Bisphenol 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 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.
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).
Over the last several decades, hundreds of experimental studies have been conducted, mostly with rats and mice...