Abstract
The liver and the mammary gland have complementary metabolic roles during lactation. Substrates synthesized by the liver are released into the circulation and are taken up by the mammary gland for milk production. The aryl hydrocarbon receptor (AHR) has been identified as a lactation regulator in mice, and its activation has been associated with myriad morphological, molecular, and functional defects such as stunted gland development, decreased milk production, and changes in gene expression. In this study, we identified adverse metabolic changes in the lactation network (mammary, liver, and serum) associated with AHR activation using 1H nuclear magnetic resonance (NMR)-based metabolomics. Pregnant mice expressing Ahrd (low affinity) or Ahrb (high affinity) were fed diets containing beta naphthoflavone (BNF), a potent AHR agonist. Mammary, serum, and liver metabolomics analysis identified significant changes in lipid and TCA cycle intermediates in the Ahrb mice. We observed decreased amino acid and glucose levels in the mammary gland extracts of Ahrb mice fed BNF. The serum of BNF fed Ahrb mice had significant changes in LDL/VLDL (increased) and HDL, PC, and GPC (decreased). Quantitative PCR analysis revealed ∼50% reduction in the expression of key lactogenesis mammary genes including whey acid protein, α-lactalbumin, and β-casein. We also observed morphologic and developmental disruptions in the mammary gland that are consistent with previous reports. Our observations support that AHR activity contributes to metabolism regulation in the lactation network.
Highlights
Mammary gland differentiation during lactation is complex and is associated with extensive changes in its structure and function.[1]
Human epidemiological studies have demonstrated associations between environmental toxicants and defects in lactation and suggest exposure to endocrine disruptors (e.g., 2,3,7,8-tetrachlorodibenzodioxin, TCDD) during pregnancy have the potential to disrupt lactation.[4−7] Several studies have shown that mammary gland differentiation defects are mediated through the aryl hydrocarbon receptor (AHR).[3,6,8−10] the precise metabolic consequences of this dysregulation remain largely unclear and differences between mouse and human AHR in terms of their relative ligand affinities and selectivity further complicate understanding the role of the AHR in the mammary gland.[11]
Our analyses revealed Ahrb mice fed beta naphthoflavone (BNF) had a significant decrease in amino acid and glucose utilization, which could be due to decreased glucose and amino acid transporter activity or to decreased release of glucose and amino acids to the serum from the liver
Summary
Mammary gland differentiation during lactation is complex and is associated with extensive changes in its structure and function.[1] During pregnancy, the gland becomes highly proliferative, initiating the development of epithelial ductal branching, elongation, and development of lobulo-alveolar structure. This differentiation process is hormone-dependent and its completion enables the synthesis of milk. The mouse has proven to be an invaluable tool for dissecting AHR signaling pathways in the mammary gland.[3,10,12−14]
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