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
Answering the Critics
Our work has been criticized because the animals in our studies were exposed by injection rather than by mouth. Humans are primarily exposed orally so there is concern that injection is not an appropriate exposure route for animal studies. This argument, although logical on its face, is not so straightforward. Injection bypasses metabolism, a process that conjugates most BPA and renders it inactive. The plastics industry has long argued that BPA is rapidly metabolized and excreted in humans, and is therefore not a threat. It has also been posited that, because non-oral administration, such as injection, bypasses metabolism, it presumably results in higher circulating levels of estrogenically active, or unconjugated, BPA. There are two significant problems with these assumptions. First, at least one study comparing oral administration and injection in neonatal rodents found no qualitative difference in the circulating levels of unconjugated BPA or its metabolites. Second, rodents and humans do not metabolize BPA the same way. In humans, the majority of the metabolites end up in the urine while in rats they are excreted in the feces. In addition, oral dosing is often stressful for animals, and does not adequately replicate exposure through dental sealants or implanted medical devices. Finally, even if most BPA is conjugated in adult humans, this may not be true for children or infants because their gastrointestinal systems are not fully mature. Considerable scientific debate persists regarding the capacity for immature rodents and humans to adequately metabolize BPA. (To see a timeline of responses to BPA, click the image at right.)
Our rodent brain research has also been challenged because of key anatomical differences between the rodent and human brains. Most significantly, in humans and other primates it appears that androgens, rather than estrogens, are primarily responsible for masculinizing the hypothalamus. Therefore, disruption of AVPV organization in rats, the argument goes, may not predict a concomitant effect in humans. Disruption within the rat AVPV does, however, clearly show that BPA has the potential to interact with developmental estrogen pathways, an effect that may impact aspects of human brain development. Another caveat is that humans have no AVPV. Humans do have kisspeptin neurons and discrete brain regions that coordinate GnRH release. So studying this neuronal population in rats will likely be informative for BPA’s effects on humans as well. These caveats again highlight the difficulties in translating results from rodents to humans but do not discount the importance of animal work by us or others. It is important to keep in mind that the developmental period in which steroid-sensitive organization occurs in humans happens largely during gestation rather than in the first few days of neonatal life. Thus, when exposing rats neonatally it is imperative to select BPA doses that correspond to prenatal exposure levels in humans.
It is clear that BPA exposure can disrupt pubertal timing and compromise the capacity to maintain a regular ovulatory cycle in rodents. It is likely that these defects result from the abnormal organization of the hypothalamic- pituitary-gonadal axis, the crucial neuroendocrine pathway that regulates reproductive function. Our work has found evidence for effects in the brain, but growing evidence suggests that the entire axis is vulnerable. For example, National Institutes of Health researchers have identified numerous reproductive-tract abnormalities in aged female mice exposed to BPA in utero at doses as low as 0.1 microgram per kilogram. We have observed cyst-like structures in rats neonatally exposed to 50 milligrams BPA per kilogram. Increased numbers of blood-filled ovarian bursae (indicative of advanced reproductive age), abnormal numbers of antral follicles, irregular chromosomes and decreased corpora lutea (tissues vital to a fertilized ovum) have also been observed by a number of research groups following exposure to BPA during development. BPA has also been found to induce apoptosis and cell arrest in cultured ovarian granulosa cells, suggesting that BPA may also impact the adult ovary. These studies indicate that the ovary may be a particularly sensitive target of BPA. Other laboratories have observed that gestational exposure to BPA at doses below the reference dose can result in numerous uterine abnormalities (including many that commonly precede carcinogenesis), alter mammary gland development, diminish the capacity to maintain pregnancy and induce abnormalities in the prostate.
It is also important to note that a handful of studies have found no effects from BPA at all. The most recent of these, published by EPA researchers in October of 2009, found no changes in the timing of pubertal onset, sexual behavior or fecundity among female rats after exposure to BPA during gestation and lactation. Inconsistent results continue to plague the field and make human risk assessment extraordinarily difficult. It is not readily clear why some effects are not easily replicated by other groups.
Resolving how to interpret evidence from laboratory animals, and soon, is pivotal because BPA is not the only endocrine disruptor people are exposed to. Thousands of other compounds are also suspected of having similar properties, including some plasticizers, flame- retardants, pesticides and anti-microbials. On top of that, it’s important to consider the combined effect of exposure to multiple endocrine disruptors. A research group at Washington State University recently reported that they could not replicate previously published BPA effects in the mouse ovary. They ultimately determined that effects were only observed in mice maintained on soy-rich diets, leading the authors to hypothesize that diet, along with methodological differences, could explain why the literature surrounding “low dose” effects of BPA is fragmented and inconsistent. The concept of mixture effects is an evolving area of endocrine-disruption research. It could have profound implications for human health if these compounds are found to be more likely to produce significant health effects collectively rather than individually.
Another sobering possibility is that endocrine disruptors could have transgenerational effects. For example, there is emerging concern that the children of DES daughters (referred to as DES granddaughters) might also develop reproductive problems. For these girls, their exposure occurred while they were only germ cells in their mothers’ developing ovaries, within the wombs of their grandmothers. This concern arose from laboratory data indicating that the offspring of female mice exposed in utero were more likely than unexposed control animals to develop reproductive-tract lesions. There are not enough human data to indicate a trend for deleterious effects in DES granddaughters. But this cohort is still quite young. Continued monitoring of these women as they age will be required.
The precise mechanisms through which endocrine-disrupting effects transmit to subsequent generations are not well understood, but emerging evidence indicates that epigenetic mechanisms might be primary. Epigenetic inheritance involves changes in gene expression patterns without changes in gene sequence. Such effects include DNA methylation and histone modifications. If epigenetic modifications occur within the germ cells, transmission to subsequent generations is possible. Randy Jirtle at Duke University found evidence in agouti mice that suggests that BPA has the potential to induce epigenetic effects. Other compounds, including polychlorinated biphenyls (PCBs) and the fungicide vinclozolin, have been shown to produce transgenerational effects, perhaps through epigenetic mechanisms. This newly discovered and evolving area of research has once again challenged toxicologists and introduced a novel method by which endocrine disruptors and other toxicants may affect vertebrate physiology and behavior.
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