There are relatively few studies that have reported no effects of developmental BPA exposure on the mouse prostate or other outcomes, and the majority of these “no effect” studies have been funded by the chemical industry [29
]. For example, one study [131
] reported that exposure of fetal mice to low doses of either BPA or the positive control, DES, produced no effect on the development of the prostate. Another study [132
] reported no effects of low doses of BPA on the prostate, although a response in their experiment required an extremely high dose of the positive control estradiol (100 μg/kg/day). This chemical-industry funded study by Tyl et al. has been used by regulatory agencies to declare that BPA is safe because it was conducted using a data reporting system named Good Laboratory Practices or GLP [133
]. It is interesting that in both of these studies that did not find any effects of low doses of BPA, the animals were maintained on Purina soy-based 5002 feed, which appears to contain ingredients that disrupt normal development of the systems that are impacted by BPA [113
]. These results suggest that some component of the diet caused a maximal increase in prostate size in control males in the study, and no further increase in size in response to either DES or BPA could then be observed. Our findings with estradiol and DES [16
] show that there is a maximum amount of increase in adult prostate size due to prenatal exposure to estrogenic chemicals, after which an increase in dose results in a decrease in prostate size, forming an inverted-U dose response curve.
It is not surprising that in addition to estrogenic drugs, estrogenic pesticides and estrogenic plastic monomers and antioxidants, there are components of formulated laboratory animal diets that can modulate the development of the reproductive system and change postnatal growth rate and reproductive organs, including the prostate [135
]. There is now evidence that phytoestrogens such as genistein (one of the primary phytoestrogens in soy) interact differently with estrogen response systems relative to BPA [26
]. The animal feed we use in our research results in lean control animals without enlarged prostates, and effects of very low doses of estrogenic chemicals on the development of accessory reproductive organs in males maintained on this diet have been consistently observed with numerous estrogenic chemicals, such as estradiol, DES, ethinylestradiol, bisphenol A and methoxychlor, in experiments conducted over many years (e.g. , ).
Figure 6 Prostate weight at different ages in CD-1 male offspring of females fed ethinylestradiol at a dose of 0.002 – 20 μg/kg/day in tocopherol-stripped corn oil from GD 14-18; controls (0 dose) were fed just oil. Males were examined at 3, 6 (more ...)
A recent study examined the effects of perinatal exposure (via the mother) to ethinylestradiol and BPA on development of the male reproductive organs in Long-Evans rats. In this study an ethinylestradiol dose of 50 μg/kg/day was required to result in a significant decrease in ventral prostate weight in the male offspring when examined in adulthood [139
], but no effect of BPA was seen. The highest dose of BPA administered in this study was 200 μg/kg/day, only 4-fold higher than the dose of ethinylestradiol dose required to alter prostate development. Because ethinylestradiol is typically at least 100-fold more potent than BPA it is likely that the BPA dose range chosen here (based on mouse exposure studies) was not wide enough establish the effective dose in this animal model, a fact that the authors acknowledged, and thus no effect on prostate development at this dose of BPA would be expected. The authors also discussed the fact that different strains of rat have widely differing sensitivities to estrogenic and antiestrogenic chemicals, which tend to vary by trait rather than in terms of a general sensitivity (or lack of it) to estrogens. This thus also emphasizes the need to consider species and strain differences when assessing results of chemical exposures.
In the study discussed above by Tyl [132
], no effects of BPA on the prostate of CD-1 mice were found at any dose, but the dose of the positive control, estradiol, required to cause an effect was 100 μg/kg/day. The prostates in the control CD-1 mice from this experiment were reported in the initial article [132
] to weigh (mean±SEM) 74.4±2.9 mg at 14 weeks old, which is an abnormally high prostate weight for this age (body weight was 40.46 ± 0.67 g). However, it is difficult to assess these data because subsequently these same animals were identified as having been examined when 18 weeks old [140
], and at a FDA hearing (September 16, 2008) in Rockville MD, Tyl presented testimony that the same animals were 24 weeks old. Given that this study was conducted under GLP guidelines, the reporting by the senior author of different data in multiple fora from a study being used to assess the risk of BPA by regulatory agencies is highly unusual.
For many years the common argument was that BPA was a weak estrogen and could not possibly cause effects at doses lower than 5000 μg/kg/day, a dose that remains the predicted no effect level (NOEL) according to US and European regulatory agencies [141
]. The large number of studies showing effects of BPA in human and animal cells at doses within and below the picogram per ml (pM) range provide ample evidence that BPA is not a weak estrogenic chemical for many responses [30
]. However, the finding that a dose of BPA below the current daily intake dose declared safe for humans throughout the lifetime by the EPA [142
] increases aromatase activity and intracellular estradiol levels in fetal prostate mesenchyme by almost 20 parts per trillion [112
] adds another layer of complexity to this debate. These findings by Arase and colleagues provide evidence that BPA can cause unexpected effects that can result in changes in endocrine function that without question can account for intracellular changes at very low, presumably completely safe, doses. There can be no argument that an intracellular increase in estradiol of 20 parts per trillion is a physiologically active concentration of estradiol. In fact, in both the fetal prostate mesenchyme [16
] and MCF-7 cells [47
], estradiol alters gene activity and stimulates proliferation at a dose of 0.28 pg/ml (1 pM). The rodent and human male fetus circulates testosterone at nM concentrations during sexual differentiation [16
], which provides high concentrations of substrate for the aromatization to estradiol in fetal tissues.