Graduate Thesis Or Dissertation
 

Chlordecone (CD), a mixed steroid X receptor (SXR) and estrogen receptor alpha(ERα) agonist, altered hepatic cholesterol (CH) homeostasis and lipoprotein metabolism

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  • Overtly non-toxic doses of organochlorine (OC) insecticides perturb lipid homeostasis in mice and rats. To increase understanding of how chlordecone (CD), an OC insecticide, modulates cholesterol (CH) homeostasis, we determined the effect of CD pretreatment on the tissue and hepatic subcellular distribution of exogenous [¹⁴C]CH. Corn oil alone or CD (5 or 15 mg/kg) was administered to C57BL/6 mice by intraperitoneal (ip) injection. Three days later, a lipid bolus dose (5 ml corn oil/kg) containing [¹⁴C]CH (10 mg/kg) was administered to corn oil or CD pretreated mice by ip injection. CD pretreatment reduced [¹⁴C]CH equivalents in the plasma non-high density lipoprotein (HDL) fraction but increased total CH concentration in the same fraction 4 hr after lipid bolus dose. Along with reduced disposition of [¹⁴C]CH to liver, CD pretreatment decreased [¹⁴C]CH equivalents in hepatic microsomal and cytosolic fractions 4 and 16 hr after ip bolus lipid, respectively and decreased relative distribution of [¹⁴C]CH to the lipoprotein-rich fraction. However CD treatment did not change total hepatic CH concentration 16 hr after lipid bolus dose. In contrast CD pretreatment stimulated biliary excretion of [¹⁴C]CH and increased total CH concentration in gallbladder 4 hr and 16 hr after ip lipid bolus, respectively. Reduced disposition of [¹⁴C]CH to liver and stimulated biliary CH excretion were not associated with altered hepatic membrane scavenger receptor class B type I (SR-BI) and ATP-binding cassette transporter G8 (ABCG8) protein contents. We then determined the effect of CD on activation of nuclear receptors, especially those involved in lipid homeostasis to characterize the specificity of CD effect. CD (10 μM) strongly suppressed LXRβ activation and increased activation for SXR (human PXR homolog). The same concentration of CD increased activation of human ERα specifically and suppressed E2-mediated ERβ activation effectively. Increased hepatic CYP3A11 protein content by western blotting supported PXR activation. Finally, we determined the effect of CD on lipoprotein metabolism. CD increased apolipoprotein A-I (apoA-I) protein content in hepatic lipoprotein-rich and microsomal fractions. A trend for increased apolipoprotein B-100 (apoB-100) protein content in hepatic microsomal fraction in CD treated animals was observed. CD modulated HDL particle size and shape by increasing more non-spherical and heterogeneous particles. At 14 days after CD treatment (15 mg/kg) apoA-I and apoB-100 but not CYP3A11 protein in hepatic microsomes was similar to controls. This work indicated altered CH homeostasis was a mode of OC insecticide action of relevance after a single low dose. These findings at least partially explain altered CH tissue distribution in CD-pretreated mice.
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