The effect of environmental Bisphenol A exposure on breast cancer associated with obesity

https://doi.org/10.1016/j.etap.2020.103544Get rights and content

Highlights

  • BPA exposure contributes to the pathophysiology of obesity and related comorbidities.

  • ERα+ breast cancer cell growth is synergistically induced by BPA and IGF-1 in obesity.

  • BPA causes poor prognosis via obesity-inflammation-aromatase axis in breast cancer.

  • BPA increases the expression of hTERT mRNA in breast cancer cells.

  • BPA negatively correlates with telomere length in advanced stage breast cancer.

Abstract

Bisphenol A (BPA) is a widely used endocrine disrupter. Its environmental exposure is a causative factor of cell aging via decreasing telomerase activity, thus leading to shortening of telomere length. Epidemiological studies confirm positive associations between BPA exposure and the incidence of obesity and type 2 diabetes (T2DM). Increased urinary BPA levels in obese females are both significantly correlated with shorter relative telomere length and T2DM. BPA is a critically effective endocrine disrupter leading to poor prognosis via the obesity-inflammation-aromatase axis in breast cancer. Environmental BPA exposure contributes to the progression of both estrogen dependent and triple negative breast cancers. BPA is a positive regulator of human telomerase reverse transcriptase (hTERT) and it increases the expression of hTERT mRNA in breast cancer cells. BPA exposure can lead to tamoxifen resistance. Among patients treated with chemotherapy, those with persistent high telomerase activity due to BPA are at higher risk of death.

Introduction

Bisphenol A (BPA) is an industrial chemical that acts as an environmental endocrine disrupter with estrogenic activity. It is widely used to make consumer products, including certain plastics; like polycarbonate, epoxy resin, as well as thermal paper, and additionally BPA can leach from dental sealants (Arenholt-Bindslev et al., 1999; Legeay and Faure, 2017; Sajiki and Yonekubo, 2003; Sonavane and Gassman, 2019). Chronic BPA exposure has been shown to be connected with an increased rate of various age-related diseases. Growing evidences indicate that the induction of reactive oxygen species (ROS) by BPA is the main driving factor of its toxicity and carcinogenic potential. Furthermore, as the consequence of BPA exposure, oxidative stress is induced and this leads to the expedition of the aging process (Rochester, 2013; Seachrist et al., 2016; Tan et al., 2015). Numerous clinical studies revealed that shorter telomere length and decreased telomerase activity are associated with age-related disorders and premature death. The environmental exposures like BPA appear to be causative factors that promote cell aging mechanisms, mainly by decreasing telomerase activity and leading to telomere length shortening and cell senescence. Since telomerase activity is a dynamic process, it is thought to be an essential alterable determinant in mediating environmental and lifestyle factors (Epel, 2009; Lin et al., 2010). Thus, without a functional telomerase, a cell undergoing cell division will have progressive telomere shortening. This leads to the telomere-dependent replicative senescence and disruption of the division capacity of the cell so that mitosis halts when a “critically” short telomere length is reached (Hallows et al., 2012). Telomere linked cellular senescence can further be a contributing factor in age-related diseases. Thus, proliferative senescence occurs with the accompanying evidence of telomere shortening as a hallmark of oxidative stress and related diseases. It is thought that slowing down the rate of telomere shortening could slow down the human aging process. (Babizhayev et al., 2014). BPA suppresses the activity of telomerase, while increasing DNA damage frequency. Indeed, epidemiological studies put forward the link between BPA exposure and the risks of obesity, type 2 diabetes mellitus (T2DM) and breast cancer (Herz et al., 2017; Hwang et al., 2018; Kim et al., 2017; Legeay and Faure, 2017). This review discusses the body of literature that highlights the adverse effects of environmental BPA exposure and telomere shortening on breast cancer patients, who suffer from obesity and type 2 diabetes.

Section snippets

BPA and obesity

Accumulating data have demonstrated that increased BPA exposure is a statistically significant risk factor for developing obesity. Mechanistically, BPA induces T2DM, adipogenesis, and adipose tissue inflammation, contributing to the pathophysiology of obesity (Legeay and Faure, 2017) (Fig. 1A). In this respect, exposure to BPA induces the proliferation and differentiation of adipocytes, as well as boosting their capacity for lipid storage (Desai et al., 2018). Although there is no direct

Type 2 diabetes and BPA

BPA contributes to the rising epidemics of obesity and T2D (Casals-Casas and Desvergne, 2011). In 2017 there were 451 million (age 18–99 years) individuals with the diabetes diagnosis worldwide. This is expected to expand to 693 million by 2045. It is estimated that almost half of all the world’s population (49.7 %) is living with diabetes but undiagnosed (Cho et al., 2018). Fourteen of the 16 studies, which cover a total of 41,320 subjects, showed that BPA exposure is positively correlated

Breast cancer and BPA

Breast cancer is the second most prevalent fatal cancer among women. Around 15 % of patients with breast cancer develop metastatic disease, and distant metastases are attributed to the 90 % of breast cancer-associated deaths (Weigelt et al., 2005). A significantly stronger correlation between increased BMI and higher breast cancer incidence was shown (Wang et al., 2016). Reviewing 79 out of 82 follow-up studies evidently demonstrated that, among the breast cancer survivors, greater BMI is

BPA and insulin-like growth factor

The Insulin/Insulin receptor signal system is both responsible for glucose homeostasis and functions as a cellular growth factor. In comparison to normal breast tissue, breast cancer cells express higher amount of the insulin receptor and have a greater susceptibility to insulin action. The insulin receptor expression grade of the tumour correlates positively with tumour size, histological properties, and the estrogen receptor content (Frittitta et al., 1993; Papa et al., 1990). Although

Conclusion and perspectives

Scientists and the public have growing concerns about BPA exposure due to the potential adverse effects of such industrial chemicals in the environment. Breast cancer and obesity are major health problems worldwide, and obesity absolutely increases the risk of this malignancy, whereas there is no direct evidence that BPA exposure causes obesity and related breast cancer. However, inadvertent environmental exposure to BPA may result in obesity-related alterations, such as cellular senescence,

Conflict of Interest

The authors declare no conflict of interest.

CRediT authorship contribution statement

Ayse Basak Engin: Writing - original draft. Atilla Engin: Writing - review & editing.

Declaration of Competing Interest

The authors report no declarations of interest.

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