Relative potency of xenobiotic estrogens in an acute in vivo mammalian assay.

Abstract

The in vii effcts ofxenoestrogens are ofinterest in relation to their potential health risk and/or beneficial efficts on humans and animals. However, the apparent in yim potency of the examined response can be confounded by a short half-ife, and the metabolism of estogens is very dependent on the nature of conversion and/or inactivation. To minimize such variables, we examined the estrogenic potency of a range of xenoestrogens in an acute in vivo assay-the stimulation of increased uterine vascular permeability in ovariectomized mice 4 hr after subcutaneous administra. tion. While estradiol (E2) and estriol (F3; a relatily weak natural estrogen) readily induced vascular responses [median effiv dose (ED50) 10-9 mol], much higher amounts of xenoestrogens were required. Bisphenol A was about 10,000-fold less potent than E4 and E, and octylphenol and nonylphenol were about 100,000-fold less potent; dioctyl phthalat, beyl buty ptalate, dibutyl phtbalate, and trichlorinated biphenol produced no effect. Coumestrol was the most active phytoestrogen, with an ED50 between 10-6 and 10-7 mol; genistein wa about 10-fold less potent than coumestrol, and neither daidzein nor formononetin produced any marked efflect, even at doses up to 1O5mol. All increases in vascular permeability could be blocked by the pure antiestrogen ICI 182,780. There was no evidence that any ofthe compounds could act as an aniesrogen in his assay or that they could exert ynegistc ef in. combion. These results indicate that even short-term exposure to most of the xenobiotic estogens can induce typical estrogenic efFecs in vivo, but their esuogenic potency is very weak even when assessed in an acute response.

Interlaboratory Comparison of Four in Vitro Assays for Assessing Androgenic and Antiandrogenic Activity of Environmental Chemicals

“…In addition to compounds naturally occurring in plants and some mycotoxins (Breithofer et al 1998;Miksicek 1994), various pesticides and industrial chemicals have shown estrogenic effects in vitro (Jobling et al 1995;Klotz et al 1996;Körner et al 1998;Miller et al 2001;Soto et al 1991;Soto et al 1995) and in vivo in mammals (Dodds and Lawson 1936;Milligan et al 1998;Nagel et al 1997;Soto et al 1991) as well as fish (Christiansen et al 2000;Donohoe and Curtis 1996;Gimeno et al 1996;Jobling et al 1996). However, we have not identified a common chemical substructure responsible for the estrogenic activity of the so-called xenoestrogens and phytoestrogens.…”

Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

“…1-10 mM, in agreement with their significant estrogenic activity when present in very large quantity. In vivo, BPA increases VEGF expression in the immature rat uterus (37 mg/kg being the lowest active dose; Long et al 2001); genistein, BPA, OP, and BBP have also been shown to increase uterine vascular permeability in ovariectomized mice (Milligan et al 1998); no evidence of any significant synergy or antagonism between the compounds were observed (Milligan et al 1998), in agreement with our data showing that low doses of xenoestrogens (i.e., below the level required to induce an estrogenic response) were ineffective in combination with a stimulatory dose of E 2 (not shown).…”

Estimating perchlorate exposure from food and tap water based on US biomonitoring and occurrence data

“…In chronic rodent studies, several of the phthalates produced testicular injury, liver injury, liver cancer, and teratogenicity, but these effects either have not been demonstrated when tested in non-human primates or are yet to be studied. In vitro studies showed that certain phthalates can bind to estrogen receptors and may have weak estrogenic or anti-estrogenic activity (Coldham et al, 1997;Harris et al, 1997;Jobling et al, 1995), but in vivo studies did not support phthalates having estrogenic effects (Milligan et al, 1998;Okubo et al, 2003;Parks et al, 2000;Zacharewski et al, 1998); however, not all phthalates…”