Bisphenol A: a threat to human health?
IntroductionBisphenol A (BPA) is an anthropogenic chemical made up of two phenolic rings and joined by a bridging group formed by the reaction of phenol with acetone (Figure 1). Solid at ambient temperatures, usually as a white powder or flake, BPA is used as the building block for polycarbonate plastic and epoxy resins, mainly in dental sealants, eyeglasses, food containers, infant bottles, reusable water bottles, medical devices, compact discs, epoxy-phenolic resins in the surface coating of drinking water storage tanks, photographic film, and in polycarbonate for water pipes, which means that BPA is almost everywhere around us in the form of our daily usable goods. As a component of polycarbonate plastic, over six billion pounds of BPA are produced each year (Welshons, Nagel, & vom Saal, 2006).
BPA acts as an endocrine disruptor that mimics the structure and function of the 17-[beta] estradiol hormone and has the ability to bind with estrogen receptors. A 2008 report by the National Toxicology Program cited the adverse effects of BPA on fetuses, infants, and children. In 2010 the Food and Drug Administration banned the use of BPA in baby bottles. In September 2010 Canada's environmental science department declared BPA to be a "toxic substance." The presence of BPA in the environment can cause serious health problems, although opinions vary on this point. Studies on BPA have shown the increased susceptibility to cancerous changes (Jenkins et al., 2009), effects on fertility and reproductive tract (Al-Hiyasat, Darmani, & Elbetieha, 2002), oxidative toxicity (Kabuto, Amakawa, & Shishibori, 2004), neurotoxic effects (Le, Carlson, Chua, & Belcher, 2008), genotoxic effects (Karim & Husain, 2010; Naik & Vijayalaxmi, 2009), and other health problems (Fernandez et al., 2007).
Exposure Assessment
Exposure is predominantly oral. BPA molecules are bound by an ester bond, which is disrupted by heat or acidic or basic conditions and releases BPA into food or beverages in con tact with the plastics (European Commission, 2008). The highest estimated BPA dietary exposures were for infants 0-6 months of age who were exclusively fed with canned liquid infant formula using polycarbonate bottles. In this case, sources of BPA exposure include migration from both the formula packaging and the polycarbonate bottle.
Infants who were either fed with formula from nonpolycarbonate bottles or exclusively breastfed had substantially lower estimated BPA exposures compared with those exclusively fed with infant formula using polycarbonate bottles. Once solid foods are introduced, an infant's exposure to BPA decreases relative to body weight (World Health Organization, 2010). BPA exposure from nonfood sources (e.g., thermal paper, medical equipment) is generally lower than that from food sources. The dietary exposure estimates for four population groups are summarized in Table 1. From this exposure estimate experts conclude that food is by far the major contributor of overall exposure to BPA for most population groups.
BPA and Human Health
Any acute or chronic changes are the result of slow and long-term exposure of BPA. Although BPA affects humans differently under various doses, we have considered the following criteria as major effects of long-term exposure.
Reproductive System
We discuss here the effects of BPA on male and female fertility. Numerous environmental toxicants adversely affect spermatogenesis in rodents and humans, which can lead to low sperm count, abnormal sperm morphology, and poor semen quality in males (Al-Hiyasat et al., 2002) along with chromosomal abnormalities, fetal loss, endometriosis, menstruation irregularities, spontaneous abortion, and reduced fertility in females (Sharara, Seifer, & Flaws, 1998). BPA is a toxicant in a group that includes other chemicals such as chlorinated hydrocarbons, pesticides, glycol ether, phthalates, and heavy metals.
BPA has been considered a weak estrogen because of its low potency compared with estradiol in assays involving nuclear receptors (Blair et al., 2001; Thomas & Dong, 2006). Low levels of BPA, however, act additively with xenoestrogen and natural estrogens (Silva, Rajapakse, & Kortenkamp, 2002; Soto, Chung, & Sonnenschein, 1994; Soto, Fernandez, Luizzi, Oles Karasko, & Sonnenschein, 1997; Tollefesen, 2002). Several studies have pointed out that rodents exposed to BPA during the prenatal or perinatal period show a large variety of adverse reproductive outcomes, including decreased epididymal weight and increased sloughing from the seminiferous epithelium (Richter et al., 2007; Salian, Doshi, & Vanage 2009a, 2009b; vom Saal et al., 1998) and increased prostate weight (Nagel et al., 1997).
