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Bisphenol A: Perinatal exposure and body weight

Bisphenol A: Perinatal exposure and body weight
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  Bisphenol A: Perinatal exposure and body weight Beverly S. Rubin * and Ana M. Soto Department of Anatomy and Cellular Biology, Tufts University School of Medicine, 136 HarrisonAvenue, Boston, MA 02111, United States Abstract Bisphenol A (BPA) is a component of polycarbonate and other plastics including resins that line foodand beverage containers. BPA is known to leach from products in contact with food and drink, andis therefore thought to be routinely ingested. In a recent cross sectional study, BPA was detected inurine samples from 92.6% of the US population examined. The potential for BPA to influence bodyweight is suggested by in vitro  studies demonstrating effects of BPA on adipocyte differentiation,lipid accumulation, glucose transport and adiponectin secretion. Data from in vivo  studies haverevealed dose-dependent and sex dependent effects on body weight in rodents exposed perinatallyto BPA. The mechanisms through which perinatal BPA exposure acts to exert persistent effects onbody weight and adiposity remain to be determined. Possible targets of BPA action are discussed. Keywords Endocrine disruptors; Obesity; Perinatal exposure; Fetal and neonatal exposure; Xenoestrogens;Body weight regulation; Fetal basis of adult disease 1. Introduction 1.1. Facts about Bisphenol A (4,4 ′  -dihydroxy-2,2-diphenylpropane) Bisphenol A (BPA) is a known endocrine disruptor that is prevalent in our environment. It wasfirst synthesized by A.P. Dianin in 1891, and BPA was further investigated in the 1930s duringa search for synthetic estrogens. Although BPA's estrogenic activity was confirmed at thattime, tests of a related synthetic compound, diethylstilbestrol (DES), indicated that DES wasa far more potent estrogen than BPA as determined in a classical estrogenicity assay of vaginalcornificaton (Dodds and Lawson, 1936). The use of BPA as a synthetic estrogen was abandonedin favor of DES which was administered to pregnant women from the late 1940s through 1971to prevent multiple pregnancy-related problems including miscarriage and premature births(Rubin, 2007). This practice was stopped after the treatment was linked to vaginal and cervicalcancers in the exposed daughters. The studies of the children of those DES treated women aswell as mouse models of early DES exposure have provided essential data and importantinsights regarding the fetal basis of adult disease (McLachlan, 2006; Newbold et al., 2006; Rubin, 2007). The chemical structures of BPA, DES and estradiol are shown in Fig. 1.Based on the relative binding affinity of BPA for the classical nuclear receptors ER alpha andER beta which is estimated to be over 1000–10,000 fold lower than that of estradiol (Kuiperet al., 1998), BPA was initially considered to be a weak environmental estrogen. However,more recent studies have revealed that BPA can stimulate cellular responses at very low © 2009 Elsevier Ireland Ltd. All rights reserved*Corresponding author. Tel.: +1 617 636 6694; fax: +1 617 636 6536. (B.S. Rubin).. NIH Public Access Author Manuscript  Mol Cell Endocrinol . Author manuscript; available in PMC 2010 February 9. Published in final edited form as:  Mol Cell Endocrinol . 2009 May 25; 304(1-2): 55. doi:10.1016/j.mce.2009.02.023. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t    concentrations and that BPA is equipotent to estradiol in some of its effects (Alonso-Magdalenaet al., 2005, 2008; Hugo et al., 2008; Zsarnovszky et al., 2005). Some of BPA's actions are attributed to its' ability to bind classical and non-classical membrane estrogen receptors(Alonso-Magdalena et al., 2005, 2008; Watson et al., 2005) as well as the G-protein-coupled receptor 30 (GPR30) (Thomas and Dong, 2006) and to act through non-genomic pathways(Leranth et al., 2008; Ropero et al., 2006; Zsarnovszky et al., 2005). Multiple cellular sites in addition to the nucleus and membrane have been proposed as targets of BPA action (Roperoet al., 2006). In addition, it has been suggested that some metabolites of BPA may be morepotent estrogens than the parent compound (Ben-Jonathan and Steinmetz, 1998). BPA has beenshown to interact differently than estradiol with the ligand binding domain of the classicalestrogen receptors (Gould et al., 1998), and differences have also been noted in the recruitmentof transcriptional coregulators (Routledge et al., 2000) lending support to the idea that BPA isnot merely an estrogen mimic.In the 1940s and 1950s, a use for BPA was identified in the plastics industry. BPA is thebuilding block for polycarbonate plastic, and it is a component of other plastics as well. BPAis also a component of epoxy resins used for some dental materials and for the lining of foodand beverage containers (;, NTP-CERHR, 2008). Additional uses for BPA include items that we come in contact with daily athome and in the workplace including the coating of CDs, DVDs, electrical and electronicequipment, automobiles, sports safety equipment, and carbonless paper. When polymerized,BPA molecules are linked by ester bonds that are subject to hydrolysis