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Environmental Factor – January 2022: Epigenetics, diverse populations and exposures combine in grantees’ lab

Environmental Factor – January 2022: Epigenetics, diverse populations and exposures combine in grantees’ lab

Rick Woychik, Ph.D., NIEHS Director's Corner
Rick Woychik, Ph.D., NIEHS Director's CornerRick Woychik, Ph.D. directs NIEHS & the National Toxicology Program. (Image courtesy NIEHS

This month marks the first anniversary of the Director’s Corner, which I launched to share innovative ideas and promote collaboration across the environmental health sciences community. Recently, I spoke to NIEHS grantee Cathrine Hoyo, Ph.D.North Carolina State University (NC State), researcher who is innovative and collaborative in his research, I think our conversation is the perfect way to start the new year.

Hoyo seeks to shed light upon how early environmental exposures can affect later life. Her research is informed by epigenetic analysis. She conducts rigorous epidemiological studies that involve diverse populations and toxic substances of great public health importance. Epigenetics refers either to chemical modifications of DNA or to the proteins associated with DNA which affect how genes are turned off and on. Hoyo is interested in increasing knowledge about conditions like obesity and liver dysfunction through the identification of epigenetic changes caused by developmental exposures to cadmium and per- and polyfluoroalkyl compounds (PFAS) and other contaminants.

Cathrine HoyoHoyo is a prolific researcher and has published nearly 160 peer-reviewed scientific papers. (Photo by Cathrine Holo)

She uses this research to develop a framework called the developmental origins health and disease (DOHaD). This framework identifies how African Americans may be affected by certain exposures. Hoyo, a native of Zimbabwe, is a Distinguished Associate Professor at NC State, where her research focuses on Epigenetics, Cancer and the Environment Laboratory. She also is co-director of the Integrative Health Science Facility Core in the university’s NIEHS-funded Center for Human Health and the Environment (CHHE).

Liver diseases, heavy metals, PFAS

Rick Woychik: You are leading the charge for the Southern Liver Health CohortNIEHS and National Cancer Institute funded the major new project titled. The goal is to increase knowledge about environmental contaminants that may be linked to liver cancer in a diverse population of 16,000 people, including fibrosis. What are you hoping to learn from this initiative?

Cathrine Hoyo: Sure. We are part of five teams developing new cohorts that will advance basic research in the country. Our group is interested in both heavy metals (PFAS) and will collect blood, urine, tissue, and other samples from a diverse adult population to track those individuals over time. The goal of this study is to identify who develops nonalcoholicfatty liver diseases, how they may progress into fibrosis, which may then lead to liver carcinoma.

One of the reasons I wanted this project to happen is because of my previous research that involved the NIEHS funded Newborn Epigenetics Study Cohort( As part of that ongoing effort, we studied a group of women in Durham, North Carolina, to learn how environmental stress — cadmium exposure — around the time of pregnancy influenced health outcomes in their children.

We found that 10% of African American children had nonalcoholic fatty liver disease by age 10 — an alarming percentage, and one that was significantly higher than what we saw in other children. If the cohort wasn’t African American, our group wouldn’t have discovered it. Diverse ethnicitiesI agree, and I believe that this diversity will be a major advantage to the Southern Liver initiative as well.

Hoyo delivered a 2013 NIEHS Keystone Science LectureHoyo delivered a 2013 NIEHS Keystone Science Lecture titled “Testing the Developmental Origins of Adult Diseases Hypothesis: The Durham Newborn Epigenetics Study.” (Photo courtesy of Steve McCaw / NIEHS)

The southeastern and southern United States have experienced the greatest increases in liver cancer incidence over the past 15-20 years. We want to know why this is, and I think we can do that by further studying the cohort of children and the Southern Liver project.

Learn how maternal exposures impact children

RW: What motivated you to study DOHaD? To combine insights from the field epigenetics with your own research?

CH: I was at Duke University in the lab of Randy Jirtle. He followed up with your experimentsInvolving The gene for the agoutiPublished a seminal paperIt was shown that certain nutritional exposures on the maternal side can cause potentially harmful epigenetic modifications in offspring. I was — and still am — interested in how the environment can affect gene expression and ultimately influence metabolic dysfunction, including obesity, so his work has been a major source of intellectual inspiration.

In my early studies, I was interested in an imprinted gene called insulin like growth factor 2. [IGF2], which regulates the body’s growth hormone. An imprinted gene’s expression is determined by the parent that gave it. Such expression is based in epigenetic modifications made to the germline, which means sperm cells and egg cells. It is possible to develop conditions such as diabetes or cardiovascular disease by losing imprinting in IGF2. Some people are predisposed to obesity.

Identifying key epigenetic factors that drive disease

RW: What happened after that research?