Regarding prepubertal or pubertal exposures, rodent studies have shown decrement in epididymal sperm counts after BPA exposure (Herath et al., 2004). During adult exposure, changes in sperm morphology such as abnormalities in the acrosomal cap, vesicle, and deformed nuclei were found in Wistar and Swiss rats at 20 [micro]g/kg day (Chitra, Latchoumycandane, & Mathur, 2003).
Prepubertal or pubertal and adult exposures show a decrease in plasma concentrations of testosterone levels (Herath et al., 2004; Takao et al., 1999) Luteinizing hormone (LH) levels were increased in BPA-treated male rats, which shows that BPA causes hormonal imbalances (Tohei, Suda, Taya, Hashimoto, & Kogo, 2001). BPA may also have antiandrogenic activity, for example at a wide range of concentration. That is, 2-400 mg/kg/day of gestation was found with significantly lower regulated steroidogenic acute regulatory protein, which is a nuclear transporter protein critical for steroid biosynthesis in steroid-producing organs such as testes, ovaries, and adrenal glands in fetal rats (Manna, Dyson, & Stocco, 2009).
BPA causes infertility or subfertility when postnatal exposure occurs at oral dosing of rats with 50 mg/kg/day by disrupting the blood-testis barrier (Li, Mruk, Lee, & Cheng, 2009), which is a hormone-dependent structure also essential for germ cell development; without proper functioning, germ cells do not develop into mature sperm. Prolonged disruption causes infertility (Bonde et al., 2010; Delbes, Hales, & Robaire, 2010). Neonatal exposure of BPA doses at 10 g/kg/day impairs fertility by protuberating Sertoli cell junctional protein (adhesion, gap, and tight junction) that leads to impaired spermatogenesis (Salian et al., 2009a).
BPA causes significant disruption of the alignment of chromosomes and aneuploidy observed in the developing oocyte in females, which is also a cause of spontaneous abortion in humans (Hunt et al., 2003). With this finding it was predicted that an increase in mortal ity of embryos would occur at a maternal dose of 25 [micro]g/kg/day (Al-Hiyasat, Darmani, & Elbetieha, 2004). Implantation of embryos is not affected at low BPA maternal doses (as low as 10 [micro]g/kg/day), and is significantly decreased only at a maternal dose of approximately 70 mg/kg/day, which is just above the low-dose range (Berger, Hancock, & deCatanzaro, 2007). In one study, BPA-exposed females delivered a significantly smaller number of pups and animals due to development of polycystic ovarian syndrome (Fernandez, Bourguignon, Lux-Lantos, & Libertun, 2010).
Neonatal exposure to BPA was associated with altered gene expression and hormone responsiveness in uterine stroma in adulthood, which could contribute to impaired fertility (Varayoud, Ramos, Bosquiazzo, Munoz De Toro, & Luque, 2008). Other effects, however, such as effects on sex hormone levels during pregnancy or oocyte quality, could also contribute to reduced fertility. Indeed, oocytes are one of the longest-lived nonregenerating cells in the body and are subject to a lifetime of environmental exposures that are difficult to quantify (Crain et al., 2008). Vascular endothelial growth factor (VEGF) plays a role in the regulation of uterine microvascular permeability and angiogenesis in the implantation process (Ferrara, Gerber, & LeCouter, 2003; Halder et al., 2000). Postnatal exposure of BPA at a dose of 0.05 mg/kg/day disturbed VEGF expression due to a change in endocrine pathways and impaired the implantation process, so negative effects on fertility occurred in adult rats (Bosquiazzo et al., 2010).
Developmental Effects
Over the last several decades, hundreds of experimental studies have been conducted, mostly with rats and mice, on the potential reproductive and developmental toxicity of BPA. To make these effects relevant to human health, researchers considered a specific dose of BPA exposure that is relevant to human exposure levels, i.e., a dose resulting in serum levels close to those observed in human serum (below 1 mg/kg/day). The reproductive and developmental effects from low-dose exposure caused permanent changes to the genital tract (Markey, Wadia, Rubin, Sonnenschein, & Soto, 2005), lower body weight, increase of anogenital distance in both genders (Honma et al., 2002), and disruption of ovarian development (Adewale, Jefferson, Newbold, & Patisaul, 2009).
