Abstract
Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects.
Highlights
Perfluorooctanoic acid (PFOA) is a member of an emerging class of contaminants known as perfluoroalkyl acids, which have been produced and used over 60 years[1]
Mean concentrations of PFOA in serum of mice in the lesser dose group was 29.34 μg PFOA/mL, which was similar to concentrations of PFOA in blood serum of persons occupationally exposed to PFOA38
Changes in the metabolic profiles of liver and brain of mice exposed to PFOA were quantified by a high-throughput target metabolomics approach and offered a connection among transcriptome, proteome and PFOA-induced hepatomegaly and neurobehavioral effects
Summary
Perfluorooctanoic acid (PFOA) is a member of an emerging class of contaminants known as perfluoroalkyl acids, which have been produced and used over 60 years[1]. PFOA can activate multiple nuclear receptors, such as peroxisome proliferator-activated receptor alpha (PPARα ), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and estrogen receptor (ER)[29] These studies focused on one or two hepatic effects of PFOA so it was deemed appropriate to investigate effects of PFOA on the liver by use of a comprehensive method. Several transcriptomic and proteomic studies[31,32,33,34,35] have been conducted on perfluoroalkyl acids (PFAAs), including PFOA, few studies have used metabolomics to elucidate PFOA-induced toxicology These studies focused on effects on metabolites in earthworm[36] and L-02 cells[37]. By analyzing changes of functionally important endogenous metabolites involved in various biochemical pathways in liver and brain, mechanisms of PFOA-induced hepatotoxicity and neurotoxicity were elucidated and potential biomarkers for exposure to PFOA were developed
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