By Daniella Gimbosh
The dangers posed by chemical compounds in various plastics have been the source of fierce debate in the scientific community, resulting in widespread concern over the exposure to humans through plastic packaging. One such chemical is Bisphenol A (BPA); BPA is a compound present in polycarbonate plastics and epoxy resins which has been observed to exert estrogenic properties, prompting its label as an endocrine-disrupting compound (Kim et al., 2015). Polycarbonate plastics are used in a large variety of packaging products, such as plastic food containers and water bottles. Epoxy resins are used in the manufacturing of coatings, such as the inside of food and beverage cans, in order to prevent the food from being contaminated with dissolved metals present in the cans (Biedermann and Grob, 1998).
More and more scientific literature is being published on the extent of plastic residues that are present in the environment, such as Hernandez et al. (2019) observing how billions of plastic microparticles and nanoparticles are released into tea from plastic teabags. Furthermore, traces of BPA have previously been detected in food, dust and a large percentage of urine samples (Cooper et al., 2011), causing major concern over its effects on human health. Such findings place an even larger importance on determining the dangers of chemicals such as BPA.
BPA is thought to be an endocrine-disrupting chemical (EDC) which exerts estrogenic properties by mimicking the actions of estrogen. EDCs can interfere with metabolic pathways and disrupt the function of estrogen-receptors (ERs) by binding to them (Park and Choi, 2014). Moreover, although there is still controversy surrounding the effects that BPA has on human health, it has previously been linked to health risks such as cancers, with animal cells containing ERs, such as ovarian and breast cells, showing susceptibility to tumour formation (Soto and Sonnenschein, 2010).
In addition to links to cancers such as estrogen receptor-positive breast cancer, it has been suggested that BPA may have adverse effects on foetal and infant prostate glands, with multiple studies suggesting that exposure to low levels of BPA during development may increase the risk of lesions and malignancies of the prostate later on in life (Ho and Tam, 2017). Different research shows a possible effects of BPA on the brain and behaviour of children, with some studies suggesting that prenatal exposure to BPA may cause white matter alterations in brain structure, leading to internalizing behavioural problems in children such as anxiety and depression (Grohs et al., 2019).
Many experiments have investigated the effects of BPA on levels of the gene Cyclin-D1 in various cells. Elevated Cyclin-D1 levels have been observed in various cancers (Musgrove et al., 1994), prompting multiple studies to investigate whether BPA causes an increase in Cyclin-D1 expression and cell viability in order to help consolidate current knowledge of BPA action through ER-dependent pathways (Zhao et al., 2019).
One such widely accepted theory is that Cyclin-D1 may disrupt the G1 cell cycle checkpoint that would otherwise initiate cell cycle delay or apoptosis. Hence, cell cycle progression is increased with higher levels of Cyclin-D1 (Resnitzky and Reed, 1995). However, BPA effect on Cyclin-D1 levels remains unclear; various experiments have seen BPA cause an increase in Cyclin-D1 levels in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells (Lee et al., 2012), whereas other scientific literature has contrastingly indicated BPA-induced cell cycle delay (Can et al., 2005). Such discrepancies in a myriad of experimental data explain the controversy surrounding BPA use in polycarbonate plastics and packaging; true clarity, with regards to the chemical effects of BPA in human cells, remains to be achieved.
Another reason why the implications and effects of BPA on the human body are still very much debated, is due to the fact that the pathway by which BPA acts to cause harm to the human body is still undetermined. Although multiple studies investigating the link between BPA and breast cancer have proposed Cyclin-D1 control of cell cycle progression through ER-dependent pathways (Sabbah et al., 1999), other literature has put forward the theory that Cyclin-D1 is affected through pathways involving androgen receptors instead (Lanzino et al., 2010; Bilancio et al., 2017). Thus, determining the exact pathway through which BPA acts to cause adverse effects in the body is of paramount importance.
It is vital to ensure that all experiments are carried out at environmental BPA concentrations (Juncker, 2018) in order to accurately determine possible harmful effects to human health that BPA-containing plastics pose (Romagnolo et al., 2016). Additionally, even though in vitro laboratory conditions still produce limitations and not all studies have produced statistically significant results, a large amount of evidence categorically implicates BPA in causing adverse effects in human cells. Due to an abundance of scientific evidence, both the EU and the FDA have strengthened the limitations of BPA levels in plastics, completely banning its use in baby bottles and packaging for formula (Juncker, 2018). However, the implications of chemical compounds in plastics on cell proliferation suggest that the use of BPA in polycarbonate plastics should be reduced even further in order to prevent harm to human health.
Kim YS, Hwang KA, Hyun SH, Nam KH, Lee CK, Choi KC. Bisphenol A and nonylphenol have the potential to stimulate the migration of ovarian cancer cells by inducing epithelial-mesenchymal transition via an estrogen receptor dependent pathway. Chem Res Toxicol. [Online] 2015;28(4):662–671. Available from: doi:10.1021/tx500443p [Accessed: 16th Sep. 2020]
Biedermann, M. and Grob, K. (1998). Food contamination from epoxy resins and organosols used as can coatings: Analysis by gradient NPLC. Food Additives & Contaminants, [online] 15(5), pp.609–618. Available at: https://www.tandfonline.com/doi/abs/10.1080/02652039809374688 [Accessed 14th Sep. 2020]
Hernandez, L.M., Xu, E.G., Larsson, H.C.E., Tahara, R., Maisuria, V.B. and Tufenkji, N. (2019). Plastic Teabags Release Billions of Microparticles and Nanoparticles into Tea. Environmental Science & Technology, [online] 53(21), pp.12300–12310. Available at: https://pubs.acs.org/doi/10.1021/acs.est.9b02540 [Accessed 14th Sep. 2020].
