Rat Testing Can Prove Chemical BPAs Effect on Humans - Research Paper Example

Topic: Rat Testing Can Prove Chemical BPA’s Effect on Humans Outline This paper focuses on exploring the various studies that have used rats as models to assess the impacts of BPA on humans. This work will seek to shed light on the following questions; An introduction to BPA What are the BPA’s effect on rats This will stem from a systematic literature review of studies of BPA employing rats as animal model Can the rat model be sufficient to prove chemical BPA effect on humans? Recommendations made on the effect of BPA on rats and its possible implications on humans risk. A conclusion Final paper: Rat Testing Can Prove Chemical BPA’s Effect on Humans BPA, Bisphenol is a weakly estrogenic monomer used n production of polycarbonate plastics that are in most cases used in food-related applications such as polycarbonate baby bottles. In addition it is applied in metallic food cans as epoxy resins, inner coatings, to prevent rusting and corrosion. BPA comprises of two phenol functional groups and with these two benzene rings and two (4, 4)-OH substituents, BPA fits in the estrogenic receptor (ER) binding pocket. Apart from binding the ER, there is evidence of this chemical also binding the thyroid hormone receptor and acting as an antagonist by preventing T3 binding (Vandenberg 77). This work will seek to review the successful use of rats as models in proving BPA’s effect on humans. Background Bisphenol A (4, 4’-isopropylidene-2-diphenol, BPA), a xenoestrogen, continued use in the production of polycarbonate plastics and epoxy resins increases the risk of oral exposure to humans to trace amounts of this monomer (Goodson 796). In the liver and intestine, uridine diphosphate-glucuronosyl transferase (UGT) catalyses the conversion of BPA to glucuronic acid conjugate BPA-monoglucuronide (BPAG) (Inoue 1084; Völkel 1281). Elimination of BPAG by rodents and humans compare differently. In humans, BPAG is eliminated in the urine (Völkel 1282) whereas in rats (rodents) it is eliminated via bile and in the feces as BPA providing chances of an enterohepatic recirculation which increases systemic exposure of BPA (Teeguarden 823). However BPAG, a principal BPA metabolite, is not estrogenic (Matthews 150). BPA is known to act in steroid hormone mediated signaling pathways by mimicking hormones involved in these pathways and as such it affects the reproductive functions. BPA falls under a class of compounds referred as endocrine disrupting compounds (EDCs) which disrupt the natural organization of hormones. Various safety-related studies have been implemented on the potential of BPA to cause adverse effects on humans given its estrogenicity (Hengstler 264). Long term health effects of BPA following exposure in various stages of life has been achieved using animal’s model data. One such study carried out by Adewale et al (38a) was to establish whether BPA exposure during neonatal stage may interfere with sex specific organization of the female rat hypothalamus. This study used rats as models for testing the effect of BPA on humans. In the study different parts of the hypothalamus known to be densely populated with estrogen receptors containing neurons were selected. These hypothalamus areas contribute in various aspects of female reproduction such as estrous regulation and mating behavior. Drawing from studies on rats, fetal, infant and pubertal stages of human development are more affected by BPA exposure as compared to the adult tissues (Selevan 451). Changes evident in the reproductive development involve an earlier pubertal and reproductive senescence and disruption of estrous cycle and ovarian and mammary gland development (Adewale 692b). In male rodents, estrogen is important in masculinization of the brain. This estrogen is generated from aromatization of testosterone released in the bloodstream from the testes. However, development of female brain is in the absence of estradiols such as estrogen and as it does not require masculinization. BPA exposure may mimic the action of estrogen and masculinize female hypothalamus, with masculinization in primates (humans) occurring via the androgen receptors (Wallen 7). Previous study by Adewale et al (690b) on the impact of BPA exposure at neonatal stage to determine is role in altering reproductive development has been carried on rats. Maturation of the reproductive organs by the hypothalamus-pituitary (HPG) axis is regulated by the gonadotropin releasing hormone (GnRH). Neural components of the HPG which regulate GnRH are sexually differentiated by the endogeneous gonadal hormones. GnRH regulation is mediated by a negative feedback loop and in females the release of GnRH is augmented in each cycle by the release of estrogens. However, regulation of this negative feedback circuit may be disrupted by hormone-like compounds such as BPA in the neonatal period (Adewale 691b). BPA exposure may act to accelerate puberty onset, premature anestrous and ovarian malformations by either disrupting organization in the HPG axis. This study on rats found that BPA was not able to defeminize the hypothalamus but may have effects on the GnRH neurons. In addition, this study demonstrated that BPA exposure at the neonatal stage was able to alter the timing of puberty. Sexual maturation in females may be subject to influence from exposure to BPA which is able to cross the placenta and also is transferred through lactation (Tsutsumi 325). The effect of BPA on the female brain was assessed by using an ERα-selective agonist called 4, 