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RP2E INRA Université de Lorraine

Characterization of the mode of action of chlordecone and chlordecone alcohol using HepG2 cell as model

Séminaire annuel de l'école doctorale SIReNa 5 Mars 2024, 05 mars, Vandoeuvre Lès Nancy, France

Baratzhanova, G., El Sheikh Saad, H., Fournier, A., Huguet-Cizo, M., Paul, A., Joubert, O.-L., Djansugurova, L., Cakir, C.

2024

Chlordecone (CLD) is organochlorine pesticides (OCP) which still can be detected in food, water and living organisms in French West Indies (Cabidoche et al., 2009). CLD mainly detected in liver that in adipose tissue, unlike other OCPs. CLD can affect the nervous system, lead to formation of carcinogenic diseases (Multigner et al., 2016). There are few data exist of specific molecular mechanism through which CLD creates these harmful effects. For example, CLD can create toxicity by interrupting natural hormones circulation through binding to intracellular receptors for which natural substances are endogenous ligands (Gely-Pernot et al., 2018; Legoff et al., 2021). CLD metabolite chlordecone alcohol (CLD-OH) also was found in environment (Le Deaut, 2009), however there are no data in literature about toxicity and mode of action of CLD-OH. Thus, the aim of this work is studying the mode of action of CLD and its metabolite CLD-OH on human hepatocarcenoma cell line HepG2. First, we studied the toxicity of different concentrations of CLD and CLD-OH on HepG2 cells by using MTT test. After, we have checked how these molecules affect on expression of three different type of genes that involved in detoxification mechanism: 1) nuclear receptor genes that involved in regulation of transcription of genes that involved in biotransformation of xenobiotics (PXR, PPARa, CAR), 2) genes that involved in I phase of biotransformation (CYP2B6, CYP3A4), 3) gene that probably involved in metabolism of chlordecone (AKR1C4). We also measured the impact of CLD and CLD-OH on ROS detection enzymes activity. We have established that the metabolite of CLD have similar pattern of cytotoxicity as mother compound. After exposure to CLD-OH, nuclear receptor genes as PXR and PPARα showed statistically significant increase in expression. The increase also was noticed in expression of cytochrome gene CYP3A4. Surprisingly, we detect significant decrease in expression of AKR1C4 after CLD treatment. We hypothesis that this decrease in AKR1C4 gene expression could be possible reason of CLD storage in liver.

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