“We’ve been working with the Metabolomics Facility now for the last couple of years,” says Curt Omiecinski, “since the National Institutes of Health released a request for applications for supplement projects to work in metabolomics. Because we had the Facility and the expertise of Andrew Patterson and Phil Smith, our lab put in for one of the supplements.”
At that point in time, Omiecinski says, he knew about the promise of metabolomics, but hadn’t used such an approach before in his lab’s studies of toxicology and carcinogenesis, which are focused now on assessing the potential toxicity of plasticizers.
“This is a group of chemicals used a lot in the plastics industry,” he explains, “and they’re manufactured – millions of pounds of these plasticizers – world-wide. We’re all exposed to them by virtue of the fact that they’re everywhere, ubiquitous, in our environment.”
Omiecinski’s lab works on two particular plasticizers known as DEHP and DINP – part of a group of chemicals called phthalates – that, he explains, “are used to make plastics soft. Whenever you’re talking about making tubing, for example, or plastic bags, you need plasticizers. And these chemicals – DEHP and DINP in particular – are not covalently bound in the material, so they can leach out. Humans around the world are exposed to these chemicals, and there’s been a lot of concern about what might be the potential toxicological impact of this.”
As is the case with many scientific studies, much of the experimental work on plasticizers has been conducted in model systems, such as rodents – which, in this case, presented Omiecinski and his lab with a unique problem.
A unique solution
“Where we came into all of this and how we are getting into the metabolomics angle,” says Omiecinski, “is that we found through other of our published studies that humans have a particular receptor for these chemicals that doesn’t exist in the mouse, or in other rodents, or in the other animal models that have typically been used to assess their toxicity. We identified this receptor as being very highly and potently activated by these chemicals of concern.”
It’s extremely difficult, he explains, to do these studies in humans, “so what we did is to create ‘humanized’ mice in which the mouse version of this receptor has been ‘knocked out’ and replaced with the human version.”
After creating their specialized lines of mice, the Omiecinski Lab treated the animals with DEHP and began utilizing the Metabolomics Facility’s capabilities to assess the chemical composition of their blood and other tissues – “the whole complexity of the metabolome,” Omiecinski says, “which includes all the biochemical changes, differences in sugar levels and lipid levels and anything else we can get our hands on in order to understand more clearly the broader impact of these exposures in our humanized rodent model system.”
“That’s the gist of what we’re trying to do in collaboration with Andrew and Phil,” he sums, “and through use of their Facility’s capabilities, which are quite remarkable. Our laboratory’s studies more traditionally involve genomics, genetic and molecular biology, and gene regulation issues that we are now combining with metabolomics, trying to understand more coordinately how those chemical exposures effect the functional biology of animals and humans. We’re working to assess, more globally, the impact of chemical interactions within our environment.”