Metabolomic analysis reveals metabolic changes caused by bisphenol A in rats

Toxicol Sci. 2014 Apr;138(2):256-67. doi: 10.1093/toxsci/kfu016. Epub 2014 Jan 21.


Bisphenol A (BPA) is a widely used material known to cause adverse effects in humans and other mammals. To date, little is known about the global metabolomic alterations caused by BPA using urinalysis. Sprague-Dawley rats were orally administrated BPA at the levels of 0, 0.5 μg/kg/day and 50 mg/kg/day covering a low dose and a reference dose for 8 weeks. We conducted a capillary electrophoresis in tandem with electrospray ionization time-of-flight mass spectrometry based nontargeted metabolomic analysis using rat urine. To verify the metabolic alteration at both low and high doses, reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were further conducted to analyze hepatic expression of methionine adenosyltransferase Iα (Mat1a) and methionine adenosyltransferase IIα (Mat2a). Hepatic S-adenosylmethionine (SAMe) was also analyzed. A total of 199 metabolites were profiled. Statistical analysis and pathway mapping indicated that the most significant metabolic perturbations induced by BPA were the increased biotin and riboflavin excretion, increased synthesis of methylated products, elevated purine nucleotide catabolism, and increased flux through the choline metabolism pathway. We found significantly higher mRNA and protein levels of Mat1a and Mat2a, and significantly higher SAMe levels in rat liver at both low and high doses. These two genes encode critical isoenzymes that catalyze the formation of SAMe, the principal biological methyl donor involved in the choline metabolism. In conclusion, an elevated choline metabolism is underlying the mechanism of highly methylated environment and related metabolic alterations caused by BPA. The data of BPA-elevated accepted biomarkers of injury indicate that BPA induces DNA methylation damage and broad protein degradation, and the increased deleterious metabolites in choline pathway may also be involved in the toxicity of BPA.

Keywords: bisphenol A; choline; metabolomics; methionine adenosyltransferase; methylation; toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Benzhydryl Compounds / toxicity*
  • Biotin / urine
  • Blotting, Western
  • Choline / metabolism
  • Dose-Response Relationship, Drug
  • Environmental Pollutants / toxicity*
  • Enzyme-Linked Immunosorbent Assay
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Metabolome / drug effects*
  • Metabolomics
  • Methionine Adenosyltransferase / metabolism
  • Methylation
  • Phenols / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Riboflavin / urine


  • Benzhydryl Compounds
  • Environmental Pollutants
  • Phenols
  • Biotin
  • Methionine Adenosyltransferase
  • bisphenol A
  • Choline
  • Riboflavin