Essay: Bisphenol A – BPA

Bisphenol A, also known as BPA, is a ubiquitous environmental toxicant. BPA is a polymerizing agent that is commonly found in items such as plastics, store receipts, dental adhesive, and lining of beverage and food cans.3 Six billion pounds per year are produced worldwide, which is prevalent in aquatic life as well.4 The Environmental Protection Agency was granted the authority to require testing, reporting and restrictions for manufacturing companies by Congress when the Toxic Substance Act was passed in 1976. Since this, science and the law has been working together to safeguard the public from the negative effects due to chemical exposures. The Agency for Toxic Substance and Disease Registry (ATSDR) was formed by congress as part of the Comprehensive Environmental response in 1980. The ATSDR is a public health agency, that is based off of scientific studies of these dangerous chemical substances and the effects they have on health. Several communities are worked with in conjunction to the ATSDR in order to keep them out of harm’s way. In the studies conducted the data collected showed essential information about the health effects BPA has. In 2014, there was a Children’s Health Exposure Analysis Resource (CHEAR) that allowed the effects the environment has on children’s health to be observed.2 The EPA has provided information of immediate exposure to toxicants and their enduring health effects to human health through model organisms. BPA is dangerous because when exposed to extreme environments (i.e. Heat, acidic or basic), the ester bond links in BPA go through hydrolysis which enables a monomer to be released.3 BPA has structural and functional resemblance to estrogen (Fig. 1), specifically 17 beta estradiol (E2) as well as, alpha and beta estrogen receptors.7 Due to the resemblance, it has shown to affect the reproductive system in both sexes disrupting gene expression in embryos as well as endocrine pathways, semen quality, and fecundity/infertility. Effects of BPA’s presence can be seen through low dose exposure, when there is high exposure the reactions are inhibited therefore no response is seen.3 Due to the increase in exposure we have of BPA, there has been in infertility. Many studies have been trying to prove what exactly does our environment have to deal with fecundity. Exposure to BPA is so common that it is impossible to not be affected by it. Mice, sea urchin, nematodes, zebrafish, and even humans have had numerous case-studies done to observe the way the exposure affects them as well as what is the relation between BPA and infertility.
Due to all the speculation of BPA and its effect on human health many questions came about. Different types of exposures such as in early stages of life, low doses, long term, and the exposure to several different toxicants and their effects were all questioned. These experiments have all of these questions in common along with one goal in mind. What exactly is the effect that BPA has on human health?
One question that is most intriguing is, what is happening at a cellular level? Sometimes we are able to see the results of situations at a cellular level meanwhile others may not be as conspicuous so they are less likely to be indicated. BPA has effected humans at a cellular level which is shown in this specific experiment with fish. Inherited chromosomes (maternal or paternal) express imprinted genes in at least one non- sex cell or extraembryonic organ (outside the embryo). Normal utero development needs the correct allele-specific expression (DNA methylation and chromatin composition) of imprinted genes in the embryo and placenta. A single hit to genes by an endocrine disruptor results in critical after-effects in health and development due to the fact that imprinted genes are functionally haploid.
Marine life is affected by BPA exposure as much as we are, due to the fact that our wastes ends up in the ocean causing the exposure to BPA on aquatic life.
Rainbow Trout (Oncorhynchus mykiss) is an ecologically and economically important species due to commercial and predator purposes. Rainbow trout showed how BPA exposure to rainbow trout eggs caused molecular reprogramming of the liver in two generations. Abnormal development, reproductive failure and disrupted metabolism are induced by chronic early and regular development exposure to BPA.12 Long term developmental issues are due to the fact that BPA is maternally transferred in fish12. In one experiment, the hypothesis BPA accumulation in rainbow trout eggs precedes effects that are long-term to be carried into following generations. Growth and changes of more than two generations were monitored from BPA containing eggs (specifically in liver transcriptome, using RNA-sequencing).12In result the eggs growth is impacted at certain stages due to BPA exposure in eggs (Fig.4). Although there was a reduction in growth, later on in their lifespan there was a catch-up period for them. This period allowed the trout to catch up on the growth scale which proved to be the BPA disrupting some sort of developmental programming. The results also proved that the second generation were BPA free(still raised from BPA-treated eggs) however, in the beginning stages of life and period of growth showed reduced growth and lipid buildup in the liver in older individuals (Fig. 3). The lowest BPA concentration which represents our environmental exposure proved to be the most harmful, which affected oocyte growth and maturation. As well as affecting the signals that deal with the last phase of oogenesis.12 The higher BPA concentration showed physical changes such as mass difference. Due to the reduced growth it suggests that BPA exposure to eggs impairs protein synthesis because it disrupts the growth hormone factor in the early development of the fish.