when exposed to hightemperatures or to acidic or basic substances (Welshons et al., 2006). Studies have shown thatBPA can leach from polycarbonate plastics and from epoxy resins and other products in contactwith food and drink and as a result, routine ingestion of BPA is presumed (Vandenberg et al.,2007a). Although ingestion is considered the major route of exposure, it is likely that humansalso gain exposure to BPA through the air and by absorption through the skin.BPA is one of the highest volume chemicals in use today. And therefore it is not surprisingthat BPA is ubiquitous in our environment and can be detected in the majority of individualsexamined in the US. Recent measurements by the Centers for Disease Control (CDC) revealeddetectable levels of BPA in urine samples from 92.6% of more than 2500 participants of thecross sectional NHANES (National Health and Nutrition Examination Survey) study (Calafatet al., 2008). Because BPA is thought to be rapidly metabolized and excreted from the body,the data from the NHANES study is suggestive of continuous exposure to the compound. Theyoungest individuals included in the NHANES data set were children between the ages of 6–12 years of age, and they showed the highest levels of exposure. This is an important findingas the data from animal studies indicate increased vulnerability to BPA exposure duringdevelopment (for review see Richter et al., 2007). In this regard, BPA has been detected inamniotic fluid, neonatal blood, placenta, cord blood and human breast milk (for review seeVandenberg et al., 2007a). Unfortunately the NHANES data set did not include samples fromchildren from birth to 6 years of age. This is the population with the highest expected exposurelevel per body weight as estimated by the US National Toxicology Program from the currentlyavailable human data (NTP-CERHR, 2008).In the 1980s, the lowest-observable-adverse-effect-level (LOAEL) for BPA was determinedat 50 mg/kg BW/day, and the US Environmental Protection Agency (EPA) calculated a“reference dose” or safe dose of 50 μ g BPA/kg BW/day. Since that time, data from manyanimal studies have revealed significant effects of exposure to doses of BPA below thecalculated safe levels particularly in response to fetal, neonatal or perinatal exposure. To date,the reported effects of perinatal exposure to BPA include: altered time of puberty (Honma etal., 2002; Howdeshell et al., 1999); prostate changes (Gupta, 2000; Prins et al., 2007; Timms Rubin and SotoPage 2  Mol Cell Endocrinol . Author manuscript; available in PMC 2010 February 9. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t    et al., 2005); altered mammary gland development and evidence of intraductal hyperplasiasand preneoplastic mammary gland lesions in adulthood (Markey et al., 2001; Munoz de Toro et al., 2005; Murray et al., 2007; Vandenberg et al., 2008); changes in the uterus and ovary (Markey et al., 2005; Newbold et al., 2007a); alterations in brain sexual dimorphisms (Kubo et al., 2003; Rubin et al., 2006); changes in brain steroid receptor levels (Khurana et al., 2000; Ramos et al., 2003); changes in behavior including reports of hyperactivity (Ishido et al., 2004; Jones and Miller, 2008), increased aggressiveness (Kawai et al., 2003), altered sexual behavior (Farabollini et al., 2002), and increased susceptibility to drugs of addiction (Jones and Miller, 2008; Mizuo et al., 2004). A review by Richter and colleagues provides a comprehensive account of the findings from in vivo  studies of BPA exposure (Richter et al.,2007). 1.2. Early exposure to BPA and body weight In our initial studies to examine the effects of perinatal BPA exposure on the reproductive axisand reproductive tract tissues, we noted that at some exposure levels, animals showed increasedbody weight (BW) relative to controls (Rubin et al., 2001). This observation was first made inoffspring born to Sprague Dawley rat dams that were exposed to bisphenol A in their drinkingwater from day 6 of pregnancy through the period of lactation. Pregnant dams were exposedto approximately 0.1 mg BPA/kg BW/day (Low Dose) or 1.2 mg BPA/kg BW/day (High Dose)and the body weights of their offspring were measured at intervals from birth through 110 daysof age. Both BPA exposed males and females showed an increase in body weight; however,the increase was more persistent in females than males. Moreover, in females, the effect wasdose-dependent as the lower exposure dose increased body weight in the offspring while thehigher exposure dose did not (see Fig. 2). This pattern is typical of the non-monotonic dose-response curves that have been reported for many actions of BPA (Vandenberg et al., 2006;Alonso-Magdalena et al., 2008; Hugo et al., 2008; Vandenberg et al., 2009). Subsequent to our first observations in Sprague Dawley Rats (Rubin et al., 2001), we notedthat the srcinal cohort of CD-1 mice, generated to study the effects of perinatal BPA exposureon hypothalamic–pituitary–ovarian axis function also showed evidence of dose-dependenteffects on body weight (unpublished observations). A more thorough examination of the linkbetween early BPA exposure and body weight regulation is currently underway in our lab. Todate, the data suggest that exposure of pregnant