Location: Arkansas Children's Nutrition CenterTitle: Infant formula feeding changes the proliferative status in piglet neonatal mammary glands independently of estrogen signaling
|MERCER, KELLY - University Arkansas For Medical Sciences (UAMS)|
|BHATTACHARYYA, SUDEEPA - University Arkansas For Medical Sciences (UAMS)|
|SHARMA, NEHA - University Arkansas For Medical Sciences (UAMS)|
|CHAUDHURY, MOUSUMI - University Arkansas For Medical Sciences (UAMS)|
|LIN, HAIXIA - University Arkansas For Medical Sciences (UAMS)|
|YERUVA, LAXMI - University Arkansas For Medical Sciences (UAMS)|
|RONIS, MARTIN - Louisiana State University|
Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/10/2019
Publication Date: 11/5/2019
Citation: Mercer, K.E., Bhattacharyya, S., Sharma, N., Chaudhury, M., Lin, H., Yeruva, L., Ronis, M.J. 2019. Infant formula feeding changes the proliferative status in piglet neonatal mammary glands independently of estrogen signaling. Journal of Nutrition. https://doi.org/10.1093/jn/nxz273.
Interpretive Summary: Soy infant formula contains plant-based components called isoflavones, i.e. genistein. These isoflavones have a similar structure to the steroid hormone, estrogen. Although there are published data in both animal models and in infants that eating soy-containing foods is not harmful, concerns persist that soy consumption may alter normal female reproductive development. To evaluate this concern, in this study young female piglets were given milk-based infant formula, soy-based infant formula, or milk-based infant formula with pure estrogen, i.e. estradiol (E2) or milk based infant formula with pure genistein (GEN, a soy isoflavone) for 21 days. Early mammary gland development was compared between the different infant formulas and sow's milk reared piglets. As expected, in piglets fed Milk+E2 formula we observed significant increases in mRNA expression of estrogen-responsive genes. In contrast, we observed no increases in estrogen-responsive gene expression in the Soy or Milk+GEN fed piglets. From these data it is concluded that isoflavones contained in soy formula do not turn on estrogen signaling pathways in the mammary gland. These findings are consistent with clinical data showing soy formula-fed infants have normal breast tissue development during infancy and early childhood. Taken together, the research does not support the idea that intake of soy formula has negative effects on infant reproductive tissues.
Technical Abstract: Soy infant formula contains isoflavones, which are able to bind to and activate estrogen receptor (ER) pathways. The mammary gland is sensitive to estrogens, raising concern that the use of soy formulas may promote premature development. We aimed to determine if soy formula feeding increases mammary gland proliferation and differentiation in comparison to other infant postnatal diets. White-Dutch Landrace piglets aged 2 d received either sow milk (Sow), or were provided milk formula (Milk), soy formula (Soy), milk formula supplemented with 17-beta-estradiol (2 mg/(kg/d);M+E2), or milk formula supplemented with genistein (84 mg/L of diet; M+G) until day 21. Mammary gland proliferation and differentiation was assessed by histology, and real-time RT-PCR confirmation of differentially expressed genes identified by microarray analysis. Mammary terminal end bud numbers were 19–31% greater in the Milk, Soy, and M+G groups relative to the Sow and M+E2, P <0.05. Microarray analysis identified differentially expressed genes between each formula-fed group relative to the Sow (+/-1.7-fold, P <0.05). Real-time RT-PCR confirmed 2- to 4-fold increases in mRNA transcripts of genes involved in cell proliferation, insulin-like growth factor 1 (IGF1), fibroblast growth factor 10 (FGF10), and fibroblast growth factor 18 (FGF18), in all groups relative to the Sow, P <0.05. In contrast, genes involved in cell differentiation and ductal morphogenesis, angiotensin II receptor type 2 (AGTR2), microtubule associated protein 1b (MAP1B), and kinesin family member 26b (KIF26B), were significantly upregulated by 2-, 4-, and 13-fold, respectively, in the M+E2 group. Additionally, mRNA expression of ER-specific gene targets, progesterone receptor (PGR), was increased by 12-fold, and amphiregulin (AREG) and Ras-like estrogen regulated growth inhibitor (RERG) expression by 1.5-fold in the M+ E2 group,P <0.05. In the soy and M+G groups, mRNA expressions of fatty acid synthesis genes were increased 2- to 4-fold. Our data indicate soy formula feeding does not promote ER-signaling in the piglet mammary gland. Infant formula feeding (milk- or soy-based) may initiate proliferative pathways independently of estrogenic signaling.