Professional Documents
Culture Documents
Anhad Brar BPA Paper
Anhad Brar BPA Paper
Anhad Brar BPA Paper
Dr. Sotckman
Biochemistry
11/29/2017
Plastics have improved the quality of our life while presenting an overwhelming cost.
However, this price is not monetary; it is a cost on the health of humanity. Most plastics that are
used today are polycarbonate plastics. These polycarbonate plastics are used in packaging of
food, water, and other essential supplies. However, polycarbonate plastics have all been made
with Bisphenol-A, or BPA1. Unfortunately, BPA is an endocrine disruptor and contains harmful
estrogenic properties2. Other information regarding BPA include its size; BPA is 53kDa3.
Yet, not only is BPA found in plastics, it is also found in epoxy resins (chemicals that are
used to coat metals and water supply pipes). From water bottles, plastic wraps, and essential
medical devices, these devices all have BPA. In general, BPA enters the human body through
one’s diet because food products that come in contact with plastics may have BPA in them4.
The first cries against BPA began in 2008 when the Canadian Government labeled BPA as a
toxin. Ever since then there have been numerous outcries against the impact of plastic on
society5. However, the question must be asked. Are these concerns biochemically valid?
As BPA is known for targeting the endocrine system, there are several cases of BPA
induced errors in reproduction and embryonic development. The most prevalent targets of the
BPA molecule are the two estrogen receptors, ERα and ERβ--ERα has a kDa of 66 while ERβ
has a kDa of 556. Under normal conditions, ERs are able to be regulated by 17β-estradiol (E2),
a small molecule that is only 272.38 Da. The interaction of ERα and ERβ with E2 allows for
gene transcription. Furthermore, the most important domain of the ERs is the C-terminal ligand-
binding domain (LBD). In fact, it is at the LBD where most hormone binding takes place7. It is at
these locations and with these biomolecules where BPA will be able to cause the most harm.
Bisphenol A is able to simulate the activation ability of ER. More specifically, it is more
effective at simulating ERβ; when bound to the ERβ receptor, it has 80% activity rather than the
60% activity on ERα. Furthermore, Bisphenol A is able to bind so effectively to the ERs because
it can bind to the N-terminal ABs of the ER. Without this N-terminal location, bisphenol A suffers
from reduced transcriptional activity. Unlike E2, Bisphenol A needs the ABs of the N-terminal in
Nuclear hormone receptors (NR) also assist with the binding of BPA. The estrogen
receptors and ligand binding domains have 12 alpha helices. It is the BPA’s ability to shift the
equilibrium constant away from the receptors. This equilibrium shift also causes the 12th alpha
helix to lose its mobility as the equilibrium shifts to the active conformation with BPA. In fact, the
12th alpha helix is unable to recover from this mobility loss because BPA acts as an antagonist
on this function. Furthermore, as an antagonist no coactivators are able to bind to the ligand
This alteration of the alpha helix is the result of BPA alteration. BPA is able to weaken
the bonds and complexes on the ER. Furthermore, BPA is able to disrupt the hydroxyl moieties
with the complexes that form on the ER. This absence of interactions forces the molecule to
undergo an unfavorable conformation, specifically against alpha helix 3 and 11. Normally, L5S5
would hold both helices together with its van der waal forces. Unfortunately, when BPA binds to
the ER it cannot bind with the L5S5. This inability to interact forces L5S5 to dynamically adapts
ERα. On the right structure, BPA is bound to the ERα. Both E2 and BPA are capable of binding
to the same structure. When E2 is bound, the structure is stable and does not have any extreme
bends in its conformation. However, the bends on the BPA structure, not only slightly change
the conformation but also stretch out the range in which the hydrogen bonds interact. The BPA
bends the R394 and the E353. However, these bends are not as extreme as the H524 bend.
