title: Chlordecone, a mixed pregnane X receptor (PXR) and estrogen receptor alpha (ERalpha) agonist, alters cholesterol homeostasis and lipoprotein metabolism in C57BL/6 mice.
abstract: Chlordecone (CD) is one of many banned organochlorine (OC) insecticides that are widespread persistent organic pollutants. OC insecticides alter lipid homeostasis in rodents at doses that are not neurotoxic or carcinogenic. Pretreatment of mice or rats with CD altered tissue distribution of a subsequent dose of [(14)C]CD or [(14)C]cholesterol (CH). Nuclear receptors regulate expression of genes important in the homeostasis of CH and other lipids. In this study, we report that CD suppresses in vitro reporter systems for human liver X receptors (LXRs) and activates those for human farnesoid X receptor (FXR), pregnane X receptor (PXR) and estrogen receptor alpha (ERalpha) in a concentration-dependent manner (0-50 muM). Consistent with human PXR activation in vitro, three days after a single dose of CD (15 mg/kg) hepatic microsomal CYP3A11 protein increases in C57BL/6 mice. CD decreases hepatic CH ester content without altering total CH concentration. Apolipoprotein A-I (apoA-I) contents of hepatic lipoprotein-rich and microsomal fractions of CD-treated mice are higher than controls. There is a significant reduction in non-high density lipoprotein CH but not apolipoprotein B-48/100 (apoB-48/100) in plasma from CD-treated mice after a 4 h fast. At 14 days after 15 mg CD/kg apoA-I and apoB-100 proteins but not CYP3A11 protein in hepatic microsomes are similar to controls. This work indicates that altered CH homeostasis is a mode of OC insecticide action of relevance after a single dose. This at least partially explains altered CH tissue distribution in CD-pretreated mice.
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
authors.forename: Junga
authors.initials: J
authors.lastname: Lee
authors.forename: Richard C
authors.initials: RC
authors.lastname: Scheri
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Curtis
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000187:drug effects / Q000378:metabolism; D053299:Apolipoprotein B-100 / Q000187:drug effects / Q000378:metabolism; D053283:Apolipoprotein B-48 / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D007631:Chlordecone / Q000008:administration & dosage / Q000633:toxicity*; D002784:Cholesterol / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000819:agonists; D017930:Genes, Reporter / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D008074:Lipoproteins / Q000187:drug effects* / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D016632:Apolipoprotein A-I; D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D007631:Chlordecone; D002784:Cholesterol; D051544:Cytochrome P-450 CYP3A; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D007306:Insecticides; D008074:Lipoproteins; D000071518:Liver X Receptors; D008565:Membrane Proteins; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C496508:Cyp3a11 protein, mouse
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