Metabolomics Reveals Aryl Hydrocarbon Receptor Activation Induces Liver and Mammary Gland Metabolic Dysfunction in Lactating Mice

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.

Ron Receptor Signaling Ameliorates Hepatic Fibrosis in a Diet-Induced Nonalcoholic Steatohepatitis Mouse Model

“…Samples were then briefly vortexed and centrifuged at 11 180 g for 10 min at 4 °C and 550 μL of the supernatant was transferred to 5 mm NMR tubes. 1 H NMR spectra of serum was acquired as previously described. , Spectral data processing and multivariate analysis was performed as previously described. , …”

“…1 H NMR spectra of serum was acquired as previously described. 23,24 Spectral data processing and multivariate analysis was performed as previously described. 23,24…”

Targeting the Aryl Hydrocarbon Receptor Signaling Pathway in Breast Cancer Development

“…Support for the premise comes from a recent report, showing that breast cancer patients who had low AhRR expression also had shorter metastasis-free survival and identified AhRR as an independent prognostic factor ( 9 ). Literature also indicates that the AhR regulates normal development of the mammary gland ( 10 – 12 ) revealing this tissue as a sensitive target of environmental pollutants containing AhR activating chemicals.…”

The Aryl Hydrocarbon Receptor Undergoes Chaperone-Mediated Autophagy in Triple-Negative Breast Cancer Cells

“…The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor essential for a variety of cellular functions; for example, this receptor is involved in xenobiotic sensing [ 7 ], normal physiological functions (such as liver development [ 8 , 9 ], immune response [ 10 , 11 ], and hematopoietic stem cell differentiation [ 12 ]), and many diseases (such as breast and other cancers [ 13 , 14 , 15 ], cardiac disorders [ 16 , 17 ], respiratory disorders [ 18 , 19 ], metabolic disorders [ 20 , 21 ], and macular degeneration [ 22 , 23 ]). AHR resides in the cytoplasm as a complex containing AHR, a dimer of HSP90, p23, and XAP2 [ 24 , 25 , 26 ].…”