CD-1 mouse dams to 0, 0.25, 2.5 or 25 μ gBPA/kg BW/day from gestational day 8 through day 16 of lactation via osmotic minipumpsresulted in dose-dependent and gender-dependent effects on body weight of the offspring(manuscript in preparation).A review of the currently available literature reveals additional reports of increased bodyweight in offspring of mothers exposed to BPA during gestation, or gestation and lactation, orin rodents administered BPA during the early postnatal period. With regard to prenatal exposureto BPA, increased body weight was reported at the time of weaning in female CD-1 mice bornto mothers that received an oral dose of 2 μ g BPA/kg BW /day on gestational days 11–17(Howdeshell et al., 1999). The difference in body weight was most pronounced in femalespositioned between two females in the uterine horn during gestation. This finding suggests thatthe magnitude of BPA's effects on body weight were influenced by subtle differences in thehormone environment in utero . In a study examining xenoestrogen effects on estrogen targetorgans, increased body weight was also reported in the female offspring of CD-1 motherstreated with 0.5 or 10 mg BPA/kg BW/day on days 15–18 of gestation (Nikaido et al., 2004).Although not apparent at 4 or 8 weeks of age, differences in body weight were obvious at 12and 16 weeks of age in this paradigm. Females born to mothers exposed to the lower dose of BPA were heavier in adulthood than those born to mothers exposed to the higher dose. As inother studies, the effects of BPA revealed a non-monotonic dose–response. Additionally, Rubin and SotoPage 3  Mol Cell Endocrinol . Author manuscript; available in PMC 2010 February 9. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t    preimplantation exposure to BPA was reported to effect body weight at weaning (Takai et al.,2001). When mouse embryos were cultured at the two cell stage in 1 nM BPA, 100 μ M BPA,or 0.1% ethanol (the solvent used to prepare the BPA solutions), no differences in pup weightwere noted at birth. However at the time of weaning on PND 21, offspring from embryosexposed to either dose of BPA were significantly heavier than control offspring.With regard to postnatal BPA exposure, male rat pups were injected with 50 μ g BPA/kg BW/ day for 4 days beginning on the day of birth, to study the effects of BPA exposure on anxiety.When their body weights were recorded on postnatal day (PND) 68, the BPA treated maleswere significantly heavier than controls (Patisaul and Bateman, 2008). In another study, CD-1female mice were treated daily from PND 1 through PND 5 with 10 μ g BPA/kg BW to studythe effects on the reproductive tract. At 18 months of age, the only time point reported, bodyweights were 11% higher in the BPA treated females relative to the controls (Newbold et al.,2007a). Finally, in a study designed to examine the potential relationship between early BPAexposure and obesity, pregnant ICR mouse dams fed a high fat diet were exposed to BPA fromday 10 of gestation though the period of lactation. After weaning the pups continued to beexposed to BPA and the high fat diet through PND 31 when they were killed (Miyawaki et al.,2007). BPA was administered in the drinking water, and exposure levels in the pregnant damswere estimated at approximately 0.26 mg BPA/kg BW/day in the low dose and 2.7 mg BPA/ kg BW/day in the high dose group. Body weights and adipose tissue weights were increasedin 31 day old male and female offspring exposed to BPA. Both sex-dependent and dose-dependent differences were observed, and a non-monotonic dose–response was noted in someof the parameters reported. In this study, animals were examined prior to adulthood and BPAexposure was ongoing at the time of sacrifice.The initial observations in our lab (Rubin et al., 2001) and others (Howdeshell et al., 1999)linking prenatal or perinatal BPA exposure to increased body weight long after the time of exposure were intriguing. Data gleaned from the studies that followed provided additionalevidence of increased body weight following perinatal exposure to BPA (Nikaido et al.,2004; Patisaul and Bateman, 2008; Newbold et al., 2007a; Miyawaki et al., 2007). The accumulating evidence linking perinatal BPA exposure to increased body weight wasparticularly interesting due to growing reports in the literature revealing effects of otherendocrine disruptors on body weight (Heindel, 2003). For example, neonatal DESadministration was found to increase body weight and adiposity in adulthood (Newbold et al.,2007b). Organotins were also reported to exert effects on adipocyte differentiation and bodyweight (Grun and Blumberg, 2006). Recent analysis of NHANES data revealed an age-dependent and gender-dependent association between urinary phthalate metaboliteconcentrations and body mass index and waist circumference in humans (Hatch et al., 2008).Furthermore, a prospective study in humans revealed a correlation between hexachlorobenzenelevels in cord blood at birth and increased body mass index at 6.5 years of age (Smink et al.,2008). In addition to contributions from diet, and exercise, emerging data from studies of endocrine disruptors lend support to the hypothesis that the increase in industrial chemicals inour environment has contributed to the significant increase in body weight over the past 40years (Baillie-Hamilton, 2002). 