Immune System
BPA has been reported to modulate immune function at doses between 2.5 and 30 [micro]g/ kg/day (Sawai, Anderson, & Walser-Kuntz, 2003; Yoshino et al., 2003), including patterns of cytokine and antibody production, response to infection, and autoimmune disease progression. T-helper lymphocytes are a source of cytokine families that stimulate inflammatory responses and resistance to intracellular infections (Th1 cytokines), or that shift the response to antibody production, resistance to extracellular organisms, and allergy (Th2 cytokines). BPA may enhance or shift the pattern of cytokine production following antigen stimulation. Skewing of the Th1/Th2 cytokine profile by endocrine-disrupting compounds has been associated with allergy and asthma (Chalubinski & Kowalski, 2006). Exposure to BPA has also been associated with modulation of innate immune system cell function, for example in the administration of 5 mg/kg/ day subcutaneously to adult BALB/c mice for 5 days (Sugita-Konishi et al., 2003).
The effects of BPA exposure on the immune system may be critically dependent on the timing of exposure. Estrogen receptor expression by lymphocytes is dependent upon the age and strain of the animal; in addition, recent evidence suggests the spleen undergoes significant molecular remodeling during puberty, resulting in both age and gender-dependent differences in immune gene expression (Lamason et al., 2006). Nevertheless, studies conducted by Yoshino and co-authors (2003) indicate similar dose-associated, gender-independent immune system effects in eight-week-old offspring of BPA-exposed dams and animals exposed as adults. These results suggest quantitative, rather than qualitative, differences in lifestage-dependent immune system sensitivity to BPA.
Neurobehavioral, Neurotoxic, and Neuroendocrine Effects
BPA-induced changes in function of the hypothalamus pituitary-gonad axis have been observed in both males and females. Effects on LH, prolactin, and brain aromatase activity in males, and disruption of LH and estrous cyclicity resulting in elongated estrous phase in females (Rubin, Murray, Bamassa, King, & Soto, 2001) have been observed on weaning mice. Low-dose exposures of BPA during development have persistent effects on brain structure, function, and behavior in rats and mice (Richer et al., 2007). The European Union report (European Commission, 2008) included a review of all studies on the effects on neurological development following prenatal and perinatal exposure to BPA. The neurotoxicity endpoints were evaluated as locomotory and exploratory activity; cognitive, emotional, social, sexual, and maternal behavior; behavior response to pharmacological challenge; brain morphology; immunohistochemistry; and receptor/gene expression. For a better understanding of the potential neurotoxicity risk of BPA, BPA should be studied in terms of validity and reliability of the test systems and for their relevance for effects on the behavior and cognitive development of humans and relevant exposure and exposure routes.
Metabolic Effects
BPA can contribute to the onset of metabolic diseases (e.g., obesity and diabetes mellitus), which may indirectly affect male fertility. Administration of BPA (i.e., 10 [micro]g/kg/day for two days) stimulated insulin production by pancreatic [beta] cells in adult mice. Adults with the highest levels of circulating BPA were more than twice as likely to develop diabetes as those with lower levels of BPA (AlonsoMagdalena, Ropero, Soriano, Quesada, & Nadal, 2010; Alonso-Magdalena, Quesada, & Nadal, 2011). BPA is lipophilic, and it can accumulate in fat stores to increase the number and size of adipocytes, thereby resulting in weight gain. Adipocytes also express endrogen receptors to which BPA binds (Pedersen et al., 2001). Obesity itself is a risk factor for diabetes, cancer, infertility, and a host of other diseases, which have also been linked to environmental toxicant exposure.
Genotoxicity
Genotoxic studies of BPA were realized using in vitro and in vivo evaluations with controversial results. Bucher (2010) reported that BPA is not a mutagen in in vitro tests, nor does it induce cell transformation. BPA has been shown to affect chromosomal structure in in vitro studies, but no evidence exists for in vivo studies. In vivo genotoxic potential of BPA was studied by Naik and Vijayalaxmi (2009) in mouse bone marrow cells using cytogenetical assays, as chromosomal aberrations, micronucleus test, and c-mitotic effects. They applied single oral doses of 10, 50, and 100 mg/kg and repeated oral doses of 10 mg/kg for five days. Their investigation revealed that although BPA failed to induce conventional chromosomal aberrations and micronuclei, its genotoxic effects were manifested in the form of achromatic lesions and c-mitotic effects in bone marrow cells of Swiss albino mice. Later they studied genotoxic effects of BPA and octylphenol (OP) in rats using comet assay. They observed significant differences in animals that received BPA 250 mg/kg/day and OP 250 mg/kg/day compared with the control group. Oral administration of BPA and OP may posses a genotoxic risk in rats at high doses of tested chemicals and may not be so critical in low doses (Ulutas et al., 2011). Furthermore, a need exists for studies to explore mechanisms of the genotoxic potential of BPA in vivo.
