ARYL HYDROCARBON RECEPTOR ACTIVATION DISRUPTS MOUSE MAMMARY GLAND AND LIVER FUNCTION DURING LACTATION

Open Access
Author:
Belton, Kerry R
Graduate Program:
Molecular Toxicology
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
October 11, 2016
Committee Members:
  • Andrew D. Patterson, Dissertation Advisor
  • Gary H. Perdew, Committee Chair
  • K. Sandeep Prabhu, Committee Member
  • Andrew D. Patterson, Committee Member
  • Connie J. Rogers, Outside Member
Keywords:
  • AHR
  • Mammary gland
  • Metabolism
  • Lactation
  • NMR
Abstract:
Environmental exposure to pesticides and xenobiotics poses a significant risk to human reproductive and lactation health. The liver and the mammary gland have complementary metabolic roles during lactation. They form the lactation network which is a system of substrate production [1] in the liver and catabolism of these chemicals in the mammary gland for milk synthesis (e.g., lactose and the glycerol backbone of milk triglycerides). In this study, we sought to investigate the effects of 5, 6-benzoflavone (BNF), a synthetic AHR activator, on the lactation network in the mouse. Using morphological and molecular techniques, as well as 1H nuclear magnetic resonance (NMR)–based metabolomics, we observed disruption of mammary gland development and metabolic function in addition to changes in gene and protein expression. 1H NMR analyses revealed significant changes in the levels of glucose and amino acids in BNF group mouse mammary tissue, compared to no significant changes in the control diet group, indicating AHR may play a role in mediating the deleterious mechanistic and metabolic effects on glands in early lactation. In the nursing dams, there were significant changes in lipid and TCA intermediates in extracts obtained from livers. The mice also had significant changes in ketones, low-density lipoprotein/ very-low-density lipoprotein (LDL/VLDL), high-density lipoprotein (HDL), phosphocholine/ glycerophosphocholine (PC/GPC). Likewise, treatment altered monounsaturated fatty acid production and caused disruption of lipid metabolites in the liver compared to control. The hepatic expression of stearoyl coenzyme A desaturase 1 and Cytochrome P450 (Cyp1a1) mRNA was significantly changed in the livers from both Ahrd (high affinity) and Ahrb (low affinity) mice following BNF treatment, suggesting effects are likely independent of Ahr. Our results thus support a possible role of the AHR in regulating the substrates synthesized by the liver during lactation.