H524 has to change its positioning completely in order to have an interaction with the hydroxyl
on BPA7. This unfavorable conformation makes it hard for the structure to maintain viable
flexibility and weakens the interactions on the ERα. The reason why this shape occurs is that
while BPA and E2 both have two hydroxyl groups on the opposite ends of their molecules, only
E2 has a continuous ring structure. The phenol rings on BPA are separated by a quaternary
carbon. Thus, BPA is able to bind to the estrogen receptors, but its unfamiliar shape causes
structural damage.
It is the combination of these biochemical interactions that allow BPA to interfere with
estrogen receptors in most organisms. Thus by modifying the structures of the estrogen
receptors, BPA can disrupt development, metabolism, and most importantly reproduction.
However, they are only able to affect the cells of certain tissues more than others because they
are selective ER modulators. Fortunately, this means that BPA will not affect every cell in the
body and that research can be done to find and treat the cells with such exposure7. However on
the other hand, expelling this chemical is not a simple feat. A study gave several volunteers
deuterium labeled-BPA and tracked their urine and blood for 42 hours. The deuterium urine’s
half life to be expelled from the body was calculated, and it was determined that BPA has a half
life of 5.4 hours. After several more trials it was determined that 76% of the BPA in one’s body
can be expelled in 5 hours8. As a result, purging one from the estrogen interfering effects of
BPA is possible.
Normally the binding of the estrogen 17β-estradiol with the estrogen receptors of ERα
and ERβ are responsible for the maintenance and development of bones, mammary glands,
bones, and the uterus7. Normally, ERs are generally inactive. When bound the ER initials
transcriptional activation. Ligands bind to the hormone binding domain on the estrogen receptor
and cause a conformational shift on the 12 alpha helices on the ER. This shift releases a novel
activation function that allows ER to dissociate from its chaperones and begins to act as a
transcription factor on the DNA9. In general, ERs tend to bind to enhancer elements in DNA and
are able to find those elements with proteins such as FOXA1, GATA3, PBX1 and AP2γ10. These
enhancer elements thus regulate the various functions, such as the maintenance and growth of
the mammary gland. Unfortunately, research has yet to yield any significant data on the specific
However, when BPA binds to an ER it not only activates it but also able to cause
adverse effects to embryonic development as well as cause obesity and other functional issues
with an organism's metabolism7. These adverse effects are brought on by the disruptive nature
that BPA imposes on the estrogen receptors. As said before, BPA interrupts the hydroxyl moties
on 17β-estradiol. Adding that phenomena with BPA’s ability to weaken the bonds on ER, BPA is
able to bring extreme harm to the body with its disruptive properties.
The complex between Bisphenol A and the ERs contain various small molecules,
ligands, modified residues, and proteins. The most prevalent ligands are 4,4'-PROPANE-2,2-
for this complex is S-hydroxycysteine - L-cysteine sulfenic acid. Primarily, the secondary
structure of the estrogen receptor will remain as an alpha helix. This complex contains 251
residues2.
The main struggle with BPA is that despite the deleterious alteration it causes to the
estrogen receptors, the molecule serves as an essential utility in society. It allows for plastics to
maintain a malleable shape; this allows companies to manipulate it to serve and package food
and water across the globe. This is because when BPA is polymerized with each other it forms
the hard plastic known as polycarbonate. Ever since 1957 when this process was discovered,
the polycarbonate plastics have taken over and replaced previous uses of metals and glass.
However in 1971, a study was conducted to determine if BPA was linked with causing
cancer. However no link to leukemia was found with BPA. Thus, the plastic industry grew. That
all changed in 1993, when researches in Stanford university reported that the BPA used in their
flasks had bined to the estrogen receptors in yeast. Following this discovery, in 1996 the Food
and Quality act was passed. However, as plastics had become massive industry in the US the
EPA had difficulty appeasing to industry and environmentalists. This lead to a massive retesting
where a wide variety of results were found that both approve and disapprove of BPA’s safety as
well as attempts to slander the credibility of the labs in which the experiments were being
conducted in. As a result, while BPA has been confirmed as an endocrine disruptor, no new
Fortunately, awareness of BPA’s effects have permeated throughout the media. Most
blogs condemn the use of BPA in items such as bottles for babies. One media blog suggests
that instead of using water bottles, individuals should drink directly from tap water. Other
solutions include carry one’s own utensils, do not eat microwaved food, do not use cheap
containers, and avoid canned food. The biggest concern that regarding BPA that the media
paints is its risk in causing cancer as well as infertility11. These believes are validated as there is
proof from experimental treatments on test subjects that BPA causes reproductive issues.
