FEATURE ARTICLE
Assessing Risks from Bisphenol-A
Evaluating human health risks from endocrine disruptors such as BPA is difficult, but animal studies suggest trouble is afoot
Heather Patisaul
The BPA Puzzle
BPA has more than one mode of action, but it is primarily recognized to be an estrogen mimic. Effects from endocrine disruption by an estrogen mimic in the developing fetus are likely subtle and not readily apparent at birth. The best example of this in humans is the tragic case of diethylstilbestrol (DES), a synthetic estrogen prescribed to upwards of 10 million women between 1938 and 1971. DES incorrectly was thought to reduce the risk of miscarriage. Instead, many children whose mothers took DES during pregnancy, both male and female, developed reproductive health problems as adults. Decades of DES use passed before indications of adverse effects were detected. A pair of physicians noted that DES daughters were more likely than unexposed women to develop an extremely rare form of vaginal clear cell carcinoma. Subsequently, malformations of the uterus, increased risk of testicular cancer, infertility and other reproductive health problems were also ascribed to fetal DES exposure. With DES, the severity of health effects corresponds to the timing and level of in utero exposure, illustrating the importance of tracking critical windows of exposure when attempting to predict potential consequences from human exposure to endocrine disruptors.
Important differences exist between DES and BPA. Most significantly, BPA is not as potent. The binding affinity of BPA for the two primary forms of estrogen receptor (ERα and ERβ) is approximately 10,000-fold weaker than that of estradiol, a natural estrogenic hormone, or of DES. To put this in context, the binding affinity of DDT and BPA are in a similar range. Also, human exposure to BPA is estimated to be relatively low—lower than the DES doses pregnant women received. Published estimates of human exposure to BPA are somewhat variable but generally fall in the range of 1 to 15 micrograms per kilogram of body weight per day or less, with infants and children on the upper end of that range and adults on the lower. Blood and urinary levels increase following the consumption of beverages from BPA-containing polycarbonate bottles, indicating that exposure rises and falls as people use products containing BPA. The EPA has set a “reference dose” of 50 micrograms per kilogram of body weight. This dose is considered safe for humans, even with daily exposure over a lifetime. It is based on the Lowest Observed Adverse Effect Level (LOAEL) of 50 milligrams per kilogram of body weight per day, the lowest dose at which any adverse effects should be observed in laboratory animals. BPA’s low estrogenic potency combined with the low level of human exposure have traditionally been interpreted to indicate little to no risk of human health effects from BPA exposure.
Yet there is growing evidence from multiple laboratories, including ours, that BPA can alter rodent reproductive physiology and behavior at doses equivalent or below the current LOAEL and, even more disturbingly, below the reference dose for humans. One of the most frequently observed consequences of low-dose exposure during development is the premature loss of a regular estrous cycle, an effect that produces an abbreviated period of fertility. We found that female rats exposed to the reference dose of 50 micrograms of BPA per kilogram for only the first four days of life developed an irregular estrous cycle as young as two and a half months of age. Rats normally remain fertile for upwards of a year. Similar effects have been reported in both rats and mice at equivalent or even lower doses.
Another well-documented effect in female rodents, observed by us and others, is disruption of pubertal timing. The effect is dose dependent: Doses near the 50-micrograms-per-kilogram reference dose advance pubertal onset, whereas higher doses delay it. Disruption of puberty is of particular interest for two primary reasons. First, it appears to be induced by lower, rather than higher, BPA doses, the mechanism for which is not well understood. Second, there is increasing evidence that puberty in girls is occurring earlier, especially in industrialized countries. Girls with advanced puberty outnumber boys with a similar condition 10 to 1, with nearly half of all African-American girls and approximately 15 percent of Caucasian girls showing clear signs of puberty, particularly breast development, by age nine. The timing of pubertal onset in humans is likely impacted by a suite of factors, including nutritional status, stress, socioeconomic status and genetics. But it has been hypothesized that exposure to estrogen-like compounds, including BPA, may partially explain this phenomenon.
Disruption of pubertal timing and the capacity to maintain a regular estrous cycle could result from developmental effects in the brain, the reproductive tract or both. Reproductive health ultimately depends on the proper organization and function of the hypothalamic-pituitary-gonadal (HPG) axis, a neuroendocrine system involving the hypothalamus; the pituitary gland, lying just beneath the brain; and the gonads (ovaries in females, testes in males). Hormones play a vital role in the sex-specific organization of all three components, so gestational exposure to endocrine disruptors has the potential to induce effects anywhere within the axis. Our laboratory’s work has focused primarily on the brain.
» Post Comment