Cancer Res Treat.  2018 Jan;50(1):111-117. 10.4143/crt.2017.001.

Proteomic Biomarkers for Bisphenol A–Early Exposure and Women’s Thyroid Cancer

• Lee HS
• Kang Y
• Tae K
• Bae GU
• Park JY
• Cho YH
• Yang M

• KMID: 2403480
• DOI: http://doi.org/10.4143/crt.2017.001

Abstract

PURPOSE
For the target treatment and prevention of women's increased thyroid cancer, we focused on risks of environmental exposure to endocrine disrupting chemicals, particularly bisphenol A (BPA), and its high susceptible exposure-timing, particularly early exposure in lives.
MATERIALS AND METHODS
Female ICR mice were exposed to BPA in utero and in early life (15, 75, and 300 mg/L of drinking water via pregnant mice and lactation). We identified BPA-responsive proteins in mice thyroid by two-dimensional gel electrophoresis, image analyses, and electrospray ionization quadrupole time-of-flight mass spectrometry. We further analyzed expression of the BPA-responsive proteins in women thyroid cancer patients (n=28).
RESULTS
We found the altered 17 proteins in BPA dose-dependent manner among the thyroid tissues of offspring mice and identified nine proteins of them, including Anxa6, Atp5b, Hspa5, and Vcp, etc. In addition, we observed the positive association between blood BPA levels and mRNA expression of the ANXA6 and VCP not in normal but thyroid cancer tissues.
CONCLUSION
Our study provides ANXA6 and VCP as proteomic biomarkers for BPA-early life exposure and their potential for women's thyroid cancer.

Keyword

Bisphenol A; Endocrine disruptors; Thyroid neoplasms; Women; Maternal exposure; Proteomics; Annexin A6; Valosin-containing protein

MeSH Terms

Animals
Annexin A6
Biomarkers*
Drinking Water
Electrophoresis, Gel, Two-Dimensional
Endocrine Disruptors
Environmental Exposure
Female
Humans
Mass Spectrometry
Maternal Exposure
Mice
Mice, Inbred ICR
Proteomics
RNA, Messenger
Thyroid Gland*
Thyroid Neoplasms*
Annexin A6
Biomarkers
Drinking Water
Endocrine Disruptors
RNA, Messenger

Figure

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  Fig. 1. The 2D gel image shows 17 protein spots were altered in bisphenol A (BPA) dose-dependent manner on thyroid tissue of female offspring by prenatal exposure to BPA.

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  Fig. 2. No differences in expression of ANXA6, ATP5B, HSP5, or VCP between normal and tumor thyroid tissues in the women thyroid patients. N, normal; T, tumor.

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  Fig. 3. Distribution of blood bisphenol A (BPA) levels. Upper part of the figure shows an outlier box plot with the square in the box showing the interquartile range: median, 1.38 μg/L.

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  Fig. 4. The positive associations between blood bisphenol A (BPA) levels and gene expressions of ANXA6 or VCP in tumor rather than normal tissues among the women thyroid cancer patients. Upper blue line, VCP in tumor tissues; lower blue line, ANXA6 in tumor tissues; upper red line, VCP in normal tissue; lower red line, ANXA6 in normal tissues; N, normal; T, tumor; For the view of figure, we excluded an outlier, who had 10.32 μg/L of blood BPA by outlier test of Grubbs [19].

Reference

References

1. Lee DW, Oh WY, Yi SH, Ku B, Lee MY, Cho YH, et al. Estimation of bisphenol A: human toxicity by 3D cell culture arrays, high throughput alternatives to animal tests. Toxicol Lett. 2016; 259:87–94.

2. Yi B, Kim C, Yang M. Biological monitoring of bisphenol A with HLPC/FLD and LC/MS/MS assays. J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878:2606–10.

3. Ghotbaddini M, Powell JB. The AhR ligand, TCDD, regulates androgen receptor activity differently in androgen-sensitive versus castration-resistant human prostate cancer cells. Int J Environ Res Public Health. 2015; 12:7506–18.

4. Andrianou XD, Gangler S, Piciu A, Charisiadis P, Zira C, Aristidou K, et al. Human exposures to bisphenol A, bisphenol F and chlorinated bisphenol A derivatives and thyroid function. PLoS One. 2016; 11:e0155237.

5. Andra SS, Makris KC. Thyroid disrupting chemicals in plastic additives and thyroid health. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2012; 30:107–51.

6. Yu GP, Li JC, Branovan D, McCormick S, Schantz SP. Thyroid cancer incidence and survival in the national cancer institute surveillance, epidemiology, and end results race/ethnicity groups. Thyroid. 2010; 20:465–73.

