Metabolite-driven remodeling of hepatic lipid metabolism by the plasticizer di-isononyl phthalate

Phthalates are widely used as plasticizers in consumer products and are suspected to be metabolism-disrupting chemicals. Di-isononyl phthalate (DINP) is commonly recognized as less hazardous substitute for more studied di(2-ethylhexyl) phthalate (DEHP).

The effects of DINP on hepatic lipid metabolism were studied using C57BL/6J mice with diet-induced obesity, and human HepaRG and C3A cell lines. The mice were orally exposed to 0, 1.5, 15 or 150 mg/kg bw/d DINP for 20 weeks, followed by assessment of glucose and insulin tolerance, hepatic histology, transcriptome and metabolome. The cells were exposed to DINP and its metabolites, followed by measurement of mitochondrial function and nuclear receptor activation.

The highest dose of DINP decreased hepatic lipid droplets and slightly attenuated weight gain and glucose tolerance of the mice. DINP exposure elevated acylcarnitine levels, indicating altered fatty acid beta-oxidation, which was accompanied by enrichment in mitochondrial and peroxisomal lipid metabolism pathways at transcriptomics level. In vitro, monoisononyl phthalate (MINP), the primary metabolite of DINP, increased mitochondrial respiration and beta-oxidation in presence of long-chain fatty acids. DINP metabolites activated peroxisome proliferator-activated receptors (PPARs) of both mouse and human, with an activation profile partially distinct from DEHP.

Our findings indicate that DINP remodels hepatic lipid metabolism through its active metabolites via PPARs at high doses, with additional modes of action at lower exposure levels. Due to species-specific differences in nuclear receptor activation potencies, the adverse or potentially beneficial nature of these effects in humans remains ambiguous.