Modulation of aryl hydrocarbon receptor mediated signaling by soy consumption and estrogens.

摘要

The polycyclic aromatic hydrocarbons (PAHs) are environmental contaminants which are produced during the incomplete burning of coal, oil and gas, garbage, or other organic substances. The potential sources include smoking, automobile exhaust, and barbecued food. These compounds bind to and activate aryl hydrocarbon receptor (AhR); activation of AhR by PAHs and other sources, including dioxins and some natural components, have been shown to result in a myriad of toxicological events such as carcinogenesis; hepatic, reproductive, immune and dermal toxicity; and endocrine disruption. This receptor is known, in reproductive tissues such as the mammary gland, to affect estrogen responsive signaling by interacting with estrogen receptor-alpha (ERalpha). We examined the interaction of ERalpha with AhR in liver and the consequences leading to changes in the expression of genes changed by the activation of AhR by 7, 12 dimethylbenz[a]anthracene (DMBA; a PAH). We demonstrated that treatment of ovariectomized rats with DMBA and estradiol (E2; an endogenous estrogen) results in the co-recruitment of AhR and ERalpha in the transcription regulatory region, xenobiotic responsive element (XRE) of CYP1A1 and AhR genes. We speculate that women with normal levels of circulating estrogens are at higher risk of PAHs-mediated toxicities such as carcinogenesis. On the contrary, consumption of soy protein isolate as in soy, a source of phytoestrogens, was demonstrated to reduce the availability of hepatic AhR to PAHs in Sprague-Dawley female rats. To delineate the mechanism an ex-vivo model was developed where the serum from the rats fed with soy was utilized to treat rat hepatoma FGC-4 cells. It was shown that treatment of cells with SPI serum reduces the stability of AhR complex by negatively affecting the association of XAP2 chaperone protein which leads to AhR ubiquitination and degradation. We demonstrated that although SPI reduces hepatic AhR levels, an increased DMBA-mediated hepatic CYP1A1 induction was observed by SPI when fed in the absence of estrogens; however, in the presence of estrogens, SPI consumption significantly reduced DMBA-mediated CYP1A1 induction as a function of reduced recruitment of ERalpha, suggesting a selective estrogen receptor (SERM) like action of soy.