4′, 4″-(4-propyl-[1H]-pyrazole-1, 3, 5-triyl) trisphenol (PPT) as a positive control. BPA works through an ER mediated pathway and studies have established that it is an effective ligand for ERβ than ERα (Routledge 35986). The organization of sexually dimorphic areas of the hypothalamus could be highly disrupted if they were exposed to low doses of BPA at the neonatal critical period. This disruption occurring at 0-4 days of the period was hypothesized to cause a disruption which resulted in male-like pattern in exposed females. Selection of the neonatal critical period in the rat models was essential as it coincides with the second trimester in humans (Bayer 100). Moreover it presents the most sensitive period in rats’ hypothalamus development (Simerly, 507). The hypothalamus region selected was ER-rich and showed sexual dimorphism in the number of receptors expressed between males and females. The study focused on the paraventricular nucleus (PVN), the ventrolateral (vI) subdivision of ventromedial nucleus (VMN), medial preoptic area (MPOA) and the arcuate nucleus. The PVN is the primary site of oxytocin synthesis, an important hormone in maternal, cognitive and sexual behaviors. The ventrolateral (vI) subdivision of ventromedial nucleus (VMN) is vital in regulation of female sexual behavior (McCarthy, 91). This area is sexually dimorphic with males possessing high numbers of serotonergic projections it receives. MPOA modulates female reproductive cycle. Polymorphism of the ER isoforms is evident in this area. Males express more ERβ than females whereas the arcuate nucleus modulates feedback regulation of female reproduction. In an effort to understand the health implication of BPA exposure to humans,’ neonatal exposure of female rats showed that BPA was able to disrupt the sex specific organization of the hypothalamus regions. These exposures increased oxytocin neurons in the PVN (Adewale 38a). BPA had no significant effects on other region studied. As compared to other regions, PVN contains a high proportion of ERβ and thus BPA may be acting via the ERβ which is highly expressed in human gestation (Weiser 309). On the effect of BPA on weight, high dose exposure (50mg/kg body weight) showed an increment of body weight at adulthood (Adewale 38a). In adipose tissues of humans, both isoforms of ER are expressed, ERα (ER1) and ERβ (ER2). Thus an early exposure of BPA may predispose infants to obesity at adulthood. The effect of BPA on the reproductive system may be mediated in the hypothalamus-pituitary-gonadal (HPG) axis by interfering with estrogen receptors. Coordination of reproduction system by the HPG axis is through the release of gonadotropin-releasing hormone (GnRH). The impact of BPA on the ERβ receptors in rats is an indication of its potential to interfere with ERβ mediate pathways in humans. This suggestion may be supported by the evidence that ERβ is highly expressed in human gestation period (Weiser 309). Metabolism of BPA will influences its estrogenicity and this may differ in rats and humans. ELsby et al (103) undertook a study to compare the effect of human and rat liver microsome on estrogenicity of BPA. This study was vital in providing a rationale for continued use of rats in testing BPA effects in humans since BPA has low activity in vitro and shows strong estrogenic activity in vivo (Elsby 103). This test employed immature female rat liver microsome since they are used to predict estrogenicity in humans. The route of administration of BPA is a contributory factor in determining the uterotrophic activity of BPA and therefore will affect the prediction made to humans. In essence oral route may require high doses to yield uterotrophic response. These large doses administered orally are due to the glucuronidation due to first-pass metabolism (Pottenger 5). However, in rats test despite the large doses required to cause uterotrophic doses, oral route provides the most likely route which humans are exposed to BPA. Uterotrophic assay to predict effect of BPA on humans may be compromised since BPA glucuronidation rate may vary between human and rats’ tissues since immature female rats are used. In another study by Kubo et al (345), they sought to determine the effect of low exposure BPA (below tolerable daily intake [TDI] =50µg/kg per day) on sexual differentiation of rats’ brain and consequently their behavior. Offspring were exposed to BPA at the critical stage of development i.e. fetal and suckling periods. Since BPA has been reported in human fetus (Brock 323), the test in rats sought to gain more insight on the effect of this endocrine disruptor. Previous studies have found that BPA increases the uterus weight and also causes prolactin release in rodents (Steinmetz 1780). As evident from Kubo et al (347) study low level of BPA below TDI was able to influence brain structure and behavior with no effect on reproductive system. Exposure of BPA even at levels below TDI disrupted normal sexual differentiation. Therefore, despite the TDI for BPA being regarded as safe, a reassessment of its effect on other body systems such as CNS is important. This test in rats may warrants further such test on humans since humans are exposed to a range of endocrine disrupters and their summed up effect may portend adverse impairment of brain function and behavior. Biochemical and molecular mechanisms are involved in the formation of memory in specific brain regions. However memory formation may b susceptible to interference after learning. These interferences may be generated from external or internal factors. BPA may