Nuclear Receptor

There is growing interest in the possible health threat posed by endocrine-disrupting chemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor gamma, retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness.

The Pregnane X Receptor (PXR) is a nuclear receptor involved in the transcriptional regulation of drug-metabolizing enzymes and transporters. In mammals, many xenobiotics induce the expression of cytochrome P4503A (CYP3A) and the multiple drug resistance 1 (MDR1) genes via the PXR pathway. Little attention has been given to studies about the identification and biological function of PXR homologues in non-mammalian species. Zebrafish is being widely used and accepted as model for toxicological and pharmacological studies to understand the mechanisms of human diseases and identify conserved signaling pathways. The aim of this study was to evaluate the in vivo expression of PXR, CYP3A and MDR1 genes in liver of zebrafish treated with the synthetic steroid pregnenolone 16α-carboninitrile (PCN), the antimycotic clotrimazole (CTZ) and the antianginal drug nifedipine (NIF). The liver of fish treated with PCN showed a 1.9-fold induction in the PXR followed by 1.8-fold induction in the CYP3A and 1.6-fold induction in the MDR1 mRNA. CTZ and NIF did not affect statistically the expression of PXR, CYP3A and MDR1. The similar pattern of mRNA expression of PXR, CYP3A and MDR1 genes found in fish treated with different PXR inducers suggests that the intrinsic association between these three genes is conserved in zebrafish.

Obesity and rheumatic disease are mechanistically linked via chronic inflammation. The orphan receptor TREM-1 (triggering receptor expressed on myeloid cells-1) is a potent amplifier of proinflammatory and noninfectious immune responses. Here, we show that the pan modulator SR1903 effectively blocks TREM-1 activation. SR1903 emerged from a chemical series of potent RORγ inverse agonists, although unlike close structural analogues, it has modest agonist activity on LXR and weak repressive activity (inverse agonism) of PPARγ, three receptors that play essential roles in inflammation and metabolism. The anti-inflammatory and antidiabetic efficacy of this unique modulator in collagen-induced arthritis and dietinduced obesity mouse models is demonstrated. Interestingly, in the context of obesity, SR1903 aided in the maintenance of the thymic homeostasis unlike selective RORγ inverse agonists. SR1903 was well-tolerated following chronic administration, and combined, these data suggest that it may represent a viable strategy for treatment of both metabolic and inflammatory disease. More importantly, the ability of SR1903 to block LPS signaling suggests the potential utility of this unique polypharmacological modulator for treatment of innate immune response disorders.

The nuclear receptor CAR (NR1I3) regulates transcription of genes encoding xenobiotic- and steroid-metabolizing enzymes. Regulatory processes that are mediated by CAR are modulated by a structurally diverse array of chemicals including common pharmaceutical and ...