrast, daidzein, a naturally occurring compound found exclusively in soybeans and other legumes, is the main isoflavone in soy and minimally influences mammary structure development. [ 26 ] Moreover, it promotes α‐ and β‐casein and lipid synthesis, cell cycle transition, and cell proliferation through mTOR activation and Cyclin D1 and SREBP‐1c expression in bovine MECs. However, daidzein induces expression and nuclear localization of estrogen receptor α (ERα), and NFκβ, [ 121 ] suggesting it may have some anti‐lactogenic properties as well.…”

“…Moreover, some polyphenols, such as those found in soy, have estrogenic activity and may positively or negatively affect hormone signaling in the mammary gland, influencing expression, and milk production. [26][27][28] Thus, understanding the molecular mechanisms through which polyphenols affect mammary gland biology will provide a valuable perspective for developing interventions to improve lactation outcomes.…”

Causes of Low Milk Supply: The Roles of Estrogens, Progesterone, and Related External Factors

“…[ [110] , [111] , [112] , [113] ] and Kumai et al. [ 114 ] have demonstrated using mouse and cow models that isoflavones have different effects on mammary gland development, TJ formation, and expression of milk components, thereby affecting milk production ( Table 2 ). Specifically, biochanin A and its metabolite genistein have been shown to inhibit mRNA expression and secretion of both β-casein and lactoferrin [ 110 , 112 ].…”

Culture Models to Investigate Mechanisms of Milk Production and Blood-Milk Barrier in Mammary Epithelial Cells: a Review and a Protocol

“…In particular, three-dimensional cultures of MECs in Matrigel form organoids with the alveolar-like luminal structure [ 109 , 110 ]. When alveolar-like organoids are cultured in medium containing prolactin and glucocorticoids, milk components are secreted into the lumen [ 109 , 111 ]. In this review, organoid refers to clusters of cells to form complex structures that partially resemble the in vivo organs and distinguishes from spheroids that are simple clusters of cells without forming complex structure.…”