Chlordecone, a mixed pregnane X receptor (PXR) and estrogen receptor alpha (ERalpha) agonist, alters cholesterol homeostasis and lipoprotein metabolism in C57BL/6 mice.
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.
Lee
Junga
J
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
Scheri
Richard C
RC
Zhang
Yuan
Y
Curtis
Lawrence R
LR
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
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
Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4001-5
8633005
Ann Endocrinol (Paris). 2001 Jun;62(3):239-47
11458177
J Nutr. 2003 Jul;133(7 Suppl):2444S-2447S
12840222
J Lipid Res. 2004 Mar;45(3):543-50
14679166
Biochem Pharmacol. 2004 Dec 15;68(12):2347-58
15548381
Toxicol Appl Pharmacol. 2002 Apr 1;180(1):11-21
11922773
Drug Metab Dispos. 2001 Nov;29(11):1467-72
11602523
Science. 1999 May 21;284(5418):1365-8
10334993
Fundam Appl Toxicol. 1994 Feb;22(2):286-92
7516299
Drug Metab Dispos. 1989 Mar-Apr;17(2):131-8
2468465
Annu Rev Pharmacol Toxicol. 1982;22:89-113
6177278
Arterioscler Thromb Vasc Biol. 1999 Dec;19(12):2960-5
10591676
Annu Rev Pharmacol Toxicol. 1982;22:517-54
6282188
Biochem Biophys Res Commun. 2005 Jun 17;331(4):1533-41
15883047
Science. 1999 May 21;284(5418):1362-5
10334992
Science. 2001 Nov 30;294(5548):1866-70
11729302
Curr Opin Lipidol. 2005 Feb;16(1):19-25
15650559
Drug Metab Dispos. 1991 May-Jun;19(3):673-8
1717217
Annu Rev Physiol. 2006;68:159-91
16460270
Neurotoxicology. 1998 Aug-Oct;19(4-5):581-90
9745915
Biochem Biophys Res Commun. 1999 Apr 2;257(1):29-33
10092505
Arch Biochem Biophys. 1984 Jun;231(2):503-10
6732245
Methods Enzymol. 1991;206:483-91
1784233
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11041-8
10500120
Metabolism. 1978 Jan;27(1):89-96
201821
J Biol Chem. 1997 Dec 26;272(52):33360-6
9407129
J Biol Chem. 2000 Sep 15;275(37):28947-53
10867000
Cell. 1998 May 29;93(5):693-704
9630215
J Toxicol Environ Health. 1978 Sep-Nov;4(5-6):895-911
83367
Seikagaku. 2003 May;75(5):391-5
12822438
J Biol Chem. 2000 Oct 20;275(42):33053-8
10918065
Mol Pharmacol. 2006 Oct;70(4):1340-9
16825483
Fundam Appl Toxicol. 1996 Nov;34(1):157-64
8937903
J Pharmacol Toxicol Methods. 1997 Mar;37(2):67-73
9174981
Environ Sci Technol. 2005 Sep 15;39(18):6952-60
16201616
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3375-80
11248086
Science. 2002 May 17;296(5571):1313-6
12016314
Cell. 1999 May 28;97(5):539-42
10367881
Genes Dev. 2000 Nov 15;14(22):2819-30
11090130
Toxicol Appl Pharmacol. 2008 Jun 15;229(3):265-72
18387646
Annu Rev Pharmacol Toxicol. 2002;42:1-23
11807162
Eur J Biochem. 1993 Sep 1;216(2):527-38
8375391
J Mol Endocrinol. 1999 Apr;22(2):103-11
10194513
J Toxicol Environ Health A. 1998 Mar 27;53(6):479-92
9537283
Rev Endocr Metab Disord. 2004 Dec;5(4):293-301
15486461
J Lipid Res. 2001 Dec;42(12):2007-14
11734573
J Clin Invest. 2001 Mar;107(5):565-73
11238557
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3369-74
11248085
Pharmacol Res. 2004 Sep;50(3):237-46
15225665
Am J Public Health. 1996 Sep;86(9):1253-9
8806377
Arterioscler Thromb Vasc Biol. 2005 Dec;25(12):2608-14
16210564
Arch Environ Contam Toxicol. 1993 Apr;24(3):365-7
7682401