Exposure to perfluorononanoic acid combined with a low-dose mixture of 14 human-relevant compounds disturbs energy/lipid homeostasis in rats

Humans are constantly exposed to a significant number of compounds and many are readily detected in human body fluids. Worryingly, several of these compounds are either suspected to be, or have already been shown to be harmful to humans either individually or in combination. However, the potential consequences of low-dose exposure to complex mixtures remain poorly understood. We have profiled the effects on rat blood plasma and liver homeostasis using metabolomics and transcriptomics following 2-week exposure to either a mixture of 14 common chemicals (Mix), perfluorononanoic acid (PFNA) at low (0.0125 mg/kg/day) or mid (0.25 mg/kg/day) doses, or a combination of Mix and PFNA. In blood plasma, 63 and 64 metabolites were significantly changed upon exposure to Mix alone or PFNA + Mix, respectively. Twelve of the metabolites were identified and comprised mainly lipids, with various lipid classes differentially affected across study groups. In the liver, expression of 182 and 203 genes—mainly related to energy homeostasis and lipid metabolism—were differentially expressed upon exposure to PFNA alone or PFNA + Mix, respectively. In general, Mix alone affected lipid metabolism evident in blood plasma, whereas effects on lipid metabolism in the liver were mainly driven by PFNA. This study verifies that a chemical mixture given at high-end human exposure levels can affect lipid homeostasis and that the combined use of metabolomics and transcriptomics can provide complimentary information allowing for a detailed analysis of affected signaling pathways.