Oxidative Toxicity
Several studies reported the occurrence of oxidative toxicity after BPA exposure in rats and mice (Chitra, Rao, & Mathur, 2003; Gong & Han, 2006). It was suggested that BPA caused tissue injury in the liver, kidney, brain, and other organs by the formation of reactive oxygen species (Bindhumol, Chitra, & Mathur, 2003; Kabuto et al., 2004). Moreover, the study of Bindhumol and co-authors (2003) revealed that low doses of BPA generate reactive oxygen species by decreasing the activities of antioxidant enzymes and increasing lipid peroxidation thereby causing oxidative stress in liver of rats. Vitamin E (a-tocopherol), a powerful lipophilic antioxidant (Yoganathan, Eskild, & Hansson, 1989), has also been shown to suppress lipid peroxidation in testicular microsomes and mitochondria (Gavazza & Catala, 2006; Lucesoli & Fraga, 1999) and to reverse the detrimental effects of oxidative stress mediated by exposure to such factors as polychlorinated biphenyls and cyclophosphamide (Senthil et al., 2004). Short-term BPA exposure may partly inhibit the reproductive function in adolescent male mice with certain stimulating effects on antioxidant ability, and supplementation of vitamin E during BPA exposure may have certain protective effects on reproductive inhibition caused by it (Fang, Zhou, Zhong, Gao, & Tan, 2013).
Carcinogenicity
BPA exposure during the perinatal period has been reported to alter both prostate and mammary gland development in ways that may render these organs more susceptible to the development of neoplasia or preneoplastic conditions.
Prostate Gland
Prenatal exposure to BPA may affect the development of prostate cancer in later life. Maternal oral dose of 10 [micro]g BPA/kg/day of gestation stimulated an increase in the number of primary prostatic ducts as well as proliferation of basal cells (the progenitor cells thought to be responsible for the development of prostate cancer) in the dorsolateral region, but not in ventral primary ducts as seen in male CD1 mouse fetuses (Timms et al., 2005). Interestingly, the similar dose of BPA administered via injection to neonatal rats resulted in 100% of the subsequent adult males exhibiting prostate intraepithelial neoplasia lesions, which are pretumorous prostate cancer lesions (Ho, Tang, Belmonte de Frausto, & Prins, 2006). In another study prenatal exposure at dose 25 [micro]g/kg/day in Wistar rats caused cell proliferation in ventral ducts (Ramos et al., 2001). This finding is different from those reported by Timms and co-authors (1999) in which male Sprague Dawley rats exposed to the highest natural serum level of E2 (17-[beta] estradiol) showed enlargement of the dorsolateral prostrate but not the ventral prostrate.
Mammary Gland
Terminal end buds of the mammary gland are particularly sensitive to carcinogenic events (Russo & Russo, 1996). It has been speculated that BPA exerts several estrogenic effects on the rodent mammary gland (Richter et al., 2007). This may be an indirect response to the modulation of the timing of puberty because early commencement of puberty can affect the development of the mammary gland through premature exposure to ovarian hormones, such as estrogen and progesterone, both of which affect growth and development (Medina, 2005). In the mammary gland, fetal exposure of female CD1 mice to BPA causes differences in ductal invasion as well the number of ducts and terminal end and alveolar buds in adults (Markey, Luque, Munoz De Toro, Sonnenschein, & Soto, 2001; Munoz De Toro et al., 2005). Fetal exposures also increased ductal area and ductal extension in (embryonic day 18) female mammary glands in the same strain of mice (Vandenberg et al., 2007) whereas in Sprague-Dawley and Wistar rats, BPA led to an increase in susceptibility to carcinogen-induced mammary tumors, although no spontaneous tumors were observed (Betancourt, Eltoum, Desmond, Russo, & Lamartiniere, 2010; Murray, Maffini, Ucci, Sonnenschein, & Soto, 2007) Hence, their increase following BPA exposure suggests that these mice may be at increased risk for mammary tumor genesis. Supporting this postulate, intraductal mammary epithelial hyperplasias have been observed in CD1 mice exposed to BPA during fetal life or prenatally (Vandenberg et al., 2008). BPA may increase mammary tumor genesis through at least two mechanisms: molecular alteration of fetal glands without associated morphological changes and direct promotion of estrogen-dependent tumor cell growth. Both results indicate that exposure to BPA during various biological states increases the risk of developing mammary cancer in mice (Lozada & Keri, 2011).
