At least for a fetus in utero, timing matters when thinking about the impact of the absence or presence of substances.  Moreover, the presence or absence of the dose may have long-term effects through epigenetic effects such as methylation . A new example arises from further research on children in utero during the Dutch Hunger Winter, as reported in a May 14, 2015 article in ScienceDaily. The article explains the following basis for the findings:

“Researchers at Columbia University’s Mailman School of Public Health and Leiden University in the Netherlands found that children whose mothers were malnourished at famine levels during the first 10 weeks of pregnancy had changes in DNA methylation known to suppress genes involved in growth, development, and metabolism documented at age 59. This is the first study to look at prenatal nutrition and genome-wide DNA patterns in adults exposed to severe under-nutrition at different periods of gestation. Findings are published in the International Journal of Epidemiology.

The study evaluated how famine exposure — defined as 900 calories daily or less — during the Dutch Hunger Winter of 1944-1945 affected genome-wide DNA methylation levels. The researchers also studied the impact of short-term exposure, pre-conception and post-conception. The study used blood samples of 422 individuals exposed to the famine at any time during gestation and 463 controls without prenatal famine exposure.


The findings show associations between famine exposure during weeks 1-10 of gestation and DNA changes, but not later in pregnancy. DNA methylation changes were also seen among individuals conceived at the height of the famine between March and May 1945 who were not exposed to all 10 weeks of early gestation. “The first ten weeks of gestation is a uniquely sensitive period when the blood methylome — or whole-genome DNA methylation — is especially sensitive to the prenatal environment,” said L.H. Lumey, MD, PhD, associate professor of Epidemiology at the Mailman School of Public Health, and last author. “This is the period when a woman may not even be aware that she is pregnant.”

The article is:   E. W. Tobi, R. C. Slieker, A. D. Stein, H. E. D. Suchiman, P. E. Slagboom, E. W. van Zwet, B. T. Heijmans, L. Lumey. Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome. International Journal of Epidemiology, 2015; DOI: 10.1093/ije/dyv043

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For toxic tort lawyers, a new interview of Gary Marchant provides notable insight into the major changes ahead for the future of toxic tort litigation. Gary’s background is as a Kirkland trained lawyer with a PhD in genetics and a Master’s degree in public policy. Today, Gary thrives in and leads the way in the multi-disciplinary approach as a leader at the Center for Law, Science and Innovation at the Arizona State University Sandra Day O’Connor School of Law.

For years, Gary has foreseen and written about  the ongoing revolution in molecular biology and its implications for toxic tort litigation; his 2009 “Ghost in the Genes” article (with others)  is a must read. See The Ghost in Our Genes: Legal and Ethical Implication of Epigenetics (2009). The new interview is titled “Genomics is Changing Causation Evidence in the Courtroom Forever.”  The interview brings Gary’s overview analysis forward to last week.

Kudos to David Schwartz of  Innovative Science Solutions for putting very good questions to someone who really can foresee the answers. You can read the interview at Innovative Science or at ASU’s always interesting blog, Bits, Bots and Biomarkers.

Disclosure: Both Gary and David are professional friends of mine, and I’m on an outside advisory committee for the LSI Center at the ASU law school.

Molecular science continues to race forward in explaining the processes that generate the various processes we label as cancers. As an example, read the following new press release from the University of Pittsburgh about a presentation on Tuesday April 21, 2015 at the annual AACR meeting. While reading, do not get hung up on the specifics. Instead, simply consider the level of detail uncovered by the researchers as highlighted by the text in bullets. Then think about your favorite toxin or product, and the questions you could be asking.


“Inflammation-Cancer Feedback Loop Discovery is a Step Toward Better Cancer Drugs
PHILADELPHIA, April 20, 2015 – New findings hidden within the complex machinery behind the vicious cycle of chronic inflammation and cancer are presented today by researchers from the University of Pittsburgh Cancer Institute, partner with UPMC CancerCenter, at the American Association for Cancer Research (AACR) Annual Meeting in Philadelphia.

The research is funded by the National Institutes of Health (NIH) and Fondazione RiMED, of Palermo, Italy.

Inflammation is an important immune system tool that helps the body rid itself of foreign invaders, such as bacteria. However, chronic inflammation can fuel tumor growth by facilitating formation of cancer blood vessels, supplying nutrients and setting cancerous cells free to colonize other parts of the body.

The basic research into the specific mechanisms promoting cancer inflammation is a critical step in the development of drugs that could interrupt this process.

“In the last 20 years we’ve recognized that chronic inflammation and cancer are connected – long-term inflammation leads to the development of dysplasia and tumor progression,” said lead author Sandra Cascio, Ph.D., a research associate in Pitt’s Department of Immunology. “Recently, scientists have provided detailed insights into molecules and cellular pathways linking inflammation and cancer. In our study, we found a new mechanism that had previously escaped us.”

The mechanism is driven by a complex of MUC1, a molecule long studied in the laboratory of senior author and Pitt immunologist Olivera Finn, Ph.D., and p65, a molecule belonging to a protein complex family known to be activated in inflammation.

  • Dr. Cascio, in collaboration with Dr. Finn, looked for MUC1/p65-mediated epigenetic modifications affecting inflammatory genes. Epigenetics refers to outside factors that modify the activity of a gene, but do not cause a more obvious genetic mutation. Sure enough, the researchers discovered that this complex, which they found specifically in cancer cells, was causing DNA to be transcribed differently than expected.
  • “Normally MUC1 is covered in sugar molecules, like leaves cover a tree in spring,” said Dr. Cascio. “When it is made by a tumor, it lacks sugar and is more like a tree in fall. Our research shows that this form of MUC1 associates with p65 and regulates transcription of pro-inflammatory cytokine genes in tumor cells. This leads to the recruitment of inflammatory cells into the tumor site. Inflammatory cells, including macrophages, produce additional cytokines that enhance the activity of MUC1 and p65, establishing a continuous positive feedback loop, or a vicious circle, resulting in tumor progression.”
  • In order to pinpoint this altered pro-inflammatory mechanism in cancer cells, Dr. Cascio and her team combed through more than 20 types of epigenetic modifications and 300 factors that allow for the remodeling of chromatin, which are macromolecules in cells that control gene expression and DNA replication.
  • Specifically, the researchers found that MUC1 and p65 involve an enzyme called the Enhancer of Zeste homolog 2, or EzH2, known to induce epigenetic modifications, in order to prompt chromatin remodeling on cytokine gene promoters.

“Developing drugs that could keep these genes from being improperly turned on and off could interrupt this cancer-inflammation process and stop the tumor growth and spread,” said Dr. Cascio. “It’s a promising avenue for future exploration.”

Joshua Sciurba, B.S., of Pitt at the time of this research, also participated in this work.

This research was funded by Fondazione RiMED and NIH National Cancer Institute grant CA56103.” (italics and bullets added)