CH: I wanted a broad list of imprinted genes to help us better understand the mechanisms by which exposures affect gene expression and obesity. A list of these genes would be a gold mine for epidemiologists because it would allow them to identify epigenetic marks that have been established in them. We would be able to determine when — and how — an exposure causes loss of imprinting.

With such a strong set of genes, we can evaluate the effects on exposures that occur early in life, even if the woman doesn’t know she’s pregnant. This knowledge could help in disease prevention and lead to therapeutic advances.

So, I started looking at known imprinted areas and I was able to continue my journey. Published a related paper 2012Together with my colleague David Skaar. I was studying imprinted genes and cadmium at the time. A group of individuals from Durham CountyWho had been exposed. I created cohort studies to examine exposures in very early gestation, and analyze the resulting epigenetic changes.

This proved inefficient so we did whole genome analysis to determine which imprinted regions could shed light on the epigenetic effects of cadmium and heavy metals exposure in early life. This type of research is more effective in certain regions than in others. We published our findingsIn the journal Environmental Health Perspectives.

I eventually collaborated with a bioinformatician. [CHHE]To dive deeper into these imprinted genes. We have identified more than 300 areas that we believe hold promise for scientists in understanding the epigenetic effects exposures. Our findings will soon be published.

Also, we are working with the biotech company Illumina to develop a platform — based on these imprinted regions — that allows other researchers to study more exposures and diseases through an epigenetic lens. I am very excited about the future.

CHHE member Keith Linder, D.V.M., Ph.D., left, chatted with Hoyo during the center’s first annual symposium in 2017.CHHE member Keith Linder, D.V.M., Ph.D., left, chatted with Hoyo during the center’s first annual symposium in 2017. From left are CHHE members Jirtle (Photo courtesy Ahmed Mohammed)

State-of-the-art equipment, research support

RW: That sounds intriguing. I think your efforts in the coming years will allow for scientific breakthroughs. You mentioned CHHE. You mentioned CHHE.

CH: Yes, absolutely. This NIEHS-funded centre has given me and other researchers more opportunities to partner, and I am grateful for that. The center employs a full-time bioinformatician, who can work in many models, including those involving zebrafish, mice or human epidemiological research.

I believe there is an unique interdisciplinary element to this system. More than 70 investigators are employed by NC State. Researchers often work with scientists at nearby universities.

I am also able to conduct studies thanks to the state-of-the art equipment and funding provided by the center. [laughs].

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The Southern Liver Health Cohort was initially a pilot project that cost $50,000. The other half of that amount was from [CHHE]The UNC was responsible for half of the remaining 50%. [University of North Carolina at Chapel Hill] Center for Environmental Health and SusceptibilityNIEHS also funds the, It has been thrilling to watch the study evolve into something more comprehensive.

House JS, Hall J, Park SS, Planchart A, Money E, Maguire RL, Huang Z, Mattingly CJ, Skaar D, Tzeng JY, Darrah TH, Vengosh A, Murphy SK, Jirtle RL, Hoyo C. 2019. Cadmium exposure MEG3The NEST Cohort methylation differences between Whites & African Americans. Environ Epigenet 5(3):dvz014.

Bultman SJ, Michaud EJ, Woychik RP. 1992. The molecular characterization of mouse agouti locus. Cell 71(7):1195–204.

Michaud EJ, van Vugt MJ, Bultman SJ, Sweet HO, Davisson MT, Woychik RP. 1994. Differential expression of an Aiapy dominant agouti gene (Aiapy), is correlated to methylation state and is affected by parental lineage. Genes Dev 8(12):1463–72.

Waterland RA and Jirtle RL. 2003. Transposable elements are targets for early nutritional effects upon epigenetic gene regulation. Mol Cell Biol 23(15):5293–300.

Do EK, Zucker NL, Huang ZY, Schechter JC, Kollins SH, Maguire RL, Murphy SK, Hoyo C, Fuemmeler BF. 2019. Associations between imprinted genes differentially methylated regions and appetitive traits in children. Pediatr Obes 14(2).

Skaar DA, Li Y, Bernal AJ, Hoyo C, Murphy SK, Jirtle RL. 2012. The human imprintome – regulatory mechanisms, methods for ascertainment and roles in disease susceptibility. ILAR J 53(3-4):341–58.

King KE, Darrah TH, Money E, Meentemeyer R, Maguire RL, Nye MD, Michener L, Murtha AP, Jirtle R, Murphy SK, Mendez MA, Robarge W, Vengosh A, Hoyo C. 2015. Geographical clustering of elevated levels of blood heavy metals in pregnant woman. BMC Public Health 15/1035.

Cowley M, Skaar DA, Jima DD, Maguire RL, Hudson KM, Park SS, Sorrow P, Hoyo C. 2018. Effects of cadmium exposition on DNA methylation in imprinting control areas and genome-wide in mothers, newborns, and their children Environ Health Perspect 126(3):037003.

(Rick Woychik Ph.D. directs NIEHS/the National Toxicology Program.

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