Chlordecone, a mixed pregnane X receptor (PXR) and estrogen receptor alpha (ER{alpha}) agonist, alters cholesterol homeostasis and lipoprotein metabolism in C57BL/6 mice

Journal Article · Mon Dec 01 04:00:00 EST 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.08.011· OSTI ID:21180485

Lee, Junga; Scheri, Richard C ^[1]; Yuan, Zhang ^[2]

---

1. Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR (United States)
2. Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX (United States)

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 [{sup 14}C]CD or [{sup 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} (ER{alpha}) in a concentration-dependent manner (0-50 {mu}M). 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.

• OSTI ID: 21180485
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 233; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOLIPOPROTEINS
CARBON 14
CHOLESTEROL
DOSES
ESTERS
ESTROGENS
HOMEOSTASIS
IN VITRO
INSECTICIDES
LIVER
METABOLISM
MICE
MICROSOMES
ORGANIC CHLORINE COMPOUNDS
POLLUTANTS
RATS
RECEPTORS
TISSUE DISTRIBUTION