Alterations in cellular lipid metabolism produce neutral lipid accumulation following exposure to the organochlorine compound trans‐nonachlor in rat primary hepatocytes

Abstract

Recent epidemiological studies have revealed significant positive associations between exposure to organochlorine (OC) pesticides and occurrence of the metabolic syndrome and there are a growing number of animal-based studies to support causality. However, the cellular mechanisms linking OC compound exposure and metabolic dysfunction remain elusive. Therefore, the present study was designed to determine if direct exposure to three highly implicated OC compounds promoted hepatic steatosis, the hepatic ramification of the metabolic syndrome. First, the steatotic effect of p,p'-dichlorodiphenyldichloroethylene (DDE), oxychlordane, and trans-nonachlor was determined in freshly isolated rat primary hepatocytes. Exposure to trans-nonachlor significantly increased neutral lipid accumulation as opposed to DDE and oxychlordane. To determine possible mechanisms governing increased fatty acid availability, the effects of trans-nonachlor exposure on fatty acid uptake, de novo lipogenesis, triglyceride secretion, and fatty acid oxidation were explored. Trans-nonachlor did not significantly alter fatty acid uptake. However, insulin-stimulated de novo lipogenesis as well as basal expression of fatty acid synthase, a major regulator of lipogenesis were significantly increased following trans-nonachlor exposure. Interestingly, there was a significant decrease in fatty acid oxidation following trans-nonachlor exposure. This decrease in fatty acid oxidation was accompanied by a slight, but significant increase in oleic acid-induced cellular triglyceride secretion. Therefore, taken together, the present data indicate direct exposure to trans-nonachlor has a more potent pro-steatotic effect than exposure to DDE or oxychlordane. This pro-steatotic effect of trans-nonachlor appears to be predominately mediated via increased de novo lipogenesis and decreased fatty acid oxidation.

Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants

“…Pesticide exposure may lead to NAFLD through an impact on lipid metabolism by (i) modifying FA uptake and efflux [ 171 ] and FFA transport, (ii) increasing lipogenesis [ 172 , 173 , 174 ] ( Table 1 ), (iii) altering oxidation pathways [ 175 ] ( Table 1 and Table 2 ), and (iv) interacting with nuclear receptors involved in the control of metabolism [ 176 , 177 , 178 ]. Some pesticides may disrupt lipid metabolism [ 179 , 180 ].…”

Alterations of Systemic and Hepatic Metabolic Function Following Exposure to Trans-nonachlor in Low and High Fat Diet Fed Male Sprague Dawley Rats

“…These data are similar to previously published in vitro data indicating exposure to trans-nonachlor has a direct effect on primary rat hepatocytes or rat hepatoma cells to increase either basal or insulin-stimulated de novo lipogenesis with a corresponding increase in insulinstimulated Fasn production in a cell type specific manner. 19,20 While the current animals were fed .5 or 5 ppm of transnonachlor in LFD or HFD for 16 weeks, it is difficult to equate intake with body burden given the bioaccumulative nature of this compound. 18 Therefore, serum levels of trans-nonachlor were determined at the end of the current study to determine body burden and evaluate how the current exposure levels correspond to known human exposure levels (Figure 7).…”

“…Briefly, total RNA was isolated using the PureLink Total RNA Isolation kit (Ambion), cDNA was synthesized from 1 µg of the obtained total RNA using the Verso cDNA Synthesis kit (Thermo Scientific), and real time PCR was performed using Sybr Green detection (Sybr Select Master Mix; Life Technologies). 14,19 Primer-BLAST software was used to design primer pairs and melting curve analysis was performed to detect possible primer-dimers. The data is expressed as fold change from the average of the control for the study, the LFD + 0 ppm fed animals.…”

“…18 Recent in vitro studies in immortalized and primary rat hepatocytes have demonstrated that exposure to trans-nonachlor can promote hepatocyte lipid accumulation which may be mediated in part by increased de novo lipogenesis. 19,20 These hepatic effects of trans-nonachlor are significant given the key role of the liver in T2D pathogenesis and that hepatic steatosis is a common pathophysiological alteration in T2D.…”

Fitossanitários e doenças hepáticas: Um desafio à saúde pública no Brasil

“…Atualmente, a teoria que subsidia o desenvolvimento das doenças hepáticas é a teoria dos múltiplos eventos (multiple-hit theory), que inclui a predisposição genética e fatores ambientais como indutores de progressão da esteatose (Fang et al, 2018;Bovi et al, 2021). O fator ambiental, enquanto um dos pontos desencadeadores da esteatose hepática não alcóolica era, até pouco tempo, desconhecido da comunidade científica, entretanto, estudos recentes apontam cada vez mais que os poluentes orgânicos persistentes e seus metabólitos são promotores de disfunções metabólicas e hepáticas (Howell et al, 2018;Armstrong & Guo, 2019;Nagaraju et al, 2020a,b).…”