“There is a lot we don’t know about CKDu,” said Harrill. “We hope to find cures by exploring clinical features, environmental exposures, and the role of heat stress.” (Photo courtesy of Steve McCaw)

NIEHS scientists were among the many presenters and session co-chairs during this year’s Society of Toxicology (SOT) conference, which took place online in April and May. Seminars and continuing education courses covered a range of topics, including emerging research areas emphasized in the institute’s 2018-2023 Strategic Plan.

Chronic kidney disease of unknown origin

In the last twenty years, the occurrence of severe kidney disease increased in farming communities in Central America, Sri Lanka, India, Thailand, Africa, and most recently, the U.S. However, patients often show no classic signs of risk, such as diabetes or hypertension. So, scientists now call the condition chronic kidney disease of unknown origin (CKDu).

“That disease is associated primarily with agricultural work,” said Alison Harrill, Ph.D., a geneticist in the NIEHS Division of the National Toxicology Program (NTP). “CKDu has accounted for more than 20,000 deaths in the last two decades,” she noted.

Figuring out what to study

Harrill pointed out that scientists are exploring whether heat stress, dehydration, and exposure to agrochemicals and toxic metals may cause the condition. But much more research is needed.

“We don’t know whether this is the same disease in all areas of the world,” said Susan Elmore, D.V.M., a veterinary medical officer and staff scientist at NIEHS.

Her team scoured the NTP database for animal studies related to agricultural chemicals and metals, looking for kidney dysfunction from exposures. They wanted to know whether kidney changes seen in such studies are similar to changes in CKDu patients. They flagged 29 chemicals for further analysis, including the following.

“CKDu has high prevalence in El Salvador and Nicaragua,” said Elmore. “The number of men dying has risen five-fold in the last 20 years.” (Photo courtesy of Steve McCaw)

• 1,1,2,2-Tetrachloroethane — Solvent in insecticides, herbicides, and fumigants.
• 8-hydroxyquinoline — Antimicrobial agent in fungicides and insecticides.
• Isophorone — Solvent in pesticides and herbicides.

“We will continue to review all [relevant] studies … with a pathology working group,” said Elmore.

Epigenetics makes a splash

Exposure to chemicals can impact health and disease by both mutating genes and modifying the epigenome. The epigenome is made up of chemical compounds and proteins that can attach to DNA and turn genes on or off without altering the underlying sequence.

In 2016, NIEHS established phase two of the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET) Program, which was the focus of a conference session. Fred Tyson, Ph.D., a program director in the institute’s Genes, Environment, and Health Branch, described the research consortium.

“TaRGET II is [designed] to determine whether environmental exposures induce specific signatures in the epigenome,” he said. A unique aspect of the initiative involves the use of surrogate tissues, including blood and skin, to predict how a given substance might affect the epigenome of a specific tissue, such as the liver.

Predicting disease risk

“Genetic diversity is a hallmark of human populations,” said Tyson. “The epigenetic signature of environmental exposure varies within populations.” (Photo courtesy of Steve McCaw)

Tyson highlighted work by Cheryl Walker, Ph.D., from Baylor College of Medicine. She studies in utero effects of tributyltin, which is an endocrine disrupting chemical used in various industries, such as paper production. Walker administered the substance to pregnant female mice, then waited until their offspring were at various developmental stages to look at effects at the DNA level.

“40% of exposed males get liver tumors,” said Tyson. “Can we identify signatures in them early that will predict which exposed animals will get liver tumors versus those that will not?”

Walker’s work tests the hypothesis that changes can been seen in surrogate tissues at five months of age — well before the animals develop tumors. Her team uses a method called RNA-seq, which takes a snapshot of all the expressed genes at a given period, and ChIP-seq, which identifies histone modifications.

The group is working to pinpoint epigenetic risk signatures in blood and skin that at five months may accurately predict which mice exposed to tributyltin will develop tumors at 10 months.

(Sheena Scruggs, Ph.D., is a digital content coordinator in the NIEHS Office of Communications and Public Liaison.)