About the Lab
The Hadsell Laboratory has historically been a bench science lab doing studies in mouse models on the actions of growth hormone, insulin, and insulin-like growth factors on mammary gland development and function in the lactating mouse. Our more recent work has shifted to studies aimed at understanding how maternal genomic factors that regulate milk production and composition. The work employs bench studies, but also high-throughput DNA sequencing, data science, and the implementation computational approaches to connecting complexity within the genome to biological outcomes within the mammary cells of lactating mice. Specific projects have focused on mammary ductal development, milk macronutrient composition, and most recently on the various fatty acids in milk and how the genome interacts with the maternal microbiome to bring about changes in these fatty acids.
The Genomic Variants Impacting Milk Yield and Composition
Current data from the Centers for Disease Control indicate that the rate of exclusive breast feeding to 6 months has risen to 24.9% nationwide, coming close to the healthy people 2020 goal of 25%. However, almost half of states in the U.S. still have rates below this goal. In addition, aside from the fact that breastfed infants and their mothers experience better health outcomes, the shortages of infant formula occurring over the last 24 months strongly indicate that continued efforts to understand the biology of lactation and to support breastfeeding are more important than ever. Our team has used GWAS with whole genome and RNA sequencing data in an inbred mouse mapping panel to identify quantitative trait loci (QTL) and sets of lactation-dependent, mammary-expressed, genes that determine milk yield and composition in mice. Our current work is generating a dataset from a large-scale RNA-seq initiative for genome-wide identification mammary-specific expression QTL (eQTL) in the lactating mouse. We have used computational tools to model variant-gene, and gene-gene interactions as regulatory networks. These networks can identify candidate variants and genes that occupy important positions or modules within the system giving them greater potential to have a high impact without compromising organism fitness. We are expanding these results to the large collection of other maternal traits that we have measured. This research project will increase our understanding of how variation in maternal genome determines lactation success. Our working hypothesis is that species-conserved gene-variant modules within regulatory networks cooperate to optimize lactation outcomes.
Impact of the Maternal Microbiome on Milk Yield and Composition
The microbiota is known to be significant regulator of human physiology and disease. In the mammary gland, there is known to be both a breast tissue microbiome as well as a breast milk microbiome and both the origin and significance of these populations are subjects of vigorous debate and research. There is also evidence to support the idea that the intestinal microbiome can influence the dynamics of circulating hormones such as estrogen and oxytocin as well as some growth factors such as IGF-I. Work by our team has employed 16S sequencing of the maternal fecal microbiome from inbred mouse strains with extreme differences in ability to produce milk in support of their growing litters. Using antenatal antibiotic treatment and fecal microbiome transplantation we are testing the importance of changes in the maternal microbiota to milk production and composition.
In silico mapping of quantitative trait loci (QTL) regulating the milk ionome in mice identifies a milk iron locus on chromosome 1.
Hadsell DL, Hadsell LA, Rijnkels M, Carcamo-Bahena Y, Wei J, Williamson P, Grusak MA.
Mamm Genome. 2018 Oct;29(9-10):632-655. doi: 10.1007/s00335-018-9762-7. Epub 2018 Aug 2.
PMID: 30073618
In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci.
Hadsell DL, Hadsell LA, Olea W, Rijnkels M, Creighton CJ, Smyth I, Short KM, Cox LL, Cox TC.
Mamm Genome. 2015 Feb;26(1-2):57-79. doi: 10.1007/s00335-014-9551-x. Epub 2015 Jan 1.
PMID: 25552398 Free PMC article.
In silico QTL mapping of maternal nurturing ability with the mouse diversity panel.
Hadsell DL, Wei J, Olea W, Hadsell LA, Renwick A, Thomson PC, Shariflou M, Williamson P.
Physiol Genomics. 2012 Aug 17;44(16):787-98. doi: 10.1152/physiolgenomics.00159.2011. Epub 2012 Jul 3.
PMID: 22759921 Free PMC article.
Gene regulation of UDP-galactose synthesis and transport: potential rate-limiting processes in initiation of milk production in humans.
Mohammad MA, Hadsell DL, Haymond MW.Am J Physiol Endocrinol Metab. 2012 Aug 1;303(3):E365-76. doi: 10.1152/ajpendo.00175.2012. Epub 2012 May 29.PMID: 22649065 Free PMC article.
Short-term administration of rhGH increases markers of cellular proliferation but not milk protein gene expression in normal lactating women.
Maningat PD, Sen P, Rijnkels M, Hadsell DL, Bray MS, Haymond MW.
Physiol Genomics. 2011 Apr 27;43(8):381-91. doi: 10.1152/physiolgenomics.00079.2010. Epub 2011 Jan 4.
PMID: 21205870 Free PMC article.
Developmental regulation of mitochondrial biogenesis and function in the mouse mammary gland during a prolonged lactation cycle.
Hadsell DL, Olea W, Wei J, Fiorotto ML, Matsunami RK, Engler DA, Collier RJ.
Physiol Genomics. 2011 Mar 29;43(6):271-85. doi: 10.1152/physiolgenomics.00133.2010. Epub 2010 Dec 28.
PMID: 21189371
Enhancement of maternal lactation performance during prolonged lactation in the mouse by mouse GH and long-R3-IGF-I is linked to changes in mammary signaling and gene expression.
Hadsell DL, Parlow AF, Torres D, George J, Olea W.
