Effects of DDT and permethrin on rat hepatocytes cultivated in microfluidic biochips: Metabolomics and gene expression study

Abstract

Dichlorodiphenyl-trichloroethane (DDT) and permethrin (PMT) are amongst most prevalent pesticides in the environment. Although their toxicity has been extensively studied, molecular mechanisms and metabolic effects remain unclear, including in liver where their detoxification occurs. Here, we used metabolomics, coupled to RT-qPCR analysis, to examine effects of DDT and PMT on hepatocytes cultivated in biochips. At 150 μM, DDT caused cell death, cytochrome P450 induction and modulation of estrogen metabolism. Metabolomics analysis showed an increase in some lipids and sugars after 6 h, and a decrease in fatty acids (tetradecanoate, octanoate and linoleate) after 24 h exposure. We also found a change in expression associated with genes involved in hepatic estrogen, lipid, and sugar metabolism. PMT at 150 μM perturbed lipid/sugar homeostasis and estrogen signaling pathway, between 2 and 6 h. After 24 h, lipids and sugars were found to decrease, suggesting continuous energy demand to detoxify PMT. Finally, at 15 μM, DDT and PMT appeared to have a small effect on metabolism and were detoxified after 24 h. Our results show a time-dependent perturbation of sugar/lipid homeostasis by DDT and PMT at 150 μM. Furthermore, DDT at high dose led to cell death, inflammatory response and oxidative stress.