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Metformin exposure during pregnancy and lactation affects milk lipid composition in a healthy nondiabetic mouse model (123598)

Adamu A Mwendolwa 1 2 , Alexandra D George 3 4 , Peter J Meikle 3 4 , Theresha Ruwan Pathiranage 1 , Meagan Craven 1 , Kathryn Aston-Mourney 1 , Fatma K Shehata 1 , Leni R Rivera 1 , Bryony A McNeill 1
  1. School of Medicine, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Victoria, Australia
  2. Biological Sciences, Mkwawa University College of Education, Iringa, Tanzania
  3. Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
  4. Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, Victoria, Australia

Lactation is a critical window for offspring development. Changes in milk composition, particularly milk lipids, can have short- and long-term effects on infant growth and development. Metformin, a commonly prescribed medication used in the treatment of gestational diabetes and other pregnancy complications, is known to affect plasma lipid metabolism. However, its possible effect on breastmilk lipids is unknown. Therefore, this study aimed to examine the effect of metformin on milk lipid composition and mammary gland lipid-related gene expression, using a mouse model.

From embryonic day 0.5 until postnatal day (PND) 13, healthy, non-diabetic C57Bl/6 mice received drinking water containing 5 g/L of metformin or control (untreated) drinking water. Milk was collected at PND13 to perform targeted lipidomics using liquid chromatography-mass spectrometry. Mammary glands were also collected from subsets of dams at PND0 and PND13 to determine the expression of genes involved in lipid synthesis and metabolism.

Lipidomics analysis quantified 583 lipid species, from 32 lipid classes. Compared to the control group, there were 282 lipids significantly altered in the metformin group, with 29.4% of lipids increased and 70.6% of lipids decreased (p-value<0.05). Lipid set enrichment analysis showed that the metformin-treated mice had decreased sphingolipids, glycerophospholipids, ether lipids, plasmalogens, and alkyl lipids in their milk, compared to the control mice. Additionally, mammary gland expressions of Srebf1, Elovl1, Fasn, Scd1, and Fads1 were lower in metformin-treated dams at PND0 but not PND13.

Metformin exposure during pregnancy and lactation in a healthy mouse significantly affects milk lipid composition and related mammary gland gene expression. These altered lipids and lipid-regulating genes have known functions in brain and immune system development, cell membrane function, and serve as a source of energy. Further research is required to determine how these changes in milk composition and mammary gland gene expression affect offspring development.