Thursday, October 17, 2013

Strongest Evidence Yet Between BPA and Thyroid Cancer

Hypomethylation Of Cdk5 Protein Offers Possible Causal Link Between BPA and Medullary Thyroid Cancer

SUMMARY: Over-expression of Cdk5 protein causes medullary thyroid carcinoma in rats. BPA causes hypomethylation (over-expression) of Cdk5-related genes. Could BPA exposure cause epigenetic changes that promote medullary thyroid carcinoma?

By Lewis Perdue
Copyright 2013, All rights reserved

Bisphenol A (BPA) has been suspected in many studies(1-5) of disrupting thyroid hormones.

In addition, BPA exposure in pregnant mice has been shown to induce epigenetic changes in offspring(6).

Various mechanisms have been proposed including hypomethlyation in early development, specifically, "CpG methylation also was decreased at another metastable locus, the CDK5 activator-binding protein (Cabp IAP)(7) .

This previous work with BPA as a thyroid endocrine distruptor may offer significant insight into the origins of medullary thyroid carcinoma (MTC) when viewed in light of a recent accidental discovery in Texas..


According to a study published Oct 14 in Cancer Cell(8) research at The University of Texas Southwestern's Department of Psychiatry were investigating the origins of dementia and created a transgenic mouse that over-expressed the Cdk5 protein they felt could be connected with myloid plaques.

The study, run by Dr. James Bibb, Associate Professor of Psychiatry and Neurology and Neurotherapeutics, quickly found that the mice had all developed medullary thyroid carcinoma.

According to this news release from UT Southwestern, although rare, medullary thyroid cancer is often fatal and that the causes for 75% of the cases are unknown.

"More than 20 years ago, mutations in a gene were found to cause about 25 percent of these cancers," said the UT Southwestern news release. "Genetic sequencing and screening has become an important diagnostic and prognostic tool for those families that share such mutations. But the causes for the remaining 75 percent of patients with this dangerous cancer have remained unknown and a source of frustration for endocrinologists and surgeons such as Dr. Nwariaku, also Associate Dean of Global Health.

Those causes may be epigenetic -- rather than genetic -- changes due to exposure to endocrine disruptors such as BPA


The UT Southwestern study showed that over-expression of Cdk5 resulted in MTC in the test animals. And the studies cited above demonstrate that BPA exposure results in hypomethylation (resulting in over expression) of  Cdk5 genes.

Because epigenetic hypomethylation results in overproduction of the relevant protein, this suggests a cause for the remaining 75% of  MTC that has not yielded its secrets to standard genome base-pair  sequencing and screening.

Because epigenetics could be indicated, this offers avenues for further investigation into potential compounds that may reverse the hypomethylation. It also suggests a plausible route for thyroid effects already shown with BPA exposure.

(1) Maternal Urinary Bisphenol A during Pregnancy and Maternal and Neonatal Thyroid Function in the CHAMACOS Study Jonathan Chevrier, Robert B. Gunier, Asa Bradman, Nina T. Holland, Antonia M. Calafat, Brenda Eskenazi, Kim G. HarleyEnviron Health Perspect. 2013 January; 121(1): 138–144. Published online 2012 October 4. doi: 10.1289/ehp.1205092

(2) Do Thyroid Disrupting Chemicals Influence Foetal Development during Pregnancy? Marie-Louise Hartoft-Nielsen, Malene Boas, Sofie Bliddal, Åase Krogh Rasmussen, Katharina Main, Ulla Feldt-RasmussenJ Thyroid Res. 2011; 2011: 342189. Published online 2011 September 11. doi: 10.4061/2011/342189

(3) Thyroid Disruption by Di-n-Butyl Phthalate (DBP) and Mono-n-Butyl Phthalate (MBP) in Xenopus laevis Ouxi Shen, Wei Wu, Guizhen Du, Renping Liu, Lugang Yu, Hong Sun, Xiumei Han, Yi Jiang, Wei Shi, Wei Hu, Ling Song, Yankai Xia, Shoulin Wang, Xinru WangPLoS One. 2011; 6(4): e19159. Published online 2011 April 22. doi: 10.1371/journal.pone.0019159
(4) Endocrine Disruptors and the Thyroid Gland—A Combined in Vitro and in Vivo Analysis of Potential New Biomarkers Cornelia Schmutzler, Inka Gotthardt, Peter J. Hofmann, Branislav Radovic, Gabor Kovacs, Luise Stemmler, Inga Nobis, Anja Bacinski, Birgit Mentrup, Petra Ambrugger, Annette Grüters, Ludwik K. Malendowicz, Julie Christoffel, Hubertus Jarry, Dana Seidlovà-Wuttke, Wolfgang Wuttke, Josef KöhrleEnviron Health Perspect. 2007 December; 115(Suppl 1): 77–83. Published online 2007 June 8. doi: 10.1289/ehp.9369

(5) Thyroid hormone action is disrupted by bisphenol a as an antagonist. Moriyama K, Tagami T, Akamizu T, Usui T, Saijo M, Kanamoto N, Hataya Y, Shimatsu A, Kuzuya H, Nakao K.  J Clin
Endocrinol Metab. 2002; 87:5185–5190. [PubMed: 12414890]

(6) Epigenetic Responses Following Maternal Dietary Exposure to Physiologically Relevant Levels of Bisphenol AA Olivia S. Anderson, S. Nahar, Christopher Faulk, Tamara R. Jones, Chunyang Liao, Kurunthachalam Kannan, Caren Weinhouse, Laura S. Rozek, and Dana C. Dolinoy Environ Mol Mutagen. 2012 June ; 53(5): 334–342. doi:10.1002/em.21692.
(7) Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development Dana C. Dolinoy, Dale Huang, and Randy L. Jirtle PNAS 2007 104 (32) 13056-13061; published ahead of print August 1, 2007, doi:10.1073/pnas.0703739104 
 (8) The Role of Cdk5 in Neuroendocrine Thyroid Cancer Karine Pozo, Emely Castro-Rivera, Chunfeng Tan, Florian Plattner, Gert Schwach, Veronika Siegl, Douglas Meyer, Ailan Guo, Justin Gundara, Gabriel Mettlach, Edmond Richer, Jonathan A. Guevara, Li Ning, Anjali Gupta, Guiyang Hao, Li-Huei Tsai, Xiankai Sun, Pietro Antich, Stanley Sidhu, Bruce G. Robinson, Herbert Chen, Fiemu E. Nwariaku, Roswitha Pfragner, James A. Richardson, James A. Bibb Cancer Cell - 14 October 2013 (Vol. 24, Issue 4, pp. 499-511)

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