Interactions of Endocrine-active environmental chemicals with the nuclear receptor PXR

Abstract

There is growing concern about the human-health impact of environmental chemicals that have the potential to disrupt normal endocrine function. Endocrine disrupting chemicals (EDCs) include structurally diverse organochlorine pesticides, polychlorinated biphenyls (PCBs), plasticizers, fungicides, herbicides and pharmaceutical compounds, and can have a profound impact on development, and on reproductive, neurological and immune system functions. While many studies have focused on the role of androgen receptor, estrogen receptor and aryl hydrocarbon receptor in mediating the effects of EDCs, other nuclear receptors that regulate steroid hormone action and metabolism may also serve as targets of EDC action. This review focuses on two classes of EDCs, PCBs and phthalate monoesters, both of which have been shown to interact with pregnane X receptor (PXR), a member of the nuclear receptor superfamily that regulates a large number of target genes, many of which have important roles in steroid metabolism and transport. Recent findings on the ability of PCBs and phthalate monoesters to activate PXR are discussed and the potential role of PXR and other intracellular receptor proteins in mediating toxicities associated with EDC exposure is considered. Finally, we discuss several gaps in our knowledge regarding the actions of EDCs and the difficulties associated with the evaluation of risks associated with exposure to these endocrine active environmental chemicals.

Keywords:

• PCBs
• phthalates
• nuclear receptors

Notes

Supported in part by NIH grant 5 P42 ES07381, Superfund Basic Research Center at Boston University (to D. J. W.).

Abbreviations: AhR, aryl hydrocarbon receptor; AR, androgen receptor; CAR, constitutive androstane receptor; CYP, cytochrome P450; DR3, direct repeat spaced by 3 nucleotides; EDC, endocrine disrupting chemical; ER, estrogen receptor; ER6, everted repeat spaced by 6 nucleotides; MEHP, mono-2-ethylhexyl phthalate; PCB, polychlorinated biphenyl; PCN, pregnenolone 16α-carbonitrile; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor, PXR, pregnane X receptor

Abbreviations: AhR, aryl hydrocarbon receptor; AR, androgen receptor; CAR, constitutive androstane receptor; CYP, cytochrome P450; DR3, direct repeat spaced by 3 nucleotides; EDC, endocrine disrupting chemical; ER, estrogen receptor; ER6, everted repeat spaced by 6 nucleotides; MEHP, mono-2-ethylhexyl phthalate; PCB, polychlorinated biphenyl; PCN, pregnenolone 16α-carbonitrile; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor, PXR, pregnane X receptor

Presented at the PCB-workshop in Champaign/Urbana, Illinois, June 2004.

Additional information

Notes on contributors

David J Waxman

Supported in part by NIH grant 5 P42 ES07381, Superfund Basic Research Center at Boston University (to D. J. W.). Abbreviations: AhR, aryl hydrocarbon receptor; AR, androgen receptor; CAR, constitutive androstane receptor; CYP, cytochrome P450; DR3, direct repeat spaced by 3 nucleotides; EDC, endocrine disrupting chemical; ER, estrogen receptor; ER6, everted repeat spaced by 6 nucleotides; MEHP, mono-2-ethylhexyl phthalate; PCB, polychlorinated biphenyl; PCN, pregnenolone 16α-carbonitrile; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor, PXR, pregnane X receptor Presented at the PCB-workshop in Champaign/Urbana, Illinois, June 2004.