be a potential candidate in interfering with memory following early exposure in fetus development. Goncalves et al (195) investigated the interference of BPA with the memory in rats. The experiment was done for short term memory (STM) and long term memory (LTM) and included inhibitory avoidance test (IAT), object recognition, open field test, Morris Water Maze (MWM). There were varying results on STM and LST despite these functions being controlled by different pathways suggesting common pathways for these two functions of the brain may exist (Cammarota 199) and BPA exposure may possibly have affected more than one pathway. Endocrine and nervous system usually interact in homeostasis. Rapid changes occur during the prenatal and postnatal stages and may be targeted by endocrine disruptors. Loss of sexual dimorphism following BPA exposure during breastfeeding was evident in this study. This dimorphism was characterized by demasculinization in males and defemenization. Various neurodevelopmental changes do occur at the lactation stage such as differentiation, functional organization and myelination and BPA may target one of these processes to affect memory and behavioral changes in rats. Loss of memory and behavioral changes may be some of the negative impact associated with BPA exposure at early development, fetal and postnatal development. Anxiety and depression are known estrogen-sensitive parameters; however spatial learning is dependent on the androgen receptors (Jones and Watson 605). Jones and Watson (605) sought to investigate how BPA may alter sexually-dimorphic systems especially the sex differences in cognitive and affective domains. One such test carried was the Elevated Maze Plus (EPM). EPM exploits the natural aversion to open spaces where an elevated platform with a central hub from which four arms emanate with two of the arms enclosed by a surrounding wall. According to Rodgers and Dalvi (801) heightened anxiety will be observed if the rats tend to increasingly hide in the closed arms while lower anxiety is when there is increased time spent on the open arms. In vitro studies have reported that BPA antagonizes androgen receptors (AR) however in vivo effects of BPA on AR has been disputed (Sohoni and Sumpter 327: National Toxicology Program II). The study with rats also sought to clear the ambiguity which persists on the effect of BPA as an AR antagonist in vivo and in vitro. The effect of BPA was assessed by examining developing male and female rats after treatment with different does of BPA. Evaluation of behavior of the rats following exposure to BPA was done in three model groups. Depression was evaluated by the Forced Swim Test, anxiety with Elevated Plus Maze (EPM), while spatial cognition was by Morris Water Maze (MWM). The low dose administered in this study to assess the physiological and behavioral patterns which are sexually dimorphic in rats showed BPA administration in low doses at perinatal stage had a non-monotonic effect. Demasculinization was evident in males as was the reduction of anxiety in females both of which are estrogenic related parameters. In relating these studies to humans BPA was administered throughout the perinatal stage. Anxiety as a measure of sex differences is thought to be influenced by ERβ (Imwalle 158). Previous studies by Matthew et al (149), have established that BPA acts ERβ in vitro and thus may influence the normal development of ERβ-mediated pathways. Since this study relied on administering BPA at prenatal stage, it is therefore plausible that maternal-associated BPA intake has the potential to influence the normal development of behaviors such as anxiety and depression in both sexes. This effect may even alter the normal sex differences existing in such behaviors. This study in rats raises concern over the existence of BPA contamination in the environment and its effect on fetal development n humans. The rats were exposed to only BPA, but it is possible that in the environment there are many types of estrogen disruptors and their combined effect on fetal development may be greater than this study found. In conclusion, endocrine disruptors such as BPA exist in the environment and exposure to these chemicals is prevalent as seen in the discussed studies. These compounds have been mentioned in literature as possible endocrine disruptors and may play roles in malformation evident in humans. However humans may not provide the perfect models for testing the roles of EDCs on reproductive development but rats may provide perfect models for such studies. This is possible due to their short lifetime as compared to non-human primates such as chimpanzee and their ease of handling. Thus, as evident from a host of literature, tests on BPA effects have been carried on rats with a further exploration of the results in humans. Humans and rats may be physically different but the physiological and anatomical features are significantly similar. Though the gestation periods may differ, the physiological environment shared in the fetus of rats and humans may the same and thus rats provide the best animal model for studying the effect of BPA on humans. Therefore given the breadth of information gathered on BPA and other ECDs from studies on rats it is thus beyond doubts that test of BPA in rats provide sufficient information on the various effects of BPA. Employing such tests on humans may be expensive, tedious and may present legal and ethical challenges. Works Cited Adewaleb, H.B., Jefferson, W.N., Newbold, R.R., and Heather B. 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