Conclusion
Data demonstrate that BPA functions as a xenoestrogen (synthetic estrogen) and changes the expression of the endocrine receptor by binding with them. Prenatal and neonatal periods are critical because during these time frames BPA exposure affects many tissue, organ, and biological pathways that compromise testicular function and semen quality directly or indirectly, thereby leading to subfertility or infertility. It appears to be species and strain specific in terms of sensitivity of particular outcomes. Extensive evidence exists that BPA affects developmental changes in the brain, behavior, and signaling systems. Results from studies may reflect that the estrogenic effect of BPA could be related to an inhibitory effect on testicular steroid genesis and spermatogenesis. Although no evidence indicates that oral ingestion of BPA by humans at exposure levels typical of its presence in the environment has adverse effects, blood BPA levels in pregnant mothers and their fetuses are of concern. BPA exposure at the workplace as seen in a cohort study also gives evidence that it has an adverse effect on male sexual dysfunction and shows a dose-response relationship of BPA exposure.
This finding not only has public health implications for male fertility, but possibly for other health outcomes as well, since male sexual function may be a more sensitive and easily measured end point that provides early signals about the adverse BPA effects on other endpoints that are more difficult to study. Associations between BPA exposure and measures of reproductive function in fertile men, however, were small and of uncertain clinical significance. Vertical transmissions of BPA exposure at different dose levels need to be confirmed by additional studies. Nevertheless, given the extensive use of BPA in consumer products to which humans are chronically exposed, these findings increase the need to examine the health effects of BPA in both occupationally and environmentally exposed populations at the relevant dose level. Aft
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Seema Srivastava, PhD
Priya Gupta, MSc
Anil Chandolia, MSc
Imtiyaz Alam, MSc
Department of Zoology
University of Rajasthan
Corresponding Author: Seema Srivastava, Associate Professor, Department of Zoology, University of Rajasthan, Jaipur-302004, Rajasthan, India. E-mail: drseemaa07@gmail.com.
TABLE 1
Sources of Exposure in Population and Its Dietary Estimates
Population Source of Exposure Dietary Exposure
Estimate
([micro]g/kg body
weight per day)
Mean 95th
Percentile
Infants Exclusively 0.3 1.3
0-6 months breastfed
Polycarbonate 2.0-2.4 2.7-4.5
bottles and formula
(a) (powder/liquid)
Formula, no 0.01-0.5 0.1-1.9
polycarbonate
bottles (a)
(powder/liquid)
Infants Breastfed and solid 0.1 0.3-0.6 (c)
6-36 food (best
months case-worst case)b
Polycarbonate 0.5-0.6 1.6-3.0 (c)
bottles and formula
(a) and solid food
(best case-worst
case) (b)
Formula only, no 0.01-0.1 0.1-1.5 (c)
polycarbonate
bottles (a) and
solid food (best
case-worst case) (b)
Children Fruits, desserts, 0.2-0.7 0.5-1.9 (c)
3+ years vegetables, meat,
soups, seafood,
carbonated drinks
(best case-worst
case) (b)
Adults Fruits, vegetables, 0.4-1.4 1.0-4.2 (c)
grains, meat, soups,
seafood, desserts,
carbonated drinks,
tea, coffee,
alcoholic beverages
(best case-worst
case) (b)
(a) Assumes formula only, no breast milk.
(b) Worst case is assuming the daily consumption of 100%
packaged food and beverages, and the best case is assuming the
daily consumption of 25% packaged food and beverages.
(c) Because of the use of the budget method model, maximum
consumption is reported in these upper range of exposure
estimates.
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| Title Annotation: | SPECIAL REPORT |
|---|---|
| Author: | Srivastava, Seema; Gupta, Priya; Chandolia, Anil; Alam, Imtiyaz |
| Publication: | Journal of Environmental Health |
| Article Type: | Report |
| Geographic Code: | 1USA |
| Date: | Jan 1, 2015 |
| Words: | 5894 |
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