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Susan C. Nagel,¹ Frederick S. vom Saal,¹ ristina A. Thayer,¹ Minati G. Dhar,¹ Michael Boechler,¹ and Wade V. Welshons²

¹Division of Biological Sciences; ²Department of Veterinary Biomedical Sciences, University of Missouri-Columbia, Columbia, MO 65211 USA

Abstract

We have developed a relative binding affinity-serum modified access (RBA-SMA) assay to determine the effect of serum on the access of xenoestrogens to estrogen receptors within intact cultured MCF-7 human breast cancer cells. We used this assay to predict low dose activity of two xenoestrogens in mice. In serum-free medium, bisphenol A, a component of polycarbonates and of resins used to line metal food cans, showed a lower relative binding affinity (RBA ; 0.006%) than octylphenol (0.072%) and nonylphenol (0.026%) , which are used as surfactants in many commercial products (all RBAs are relative to estradiol, which is equal to 100%) . In 100% serum from adult men, bisphenol A showed a higher RBA (0.01%) than in serum-free medium and thus enhanced access to estrogen receptors relative to estradiol. In contrast, octylphenol showed a 22-fold decrease in RBA (0.0029%) and nonylphenol showed a 5-fold decrease in RBA (0.0039%) when measured in adult serum. This indicates that, relative to estradiol, serum had less of an inhibitory effect on the cell uptake and binding in MCF-7 cells of bisphenol A, while serum had a greater inhibitory effect on octylphenol and nonylphenol relative to estradiol. Extrapolation of these relative activities in adult serum predicted that the estrogenic bioactivity of bisphenol A would be over 500-fold greater than that of octylphenol in fetal mouse serum. Bisphenol A and octylphenol were fed to pregnant mice at 2 and 20 g/kg/day. Exposure of male mouse fetuses to either dose of bisphenol A, but to neither dose of octylphenol, significantly increased their adult prostate weight relative to control males, which is consistent with the higher predicted bioactivity of bisphenol A than octylphenol in the RBA-SMA assay. In addition, our findings show for the first time that fetal exposure to environmentally relevant parts-per-billion (ppb) doses of bisphenol A, in the range currently being consumed by people, can alter the adult reproductive system in mice. Key words: bisphenol A, endocrine disruptors, environmental estrogens, 17ß-estradiol, fetus, 4-nonylphenol, 4-octylphenol, prostate, sexual differentiation, xenobiotics, xenoestrogens. Environ Health Perspect 105:70-76 (1997)

Address correspondence to W.V. Welshons, Department of Veterinary Biomedical Sciences, E102 Veterinary Medicine, University of Missouri-Columbia, Columbia, MO 65211 USA.

Supported by NIH AG08496 and Food for the Twenty-First Century Animal Reproductive Biology Program at the University of Missouri-Columbia to F.S.vS, and by NIH CA50354 and UMC MO-VMFC0018 to W.V.W. We thank Daniel M. Sheehan and Dennis B. Lubahn for critical reading of the manuscript. The animal experiments were approved by the University of Missouri Animal Care and Use Committee and conformed to NIH standards for the care and use of animals in research. Part of this work was reported at the 77th Annual Meeting of the Endocrine Society and the 28th Annual Meeting of the Society for the Study of Reproduction.

Received 14 June 1996 ; accepted 25 September 1996.