Department of Veterinary Physiology & Pharmacology, Texas A&M University, 4466 TAMU, College Station, Texas 77843-4466
ABSTRACT
The article highlighted in this issue is "Bisphenol A-Induced Increase in Uterine Weight and Alterations in Uterine Morphology in Ovariectomized B6C3F1 Mice: Role of the Estrogen Receptor" by Andriana D. Papaconstantinou, Thomas H. Umbreit, Benjamin R. Fisher, Peter L. Goering, Nicholas T. Lappas, and Ken M. Brown (pp. 332339).
The endocrine disruptor hypothesis suggests that a global decrease in male reproductive capacity and increased incidence of breast cancer in women may be due to background environmental exposures to hormonally active agents such as industrial-derived or naturally-occurring estrogenic chemicals This hypothesis has advocates and skeptics (Safe, 2000); however, the ultimate resolution of the debate will rest on results of ongoing and future studies with various human cohorts.
Adverse effects of hormonally-active chemicals can be observed in laboratory animals over their lifetimes; however, in utero and early postnatal periods of exposure are particularly important since high or low hormone levels during this period of developmental programming can result in permanent changes or damage in the offspring. This testing paradigm is now extensively used for investigating compounds for suspected endocrine-disrupting activity.
Bisphenol A (BPA) and nonylphenol are among those industrial compounds which have generated the most concern on the part of regulatory agencies and scientists due to their high production and widespread use. It is clear from simple in vitro studies that both compounds bind the estrogen receptor (ER and ERß), induce estrogen-dependent gene expression/responses and, in these assays, are weakly estrogenic compared to 17ß-estradiol (E2). The low dose effects of BPA on prostate weight increase in male offspring exposed in utero observed by Nagel and coworkers (1997), but not other investigators (Cagen et al., 1999
), has focused attention on this compound. In the highlighted paper, Papaconstantinou and coworkers have investigated a less controversial, but well-characterized estrogenic response, namely induction of various estrogen-dependent uterine effects in ovariectomized B6C3F1 mice.
Most previous studies in 19- to 21-day-old or ovariectomized rodents have shown that BPA is only estrogenic at high doses; this study examines both BPA-induced uterine wet weight increases and morphologic changes at doses of 0.02, 0.8, 2 or 8 mg/day for 4 days. The authors estimate EC50 values of 0.72 mg/day for BPA compared to 19.4 ng/day for E2, but these values do not represent true potency comparisons because BPA induces less uterine wet weight increase (< 2-fold) compared to E2 (> 5-fold). Interestingly, the BPA-induced response observed in study number 4 is similar over doses from 0.8 to 8 mg/day, and this response is not inhibited by cotreatment with the "pure" antiestrogen ICI 182,780 at a dose of 20 µg/day (Fig. 1), whereas inhibition was observed at a higher dose of the antiestrogen (200 ng/day). In contrast, the low dose of the antiestrogen almost totally blocked a > 5-fold induction response by E2 (Fig. 1
). Morphometric changes by E2 and BPA are small, but the low dose (20 µg/day) of ICI 182,780 inhibited E2-induced thickening of luminal epithelium, stroma and myometrium. Interactive effects of BPA with the low dose of antiestrogen were not observed and the high dose of ICI 182,780 appeared to be estrogenic.
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A second paper in this issue of Toxicological Sciences, "Neonatal Exposure of Male Rats to Nonylphenol Has No Effect on the Reproductive Tract," by J. Odum and J. Ashby, pp. 400404, deals with a closely related topic. These authors found in their study that neonatal exposure to nonylphenol (in Aracchis oil) does not affect the reproductive tract of male rats, in contrast to results of a previous study, which used nonylphenol and DMSO as a solvent carrier (Lee, 1998). This is another example of divergent effects observed for the same estrogenic compound in comparable assays, and explanations for these differences are currently lacking. These present apparent discrepancies make the assessments of xenoestrogenic compounds extremely controversial while concomitantly highlighting the need to resolve these potentially important public health concerns.
NOTES
For correspondence via fax: (979) 862-4929. E-mail: ssafe{at}cvm.tamu.edu.
REFERENCES
Cagen, S. Z., Waechter, J. M., Jr., Dimond, S. S., Breslin, W. J., Butala, J. H., Jekat, F. W., Joiner, R. L., Shiotsuka, R. N., Veenstra, G. E., and Harris, L. R. (1999) Normal reproductive organ development in CF-1 mice following prenatal exposure to bisphenol A. Toxicol. Sci. 50, 3644.[Abstract]
Lee, P. C. (1998) Disruption of male reproductive tract development by administration of the xenoestrogen, nonylphenol, to male newborn rats. Endocrine 9, 105111.[ISI][Medline]
Nagel, S. C., Vom Saal, F. S., Thayer, K. A., Dhar, M. G., Boechler, M., and Welshons, W. V. (1997) Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ. Health Perspect. 105, 7076.[ISI][Medline]
Safe, S. (2000) Endocrine disruptors and human health is there a problem: an update. Environ. Health Persp. 108, 487493.[ISI][Medline]