Zebrafish (Danio Rerio) are model fish due to their homology of their genome being 70% similar to humans and the fact that they are being equally exposed, if not more to BPA due to our waste that is contaminating the aquatic environment.1 Therefore, In order to understand biological, chemical and genetic structures that are effected there is a need for toxin observation and it’s costs due to exposure. Fish, wildlife and ourselves have been greatly affected by toxins found the environment. Water pollution has been suspected to be the cause of damage to the reproductive health, lifespan, embryonic and larval development of fish populations.2 In one experiment the dose amount vs. effects was tested, the low dose of BPA exposure being 5 μg/L, the intermediate dose being 10 μg/L, and the high BPA dose being 20 μg/L. The goal was to determine which of these concentrations (which are common in the environment today) would have an effect on the reproductive system. The results of the experiment showed a blocked ovulation period on the eighth day of the BPA treatment in fish on the low BPA concentration. The fish that received the intermediate(10 μg/L) BPA concentration and high concentration(20 μg/L) did not show significant changes compared to the control fish with no BPA concentration. The low concentration of BPA (5 μg/L) significantly affected estrogen receptor 1 and estrogen receptor 2a yet not the other genes involved in oocyte growth such as; estrogen receptor 2b, steroidogenic acute regulatory protein, cytochrome, and follicle stimulating hormone receptor (Fig.4). This experiments conclusion was in line with the rainbow trout’s conclusion, the lowest concentration of BPA proved to be the most harmful. This affected the D.rerio maturation and oocyte growth.
In another experiment zebrafish were used to detect toxicants (including BPA) and to discover the health related effects exposure has to humans. Zebrafish are not only great to experiment on because of their genome is similar to humans but their embryo and larvae are transparent which allows observation to see if there are any malformations in early stages. Zebrafish were treated by putting BPA (powder form) mixed in with their fish food. Fish that were sexually mature (usually 3 months) were used and marked by fluorescent dye. Fish were divided into 3 groups of 8 fish resulting in a total of 24 fish treated. Each group was separated into its own aquarium and fed with food that could or could not be BPA treated, twice a day for 6 months. To test the fertility of the fish they were mated with untreated fish(Fig 9). Offspring was then cultivated and observed for mutations. Some effects of the BPA food were a decrease in size of ovaries to the point they almost disappeared. Males that were tested also showed a decrease in testes size and fertility(Fig. 10). In the initial generation which automatically resulted in survival rate being lowered, an increased rate of abnormality in offspring due to the ovaries and testes retracting. The first generation appeared normal but when getting a deeper look their reproductive tissues were deformed. In the first generation there were higher percentage of sterile males. This not only showed the affect it had on women’s reproductive system but males as well. Both sexes had a significant drop in the number of infertile fish. The way the embryos were inviable were due to physical characteristics, most died due to coagulation before hatching and those who hatched had abnormalities such as spine curvature, two heads, etc. These data sets proved that the effects of BPA can last through generations, these where F2 generations being affected by the exposure F0 had.
Mice are another model figure that has been widely studied, due to their reproductive and genetic similarity to humans. BPA is an environmental endocrine disruptor (ED) which is a synthetic chemical that has resemblance toward natural hormones which affect development and fertility. Genes that are haploid undergo epigenetic resetting between generation and susceptible to environmental insults are called imprinted genes.3 The parental-specific methylation at different methylated regions are sustained in somatic cells throughout the lifespan of the individual, but reset specifically between generations in the germ line. In this experiment, epigenetic divergence caused by BPA exposure to imprinted genes was screened for. The effects of BPA on the preservation of imprinted gene expression were measured by a multiplex allele specific assay was generated. Mimicking or blocking endocrine actions are a few ways in which endocrine disruptors can affect methylation patterns and gene expression of DNA.13 It is hypothesized that the two parental chromosomes epigenetic reciprocal can be altered by hormone-like chemicals, gene expression and DNA methylation. 3,13 Measuring 39 imprinted transcripts for allele specific expression (using multiplex SNuPE) and characterization of the imprinted gene expression on mouse chromosome 7 were performed.13,3 Treated with BPA as well as a control oil were pregnant mice 8.5 to 12.5-days post conception (dpc). On the 13.5 dpc, yolk sac, placenta, head, body, heart, liver, lung, stomach, and intestines of the embryos that were treated were isolated to obtain RNA.3 When exposure to BPA specifically at different parts of development the correct expression of imprinted genes is disturbed as shown through the data. BPA at 0.02 mg exposed to fetus caused decrease sperm production (Fig. 6).
