Superfund Research Program
PPAR, Hormones, and Xenobiotics
Project Leader: David J. Waxman
Grant Number: P42ES007381
Funding Period: 2000 - 2005
There is growing concern about the effects on human health of environmental chemicals that can disrupt normal endocrine function. Endocrine disrupting chemicals (EDCs), which include structurally diverse organochlorine pesticides, polychlorinated biphenyls (PCBs), plasticizers, fungicides, herbicides and pharmaceutical compounds, can have a profound impact on development and on the functioning of human reproductive, neurological and immune systems. While many studies have investigated the role of androgen, estrogen, and aryl hydrocarbon receptors in mediating the effects of EDCs, other nuclear receptors that regulate steroid hormone action and metabolism may also serve as targets of EDC action.
During the past year, Dr. Waxman and his research team have focused on two classes of EDCs, PCBs and phthalate monoesters, which have both been shown to interact with pregnane X receptor (PXR). PXR is a member of the nuclear receptor superfamily that regulates a large number of target genes, many of which play important roles in steroid metabolism and transport. The researchers completed studies on the ability of phthalate monoesters to activate PXR and are currently considering investigating the potential role of PXR and other intracellular receptor proteins in mediating toxicities associated with EDC exposure.
The researchers have also begun to investigate the actions of environmental chemicals that exert reproductive toxicities, with special emphasis on environmental estrogens and anti-androgens that induce gonadal toxicities in exposed mammals. A major goal of these studies is to clarify the role of aryl hydrocarbon (Ah) receptor and its interactions with estrogen receptor and androgen receptor in mediating environmental chemical-induced testicular toxicities using cell-based and in vivo rodent models. A second major goal is to clarify how environmental chemicals exert endocrine disrupter activity indirectly, through the actions of protein kinases on nuclear receptor-dependent transcription, as exemplified by the action of methoxyacetic acid, the active metabolite of the industrial solvent ethylene glycol monomethyl ether. The researchers have begun to study the role of Ah receptor in the estrogen receptor-stimulatory actions of xenoestrogens. They are also investigating the effects of methoxyacetic acid on the transcriptional activity of androgen receptor and estrogen receptor and its impact on the contribution of these nuclear receptors to environmental chemical-induced testicular toxicities. These studies, which are expected to enhance understanding of the nuclear receptor-dependent mechanisms through which endocrine-active environmental chemicals induce male gonadal toxicities, ultimately may help identify strategies to improve the detection and prevention of adverse effects in exposed individuals.