J Endocrinol. 2008 Jul;198(1):61-70. doi: 10.1677/JOE-07-0556.
PMID: 18577570
Decreased lactation capacity and altered milk composition in insulin receptor substrate null mice is associated with decreased maternal body mass and reduced insulin-dependent phosphorylation of mammary Akt.
Hadsell DL, Olea W, Lawrence N, George J, Torres D, Kadowaki T, Lee AV.
J Endocrinol. 2007 Aug;194(2):327-36. doi: 10.1677/JOE-07-0160.
PMID: 17641282
Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2.
Dearth RK, Cui X, Kim HJ, Hadsell DL, Lee AV.
Cell Cycle. 2007 Mar 15;6(6):705-13. doi: 10.4161/cc.6.6.4035. Epub 2007 Mar 20.
PMID: 17374994 Review.
The declining phase of lactation: peripheral or central, programmed or pathological?
Hadsell D, George J, Torres D.
J Mammary Gland Biol Neoplasia. 2007 Mar;12(1):59-70. doi: 10.1007/s10911-007-9038-4.
PMID: 17286209 Review.
Changes in secretory cell turnover, and mitochondrial oxidative damage in the mouse mammary gland during a single prolonged lactation cycle suggest the possibility of accelerated cellular aging.
Hadsell DL, Torres D, George J, Capuco AV, Ellis SE, Fiorotto ML.
Exp Gerontol. 2006 Mar;41(3):271-81. doi: 10.1016/j.exger.2005.12.005. Epub 2006 Jan 25.
PMID: 16442254
Gene expression in the human mammary epithelium during lactation: the milk fat globule transcriptome.
Maningat PD, Sen P, Rijnkels M, Sunehag AL, Hadsell DL, Bray M, Haymond MW.
Physiol Genomics. 2009 Mar 3;37(1):12-22. doi: 10.1152/physiolgenomics.90341.2008. Epub 2008 Nov 18.
PMID: 19018045 Free PMC article.
Overexpression of des(1-3) insulin-like growth factor 1 in the mammary glands of transgenic mice delays the loss of milk production with prolonged lactation.
Hadsell DL, Torres DT, Lawrence NA, George J, Parlow AF, Lee AV, Fiorotto ML.
Biol Reprod. 2005 Dec;73(6):1116-25. doi: 10.1095/biolreprod.105.043992. Epub 2005 Aug 3.
PMID: 16079306
The insulin-like growth factor system in normal mammary gland function.
Hadsell DL.
Breast Dis. 2003;17:3-14. doi: 10.3233/bd-2003-17102.
PMID: 15687673
Diminished milk synthesis in upstream stimulatory factor 2 null mice is associated with decreased circulating oxytocin and decreased mammary gland expression of eukaryotic initiation factors 4E and 4G.
Hadsell DL, Bonnette S, George J, Torres D, Klimentidis Y, Gao S, Haney PM, Summy-Long J, Soloff MS, Parlow AF, Sirito M, Sawadogo M.
Mol Endocrinol. 2003 Nov;17(11):2251-67. doi: 10.1210/me.2002-0031. Epub 2003 Aug 7.
PMID: 12907752
Targeted disruption of the IGF-I receptor gene decreases cellular proliferation in mammary terminal end buds.
Bonnette SG, Hadsell DL.
Endocrinology. 2001 Nov;142(11):4937-45. doi: 10.1210/endo.142.11.8500.
PMID: 11606462
Inability of overexpressed des(1-3)human insulin-like growth factor I (IGF-I) to inhibit forced mammary gland involution is associated with decreased expression of IGF signaling molecules.
Hadsell DL, Alexeenko T, Klimentidis Y, Torres D, Lee AV.
Endocrinology. 2001 Apr;142(4):1479-88. doi: 10.1210/endo.142.4.8087.
PMID: 11250928
Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis.
Hadsell DL, Murphy KL, Bonnette SG, Reece N, Laucirica R, Rosen JM.
Oncogene. 2000 Feb 17;19(7):889-98. doi: 10.1038/sj.onc.1203386.
PMID: 10702797
Transgenic hypersecretion of des(1-3) human insulin-like growth factor I in mouse milk has limited effects on the gastrointestinal tract in suckling pups.
Burrin DG, Fiorotto ML, Hadsell DL.
J Nutr. 1999 Jan;129(1):51-6. doi: 10.1093/jn/129.1.51.
PMID: 9915875
Targeted expression of des(1-3) human insulin-like growth factor I in transgenic mice influences mammary gland development and IGF-binding protein expression.
Hadsell DL, Greenberg NM, Fligger JM, Baumrucker CR, Rosen JM.
Endocrinology. 1996 Jan;137(1):321-30. doi: 10.1210/endo.137.1.8536631.
PMID: 8536631
Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland.
Lee AV, Zhang P, Ivanova M, Bonnette S, Oesterreich S, Rosen JM, Grimm S, Hovey RC, Vonderhaar BK, Kahn CR, Torres D, George J, Mohsin S, Allred DC, Hadsell DL.
Endocrinology. 2003 Jun;144(6):2683-94. doi: 10.1210/en.2002-221103.
PMID: 12746333
USDA/ARS Children's Nutrition Research Center
The Hirschi Lab is part of the USDA/ARS Children's Nutrition Research Center which houses laboratories, state-of-the-art equipment, a greenhouse, observation labs, research volunteer accommodations, a metabolic kitchen, and an elite group of research scientists.