Cooper JE, Kendig EL, Belcher SM. Assessment of bisphenol A released from reusable plastic, aluminium and stainless steel water bottles. Chemosphere. [Online] 2011;85(6): 943–947. Available from: doi:10.1016/j.chemosphere.2011.06.060 [Accessed: 12th Sep. 2020]
Park MA, Choi KC. Effects of 4-nonylphenol and bisphenol A on stimulation of cell growth via disruption of the transforming growth factor-β signaling pathway in ovarian cancer models. Chem Res Toxicol. [Online] 2014;27(1):119–128. Available from: doi:10.1021/tx400365z [Accessed: 17th Sep. 2020]
Soto AM, Sonnenschein C. Environmental causes of cancer: endocrine disruptors as carcinogens. Nat Rev Endocrinol. [Online] 2010;6(7):363–370. Available from: doi:10.1038/nrendo.2010.87 [Accessed: 15th Sep. 2020]
Ho, S.-M. and Tam, N.N.C. (2015). Organoid model shows effect of BPA on prostate development. Nature reviews. Urology, [online] 12(12), pp.658–659. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207209/ [Accessed 14th Sep. 2020].
Grohs, M.N., Reynolds, J.E., Liu, J., Martin, J.W., Pollock, T., Lebel, C. and Dewey, D. (2019). Prenatal maternal and childhood bisphenol a exposure and brain structure and behavior of young children. Environmental Health, [online] 18(1). Available at: https://ehjournal.biomedcentral.com/articles/10.1186/s12940-019-0528-9 [Accessed 14th Sep. 2020].
Musgrove EA, Lee CS, Buckley MF, Sutherland RL. Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. Proc Natl Acad Sci U S A. [Online] 1994;91(17):8022–8026. Available from: doi:10.1073/pnas.91.17.8022 [Accessed: 16th Sep. 2020]
Zhao Q, Howard EW, Parris AB, Ma Z, Xing Y, Yang X. Bisphenol AF promotes estrogen receptor-positive breast cancer cell proliferation through amphiregulin-mediated crosstalk with receptor tyrosine kinase signaling. PLoS One. [Online] 2019;14(5):e0216469. Available from: doi:10.1371/journal.pone.0216469 [Accessed: 20th Sep. 2020]
Resnitzky D, Reed SI. Different roles for cyclins D1 and E in regulation of the G1-to-S transition. Molecular and Cellular Biology. [Online] 1995;15(7): 3463–3469. Available from: doi:10.1128/mcb.15.7.3463 [Accessed: 18th Sep. 2020]
Lee HR, Hwang KA, Park MA, Yi BR, Jeung EB, Choi KC. Treatment with bisphenol A and methoxychlor results in the growth of human breast cancer cells and alteration of the expression of cell cycle-related genes, cyclin D1 and p21, via an estrogen receptor-dependent signaling pathway. Int J Mol Med. [Online] 2012;29(5):883–890. Available from: doi:10.3892/ijmm.2012.903 [Accessed: 12th Sep. 2020]
Can A, Semiz O, Cinar O. Bisphenol-A induces cell cycle delay and alters centrosome and spindle microtubular organization in oocytes during meiosis. MHR: Basic science of reproductive medicine. [Online] 2005;11(6): 389–396. Available from: doi:10.1093/molehr/gah179 [Accessed: 18th Sep. 2020]
Sabbah M, Courilleau D, Mester J, Redeuilh G. Estrogen induction of the cyclin D1 promoter: Involvement of a cAMP response-like element. Proceedings of the National Academy of Sciences of the United States of America. [Online] 1999;96(20): 11217–11222. Available from: doi:10.1073/pnas.96.20.11217 [Accessed: 12th Sep. 2020]
Lanzino M, Sisci D, Morelli C, et al. Inhibition of cyclin D1 expression by androgen receptor in breast cancer cells–identification of a novel androgen response element. Nucleic Acids Res. [Online] 2010;38(16):5351–5365. Available from: doi:10.1093/nar/gkq278 [Accessed: 12th Sep. 2020]
Bilancio A, Bontempo P, Di Donato M, Conte M, Giovannelli P, Altucci L, et al. Bisphenol A induces cell cycle arrest in primary and prostate cancer cells through EGFR/ERK/p53 signaling pathway activation. Oncotarget. [Online] 2017;8(70): 115620–115631. Available from: doi:10.18632/oncotarget.23360 [Accessed: 14th Sep. 2020]
Juncker J-C. COMMISSION REGULATION (EU) 2018/213 of 12 February 2018 on the use of bisphenol A in varnishes and coatings intended to come into contact with food and amending Regulation (EU) No 10/2011 as regards the use of that substance in plastic food contact materials. [Online] Europa.eu. European Union; Available from: https://eur-lex.europa.eu/eli/reg/2018/213/oj [Accessed: 14th Sep. 2020]
Romagnolo DF, Daniels KD, Grunwald JT, Ramos SA, Propper CR, Selmin OI. Epigenetics of breast cancer: modifying role of environmental and bioactive food compounds. Molecular nutrition & food research. [Online] 2016;60(6): 1310–1329. Available from: doi:10.1002/mnfr.201501063 [Accessed: 18th Sep. 2020]