Investigation of the Role of the Aryl Hydrocarbon Receptor and Endocrine Disrupting Chemicals in Equine Metabolic Syndrome

Equine Metabolic Syndrome (EMS) is characterized by abnormalities in insulin regulation, increased adiposity and laminitis. In a large across-breed study, our lab has demonstrated that genetics and the environment play a role in EMS. Further, multi-level regression modeling has demonstrated that 23-49% of the variability in EMS phenotypic measures is related to shared environment; yet only 4-18% of this variability is explained by measured environmental factors including diet, exercise and season.  Recent work has identified associations between Endocrine Disrupting Chemicals (EDCs) and human metabolic syndrome and other endocrine abnormalities. To investigate the possibility that EDCs could be a factor in the unexplained variance, the proximity of horses to US EPA ‘Superfund sites’ harboring EDCs was evaluated. Horses from farms within 30 miles of a Superfund site were significantly more likely to have a history of laminitis (p = 0.002) and have higher post oral sugar challenge insulin concentrations (OST INS) (p=0.00005).

GWAS in 286 Morgan horses identified the aryl hydrocarbon receptor (AHR) as a candidate gene for EMS. The AHR is responsible for metabolism of EDCs following their ingestion. A single SNP within the AHR was associated with OST INS values (p = 0.002), and 7 SNPs within two haplotypes across the AHR trans-activation domain were strongly associated with OST INS (p=0.0007 and 0.0009). A direct association between EDCs and EMS, and the gene-by-environment interaction between AHR and EDCs is currently being evaluated by quantification of AHR activating compounds in the plasma of 300 horses.