7. Lee S, Lee YY, Yoon HJ, Choi E, Suh M, Park B, et al. Responses to overdiagnosis in thyroid cancer screening among Korean women. Cancer Res Treat. 2016; 48:883–91.

8. Bae JM. Overdiagnosis: epidemiologic concepts and estimation. Epidemiol Health. 2015; 37:e2015004.

9. Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol. 2013; 2013:965212.

10. Caini S, Gibelli B, Palli D, Saieva C, Ruscica M, Gandini S. Menstrual and reproductive history and use of exogenous sex hormones and risk of thyroid cancer among women: a meta-analysis of prospective studies. Cancer Causes Control. 2015; 26:511–8.

11. Oh CM, Jung KW, Won YJ, Shin A, Kong HJ, Lee JS. Age-period-cohort analysis of thyroid cancer incidence in Korea. Cancer Res Treat. 2015; 47:362–9.

12. Prins GS, Tang WY, Belmonte J, Ho SM. Perinatal exposure to oestradiol and bisphenol A alters the prostate epigenome and increases susceptibility to carcinogenesis. Basic Clin Pharmacol Toxicol. 2008; 102:134–8.

13. Yang M, Kim SY, Chang SS, Lee IS, Kawamoto T. Urinary concentrations of bisphenol A in relation to biomarkers of sensitivity and effect and endocrine-related health effects. Environ Mol Mutagen. 2006; 47:571–8.

14. Kim M, Bae M, Na H, Yang M. Environmental toxicants-induced epigenetic alterations and their reversers. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2012; 30:323–67.

15. Uauy R, Kain J, Corvalan C. How can the Developmental Origins of Health and Disease (DOHaD) hypothesis contribute to improving health in developing countries? Am J Clin Nutr. 2011; 94(6 Suppl):1759S–64S.

16. Feinberg AP, Fallin MD. Epigenetics at the crossroads of genes and the environment. JAMA. 2015; 314:1129–30.

17. Lee HS, Pyo MY, Yang M. Set, a putative oncogene, as a biomarker for prenatal exposure to bisphenol A. Asian Pac J Cancer Prev. 2012; 13:2711–5.

18. Garcia-Arevalo M, Alonso-Magdalena P, Servitja JM, Boronat-Belda T, Merino B, Villar-Pazos S, et al. Maternal exposure to bisphenol-A during pregnancy increases pancreatic beta-cell growth during early life in male mice offspring. Endocrinology. 2016; 157:4158–71.

19. Analytical Methods Committee. Using the Grubbs and Cochran tests to identify outliers. Anal Methods. 2015; 7:7948–50.

20. Rahman MS, Kwon WS, Yoon SJ, Park YJ, Ryu BY, Pang MG. A novel approach to assessing bisphenol-A hazards using an in vitro model system. BMC Genomics. 2016; 17:577.

21. Yang M, Lee HS, Pyo MY. Proteomic biomarkers for prenatal bisphenol A-exposure in mouse immune organs. Environ Mol Mutagen. 2008; 49:368–73.

22. Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A. 2007; 104:13056–61.

23. Pozo K, Castro-Rivera E, Tan C, Plattner F, Schwach G, Siegl V, et al. The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell. 2013; 24:499–511.

24. Lomnytska MI, Becker S, Gemoll T, Lundgren C, Habermann J, Olsson A, et al. Impact of genomic stability on protein expression in endometrioid endometrial cancer. Br J Cancer. 2012; 106:1297–305.

25. Sakwe AM, Koumangoye R, Guillory B, Ochieng J. Annexin A6 contributes to the invasiveness of breast carcinoma cells by influencing the organization and localization of functional focal adhesions. Exp Cell Res. 2011; 317:823–37.

26. Vila de Muga S, Timpson P, Cubells L, Evans R, Hayes TE, Rentero C, et al. Annexin A6 inhibits Ras signalling in breast cancer cells. Oncogene. 2009; 28:363–77.

27. Lorenz S, Eszlinger M, Paschke R, Aust G, Weick M, Fuhrer D, et al. Calcium signaling of thyrocytes is modulated by TSH through calcium binding protein expression. Biochim Biophys Acta. 2010; 1803:352–60.

28. Xiong Q, Zhan S, Zhang N, Ge W, Wang T. Protein profiling of papillary thyroid carcinoma with and without lymph node metastasis: a proteomic study. Int J Clin Exp Pathol. 2016; 9:3057–69.

29. Meyer H, Bug M, Bremer S. Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol. 2012; 14:117–23.

30. Chapman E, Maksim N, de la Cruz F, La Clair JJ. Inhibitors of the AAA+ chaperone p97. Molecules. 2015; 20:3027–49.