When toxins enter our bloodstreams, the liver and kidney act to eliminate them before they increase our health risks.
So what happens when those organs encounter the pharmaceuticals, plastics and forever chemicals that exist in our food, soil and bodies of water such as Lake Erie?
From left, graduate students Bivek Timalsina, Ben French and Emily Crossley examine the kidney cells from the research to study how pre-existing conditions, such as Type 2 diabetes, could increase susceptibility to emergent chemicals.
Researchers at The University of Toledo studied the effect of these toxins, known as “emergent chemicals,” on human cells and found that pre-existing conditions, such as Type 2 diabetes, could increase susceptibility to the toxins.
With funding from Ohio Sea Grant, Associate Professors David Kennedy and Steven Haller at The University of Toledo College of Medicine and Life Sciences used liver and kidney cells from biopsy samples donated by patients with and without diabetes to explore the issue.
A growing health concern, diabetes affects 37.3 million Americans, or 11.3% of our country’s population, according to the U.S. Centers for Disease Control and Prevention. The International Diabetes Federation reports that 6.7 million deaths worldwide were attributed to the disease in 2021.
“This common disease has well-known impacts on how both the liver and kidney perform their metabolic functions, including the detoxification of impurities in our body,” Haller said.
“It is important to understand whether this common disease also affects the way our body handles these specific chemicals of concern, and if so, to understand the ways that this occurs,” said Kennedy. “This information will help us design targeted ways to help with prevention, diagnosis and treatment of exposure to these toxins not only in healthy populations but also in vulnerable and at-risk populations such as those with Type 2 diabetes.”
The researchers selected for their study abundant and representative chemicals that occur in the Great Lakes:
- Perfluorooctanoic acid, or PFOA, used to make products that resist heat, oil, stains, grease and water. Known as a “forever chemical,” it does not break down in the environment and is linked to health problems including cancer.
- Polystyrene nanoplastics that can come from larger plastics that have broken apart; resin pellets used for plastic manufacturing; or microbeads, which are small, manufactured plastic beads used in health and beauty products.
- 17α-ethynylestradiol (EE2), a synthetic hormone used in medications for humans as well as livestock and aquaculture activity and that contaminates raw and treated wastewater.
They found that in cells from liver and kidney biopsies, forever chemicals suppressed the immune response, nanoplastics increased inflammation and residual pharmaceuticals increased markers of kidney injury. In cells from patients with diabetes, those results were more pronounced, indicating those patients may be more susceptible to and have greater damage from the toxins.
Electron micrograph image from human diabetic kidney cells demonstrating the presence of microplastic particles (see arrows) within the cells.
“In diabetes, where you have a metabolic disorder, those pathways are already altered or dysregulated. When you add these chemicals on top, they further disturb those pathways, including fat or lipid metabolism,” Kennedy said, explaining that if the liver and kidney are storing fat rather than metabolizing it, they can’t properly perform their normal metabolic detoxification functions. “The liver and kidney are not meant to store fat. If your liver cells start to store fat, then it’s like you’re taking your Formula 1 race car designed to run fast races and turning it into a U-Haul moving van.”
Rapid response
By studying human cells obtained from patients who provided informed consent for research, Kennedy and Haller could quickly generate results that can be directly applied to human health rather than, say, bridging a gap from animal testing and models.
“As much as we can, we’re going to take human cells closer to an actual living, moving, breathing organ. It gives us good data where we’re not 12 steps removed from reality. It’s a lot more applicable,” Kennedy said.
Associate Professor David Kennedy and graduate student Emily Crossley examine dysregulated genes in human kidney cells following exposure to emergent chemicals.
For this study they used fully automated high throughput quantitative genetic analysis and RNA-Sequencing via the Women & Philanthropy Genetic Analysis Instrumentation Center, which Haller and Kennedy co-direct. This enabled them to test and compare healthy versus diseased cell response to the emergent chemicals for thousands of genetic markers simultaneously and quickly. For example, they tested the cells for genes that cause cancer, initiate inflammation and fibrosis (tissue scarring), and are responsible for organ specific stress and toxicity response including DNA damage as well as other types of cellular damage that ultimately progress to cell death if not repaired.
They anticipate the study will lead to the development of new safety guidelines for the exposure to these emergent chemicals of concern for individuals with pre-existing diseases and other susceptible conditions.
Diagnosis and treatment
One of the most definitive ways to determine disease damage is through a liver or kidney biopsy — an invasive procedure for patients.
Associate Professors David Kennedy, left, and Steven Haller study how emergent chemicals like microplastics and “forever chemicals” could affect people with pre-existing conditions.
“If we did a biopsy, we could do genetic analysis, but what if there’s a set of those genes that expresses something that can be detected in the blood or the urine rather than a biopsy?” Kennedy said.
“Right now there are not commonly available tests for health care workers to use to detect and diagnose emergent chemical exposure events in their patients,” Haller said.
“Now that we know the specific molecular pathways that are dysregulated by these chemicals, we are in the process of validating specific therapeutic strategies, including lab developed peptides, that can potentially restore normal cell functioning after emergent chemical exposure,” said Kennedy.
“One of our main priorities is disseminating our research to health care providers and public health officials so that the knowledge gained can be applied to improve prevention, diagnosis and treatment of patients who are exposed to these chemicals.”
Steven Haller
They will expand their research using tissue samples from a biobank, the Environmental, Occupational and Community Medicine Biorepository, to develop diagnostic and therapeutic approaches to combat adverse health effects following exposure to emergent chemicals. They plan to expand the research to other diseases such as cancers or cardiovascular disease.
“We can’t create a study where we ask someone to volunteer to eat a credit card’s worth of plastic, so essentially we have biobanks where we’ve collected blood, urine, tissue samples from volunteers who in the course of their medical treatment have extra samples left over and agree to donate them,” Kennedy said.
“The patients consent to say, ‘Yes, you can keep my tissue for future studies.’ These are people who live and recreate around Lake Erie,” Haller said, stressing the relevancy to the emergent chemicals in the lake.
Protecting public health
Haller and Kennedy will continue developing resources for health care providers to stay up to date with the emerging science.
For instance, they collaborate with the Toledo Lucas County Health Department Environmental Pollutants Subcommittee on ways their research can be used to address community concerns.
University of Toledo bioengineering undergraduate student Shereen Yassine presented a poster on the emergent chemicals research at the national Biomedical Engineering Society Annual Scientific Meeting.
“Our partnership with the Toledo Lucas County Health Department Environmental Pollutants Subcommittee has helped us identify new areas where our research can be applied to help in shared public health areas of concern,” said Haller. “For example, little is known about the impacts of these chemicals on maternal health or child development, so we are now in the process of designing studies to address these critical knowledge gaps.
“This has been very fruitful and exciting for both of us,” Haller said.
“In addition, one of our main priorities is disseminating our research to health care providers and public health officials so that the knowledge gained can be applied to improve prevention, diagnosis and treatment of patients who are exposed to these chemicals,” Haller said. “To this end, we have not only given national and international presentations on this research to key health care professionals, but we have also integrated our research into our medical education efforts for our medical students, residents and faculty to help equip them with the most up-to-date research in this area.”