Nano Active: Strongest Evidence Yet Between BPA and Thyroid Cancer

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..

ACCIDENTAL DISCOVERY

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

CAUSAL ROLE FOR BPA IN MEDULLARY THYROID CARCINOMA?

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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ABOUT THE AUTHORS

LEWIS PERDUE

I have an academic and vocational background in biology, organic chemistry, environmental science, high-energy physics and nuclear engineering.

I graduated from Cornell University with a B.S. degree in 1972.

My serious lifelong involvement with science began as a uber-geek that involved university graduate-level work as a teen. That eventually landed me as a finalist in the Westinghouse (now Intel) Science Talent Search. I also won several prizes at the 1966 International Science Fair for a propulsion engine I designed to use the solar flux for fuel.

NASA, the U.S. Air Force and the National Academy of Sciences awarded that work numerous citations. As a result, I was able to attend summer school in the Aerospace Engineering at Mississippi State University.

The next summer, I worked an internship at Westinghouse where I helped improve spectrographic test equipment and prototyped solar flux instruments for a Mars fly-by. (At least one of these I hand-crafted flew in the Mariner satellites).

During that internship, I also calibrated neutron density devices for military and civilian nuclear reactors. To the best of my knowledge, no reactors have ever melted down or malfunctioned because of this work. Of course, the military program was classified, so only the NSA knows if I blew something up.

Despite my original research in physics, I maintained my education and knowledge of biology from an early age. I was fortunate to have been mentored and tutored during my high school years by Dr. Arthur C. Guyton, professor, medical researcher and the author of the world's best-selling human physiology textbook

I majored in biology with an emphasis on Ecology, Evolution And Systematics at Cornell University's College of Agriculture and Life Sciences where I graduated with distinction in 1972.

While at Cornell, I worked full-time as a newspaper reporter, this time for the Ithaca Journal.

My A+ grades in organic chemistry and discovery of more than two dozen errors in the class textbook (primarily in quantum bonding orbitals) prompted Cornell's chemistry department to recruit me as a major in their department.

Unfortunately, I couldn't find a way to support myself except as a newspaper reporter. While I was willing to do that, the prospects for financial survival for Ph.D. work were a grim. I could study, or I could eat. Not both. And that deflected my vocational choices toward full-time writing and part-time scientist.

Over the intervening years, I've continued to stay current through careful reading of scientific journals and my study of updated textbooks particularly on quantum physics, and molecular genetics.

I've been the founder or early-stage staffer in three technology start-ups, worked as a Washington (D.C.) Correspondent, a Congressional and gubernatorial aide and taught on the faculties at Cornell and UCLA.

In 2012, I discovered that thousands of acres of California's finest vineyards are drip-irrigated with highly treated, recycled sewage water.

That discovery led me to dig deeper into compounds that are biologically active in nano and pico concentrations -- potentially Endocrine Disrupting Compounds and other chemicals of emerging concern.

This totally re-invigorated my molecular biology and organic chemistry enthusiasms, and led me to found this blog and initiate the online partnership with biologist Becca Yeamans.

Unless you have had enough already, you can click here for more.

BECCA YEAMANS

Becca L. Yeamans, is a biomedical scientist with extensive research and laboratory experience in clinical research trials in immunology and neurology. Educated in environmental sciences, she is the author of several papers in peer-reviewed journals,

She was born and raised in the Northeast Kingdom of Vermont, and also freelances as a writer specializing in the Environmental Sciences as well as the world of wine, enology, and viticulture.

She received her Bachelor of Science in Biology in 2004 from Saint Michael’s College in Colchester, Vermont and her Master of Science in Environmental Sciences (with a focus in Ecology) in 2011 from the University of Virginia in Charlottesville, Virginia.

Her undergraduate research focused on species diversity of ants and other ground-dwelling macroinvertebrates in fragmented habitats caused by human interference, with implications for using ants as potential indicators of environmental health.

This work has since led to several published articles in peer-reviewed journals.

Her graduate work at the University of Virginia resulted in her excelling in course and laboratory work throughout the disciplines of geology, atmospheric science, hydrology, and ecology.

Her strong writing and research skills led to successful grant applications to fund her Masters’ thesis, entitled “Ecological and Evolutionary Shifts in Pollen Chemistry and Their Implications for Pollinators”, which shed light on some of the important questions in the field of pollination evolutionary ecology and is a key contributor to the study of pollen nutritional quality for bees.

Her research experience extends from the Environmental Sciences to biomedical research and also clinical research. While working in a Harvard Medical School-affiliated Immunology laboratory in Boston, MA, her hard work and dedication to the world of research led to her establishment of a human-to-mouse skin transplantation model to study burn-injury; a first for the laboratory.

Her vast research experience has also included managing and administering clinical research trials in Neurology, specifically focused on symptom management and therapies in Multiple Sclerosis.

Aside from published peer-reviewed journal articles based on her past work, Becca’s passion for writing took off with the establishment of her blog, The Academic Wino.

The Academic Wino is a highly technical blog, and is dedicated to dissecting and reviewing current research in enology and viticulture, while providing insights and thoughts on the current state of research related to wine.

The articles reviewed span nearly every aspect of academia, and provide a public forum to discuss the state of research related to wine. She is also a freelance writer for several wine-related online publications, in addition to managing her own personal blog.

Becca Yeamans lives in Charlottesville, Virginia with her loving fiancé, their two dogs, Coaty the Greyhound and Crystal the Golden Retriever, as well as their cat, Cassie.

When she’s not up to her elbows in peer-reviewed scientific journals, she can be found spending time with her human and animal family at a winery, microbrewery, or up in the mountains.