Low exposure of BPA affects certain imprinted genes, while high exposure to BPA affects other imprinted genes in “non-substantial” ways.3 In high dose studies there are effects which are not seen physically but appear due to low dose encounters of BPA , the dosage amount depends on whether the response is hindered or not.13 This is important data to conclude from the experiment because in human serum the average levels of BPA are 0.5 to 10 ng/ml 13, which are higher than the levels in mice which cause harmful effects.3
For the first time it has been shown that environmental disturbances and man-made compounds have the potential to alter genetic reprogramming events in early embryonic development. The earliest stage of human pregnancy that seems to be the most sensitive developmental window is even before a women is “clinically recognized” as pregnant therefor, to reduce the health effects exposure should be limited even before a women gets pregnant.13 Unfortunately, BPA is everywhere, to avoid exposure completely would be impossible. However, limiting your exposure can help lessen the chances of BPA induced abnormalities.
C. elegans.
The effects that BPA exposure has on the formation and development of an embryo was investigated through a specific type of nematode, C. elegans. This subject was used because of its efficient cost and short reproductive cycle as well as offspring size. In order to get the least amount of percent error you need many test subjects and the capacity to hold them and care for them properly. C. elegans can produce up to 300 eggs as well, as their size is relatively small. Constant exposure to a high concentrate of BPA throughout development has been proven to decrease fecundity.6In this experiment C. elegans had four hours of low dose (0.1 µM to 10 µM) exposure to BPA. Immediately the number of viable eggs that were laid as adults decreased, not to mention the worms that took longer to become habituated with the stimuli had exposure to BPA as embryos. This subtle neuronal function leads to the conclusion that BPA can affect behavioral changes.6 The detrimental effects due to BPA exposure in embryos were emphasized not only in reproductive defects but developmental and neuronal defects as well.
Bisphenol A exposure is harmful to fertility and development of the embryo. How severe the repercussions of Bisphenol A exposure depend on the amount of exposure. Effects of long term exposure to Bisphenol A are difficult to recognize. Meanwhile, the effects of short term exposure to Bisphenol A are more prevalent. Due to the fact that Bisphenol A is found in many of the products that we as humans use daily, it is important to come to terms of the effects. The experiments above show the effect Bisphenol A has on marine life due to its vulnerability caused by human waste polluting its entirety. Every product that we use ends up in their environment and they are effected. The other experiments with mice and C.elegans are modified because they are not as susceptible. Susceptible or not the effects of bisphenol A were conclusive, long term exposure showed that the results were hard to find, meaning they were on the cellular level. Short term exposure had effects that were visible to the eye, meaning the sexual organs were distorted or behavior differences were noticed. This is alarming because this means that we might not even be able to detect the effect BPA exposure is having on ourselves until it is too late.
Conclusion
Although there have been several experiments discussed they have all resulted in one concluding factor. Bisphenol A is effecting the reproductive system in some way; infertility, developmental, viability of offspring, and abnormal offspring. This is eye opening not only because this is not just effecting the human race but it is also effecting marine life which is an imperative source of food. BPA is effecting our water, food, and some medicinal supply by affecting marine life. If our food is being affected and we, ourselves are being effected, we are getting a double dose of exposure through our man-made products and through food. The longer the exposure is the more serious the results become. BPA exposure and the increased chances a women has to pregnancy troubles or infertility issues has been linked, giving substantial evidence as to why BPA awareness must be publicized. Not only does it affect you or your food but it can affect your future. The experiments with rainbow trout had shown that exposure to high dose of BPA will show physically an abnormality but when exposed to low dose far worse effects occur. The embryo is not viable, generations of embryos have abnormalities and infertility issues, the parent itself has an increase in infertility. These conclusions were also confirmed by the experiments done on the zebrafish. These experiments were done with BPA exposure that is found in our environment, this means that this is happening to everyone. There has been a striking increase in infertility over the past years along with the increase of these products that contain BPA. Molecularly, Genetically, and physically marine life, humans, mice, and nematodes are being effected. The results of the experiments were detected and made known because of research imagine how the exposure to BPA is effecting your body. Imagine how many unknown flags have gone unseen due to it not being a physical abnormality. It is time BPA is made aware and known not only for ourselves but for our planet. The more BPA causes infertility issues the more populations will start to decrease, the less populations we have, the more problems will occur with the food-chain. BPA does not only effect your reproductive system, there are other ways that BPA could be affecting you and other species negatively.