Furthermore, there is a plethora of research that is being performed to find the link with BPA
and cancer.
I personally believe that the scientific data is valid as it has been able to withstand the
test of time. There is clear biochemical evidence that BPA can cause issues with normal
everyday function. Furthermore, BPA can get into one’s system by being overexposed to
plastics. Unfortunately, plastic has grown and developed since the 1950s and has risen in
industrial rank. Furthermore, plastics provide an essential utility to storage. Thus as most people
are used to the quality of life that plastics bring it would be extremely difficult to abandon such a
lifestyle. Even though this molecule can be purged, the global effects and conveniences of
plastics will eventually overwhelm and consume those who valiantly attempt to resist. It is not a
matter of where one exposure causes doom. One exposure in a lifetime will not cause any
permanent damage to one’s ERs. Rather it is the constant exposure based on the conveniences
There are certain biochemical tasks that must be overcome if the BPA epidemic were to
be solved. In order to make effective drugs to cancel out BPA’s influence, researchers must
isolate and identify what genes the ERs transcribe to. A potential means to understand what
genes are targeted is to place a tracer on the ERs and use the tracer to track what genes are
being bound on. Furthermore, as BPA can be excreted, there may be a way to force out all the
BPA from one’s body in order to prevent the buildup of carcinogenic materials. I am of the belief
that the best way to combat diseases and medical contaminants is through biochemical
applications in the medical field, especially because BPA and plastics are responsible for the
that the scientific community work to see if any substitute to BPA infused plastic can be made.
As this study goes on, it may also be beneficial to devise medication that can block BPA from
binding to and manipulating the endocrine receptors. If the substitute ends up having more
References
2:(2011) Crystal structure of hERa-LBD (Y537S) in complex with bisphenol-A, Protein Data
Bank 3UU7.
http://www.rcsb.org/pdb/explore/explore.do?structureId=3UU7
3: Hiroi T., Okada K., Imaoka S. Osada M., Funae Y., (2006) Bisphenol A binds to protein
disulfide isomerase and inhibits its enzymatic and hormone-binding activities, Endocrinology
147(6), 2773-2780
5: Vogel S.A., (2009) The Politics of Plastics: The Making and Unmaking of Bisphenol A
“Safety”, Am J Public Health 99, S559-2566
6: Gimeno-Martos S., Gonzáles-Arto M., Caso M., Gallego M., Cebrián-Pérez J.A., Muiño-
Blanco T., Pérez-Pé R., (2017) Steroid hormone receptors and direct effects of steroid
hormones on ram spermatozoa, Reproduction 154(4), 469-481
7: Delfose V., Grimaldi M., Pons J.L., Boulahtouf A., le Maire A., Cavilles V., Labesse G.,
Bourget W., Balaguer P. (2012) Structural and mechanistic insights into bisphenols action
provide guidelines for risk assessment and discovery of bisphenol A substitutes, Proceedings of
the National Academy of Sciences of the United States of America 109(37), 14930–14935
8: Stahlhut R.W., Welshons W.V., Swan S.H., (2009) Bisphenol A Data in NHANES Suggest
Longer than Expected Half-Life, Substantial Nonfood Exposure, or Both,Environmental Health
Perspectives 117(5), 784-789
9: Maggi A.,(2011) Liganded and unliganded activation of estrogen receptor and hormone
replacement therapies, Biochimica et Biophysica Acta (BBC) 1812(8), 1054-1060
10: Carrols J.S.,(2016) Mechanisms of oestrogen receptor (ER) gene regulation in breast
cancer ,European Journal of Endocrinology 175(1), R41-R49
11: Newton P.B., (2016), What is BPA? Why is it bad for us? And how you can avoid it,1M♀,
Blog