1.3. Possible mechanisms of action of BPA in body weight regulation How perinatal exposure to BPA may exert lasting effects on body weight remains to bedetermined. Some potential targets of BPA action in this regard are discussed in the paragraphsthat follow. 1.3.1. BPA action on preadipocytes— Results of several in vitro  studies of 3T3-L1 cellshave indicated that micromolar concentrations of BPA enhance adipocyte differentiation and Rubin and SotoPage 4  Mol Cell Endocrinol . Author manuscript; available in PMC 2010 February 9. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t    lipid accumulation in target cells in a dose-dependent manner (Masuno et al., 2002, 2005; Wada et al., 2007). Additionally, bisphenol A was found to enhance basal glucose uptake inmature mouse 3T3-F443A adipocytes due to increased GLUT 4 protein (Sakurai et al.,2004). Most recently Bisphenol A was shown to increase gene expression of adipogenictranscription factors in 3T3-L1 preadipocytes (Phrakonkham et al., 2008). If similar actions of BPA occur in vivo , they would be expected to contribute to increased adiposity and increasedbody weight. Whether BPA may exert similar dose-dependent effects on adipocytedifferentiation perinatally, and whether such effects contribute to increased adiposity later inlife remains to be determined. It is interesting to note that female fetuses of pregnant damsexposed to BPA (0.25 μ g/kg BW/day), beginning on gestational day 8, showed evidence of accelerated maturation of the mammary fat pad when examined on gestational day 18(Vandenberg et al., 2007b). 1.3.2. BPA as an estrogen— BPA's actions as an estrogen may contribute to effects onbody weight. Sex-dependent and dose-dependent differences in body weight in response toearly postnatal exposure to DES, an estrogenic compound with structural similarities to BPAhave been reported (Newbold et al., 2008). Those studies demonstrated increased body weightat 4 months of age in females exposed to DES (1 μ g DES/day) from postnatal days 1 through5. In contrast, males exposed to DES during that time period demonstrated a decrease in bodyweight relative to controls at 4 months of age. The administration of another estrogeniccompound, the soy isoflavone, genistein to 4 week old male and female mice (in doses of 50–200,000 μ g/kg/day for 15 days) also revealed dose and sex-dependent effects on adipose tissuedeposition (Penza et al., 2006). In this specific paradigm, the males proved to be more sensitiveto the effects of genistein showing increased adipose tissue deposition following treatment withnutritional doses of genistein and a significant decrease in fat pads when they were treated withpharmacological doses of the compound. It is intriguing to note that continuous exposure of male mice from conception through adulthood to a high phytoestrogen diet (containing highlevels of genistein as well as diadzein) resulted in decreased adiposity, increased energyexpenditure, and improved glucose and lipid metabolism (Cederroth et al., 2007, 2008). These data further suggest the importance of the dose and the precise timing of exposure to estrogeniccompounds as well as the compounds themselves in determining their effects on adiposity andglucose homeostasis.As mentioned previously, BPA may bind the classical nuclear estrogen receptors as well asclassical and non-classical membrane estrogen receptors and GPR-30 (Alonso-Magdalena etal., 2005, 2008; Kuiper et al., 1998; Thomas and Dong, 2006; Watson et al., 2005). Data from in vitro  studies have revealed similarities between the action of estrogen and BPA on the geneexpression of adipogenic transcription factors (Phrakonkham et al., 2008). In addition, bothBPA and estradiol were reported to inhibit adiponectin secretion from human adipocyteexplants in a (non-monotonic) dose-dependent manner (Hugo et al., 2008). There is alsoevidence from in vivo studies to suggest that neonatal estrogenization can increase body weight(Ruhlen et al., 2008). In addition, as discussed above neonatal exposure to DES, which istypically considered a more potent estrogen than BPA, can increase body weight and adiposityin females (Newbold et al., 2008). When considering perinatal exposure to BPA, it is importantto note that the fetal and neonatal liver produces high levels of alpha fetoprotein (AFP), themajor estrogen binding plasma protein of the developing rodent. AFP is thought to protecttissues of the perinatal rodent from excessive exposure to estradiol (Toran-Allerand, 1984).Because BPA shows limited binding to serum proteins (Milligan et al., 1998), relative toestradiol, BPA may have increased access to the tissues of the developing fetus or neonate,and as a result, its' actions as an estrogen may be greater than expected.The role of estrogens in body weight regulation is complex and not yet well understood.Although perinatal exposure to estrogenic compounds can lead to increased body weight, Rubin and SotoPage 5  Mol Cell Endocrinol . Author manuscript; available in PMC 2010 February 9. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  
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