January 12, 2022
Cetewayo Rashid, Ph.D., University of Kentucky
Abstract: Sofas, office chairs, and automobile seats are manufactured using polyurethane foams that have been sprayed with flame retardants, such as Tris (1,3-dichloro-2-propyl) phosphate (TDCPP). TDCPP off-gases, contaminating indoor spaces where these foams are located.
TDCPP is stable in the environment but is readily metabolized to bis (1,3-dichloro-2-propyl) phosphate (BDCPP) once it enters the body. 90 percent of Americans have detectable BDCPP in their urine, indicating ubiquitous exposure. Recent studies utilizing data from the National Health and Nutrition Examination Survey found a significant positive association between urinary BDCPP levels and metabolic syndrome, with the components central adiposity and hyperglycemia carrying the association. Interestingly, the association with BDCPP and metabolic syndrome was found only in men.
The objective of Rashid’s study was to determine whether there is a causal relationship between TDCPP exposure and metabolic disruption. For this purpose, TDCPP was incorporated into purified low phytoestrogen diets to mimic the primary route of exposure in humans. Male and female C57BL/6J mice were exposed to either 0.1% DMSO, 0.02, 1 or 100 mg TDCPP/kg/day for five weeks. Rashid and his team performed body composition analysis and evaluated glucose homeostasis. They found a dose-dependent increase in fat mass:lean mass ratio in male mice at the two higher doses while male mice given the highest dose were also insulin resistant. Similar to observations in humans, TDCPP did not affect adiposity or glucose homeostasis in females. Finally, they screened TDCPP for nuclear receptor agonist activity in vitro. Of the 26 nuclear receptors tested, TDCPP activated only farnesoid X and pregnane X receptors. PXR target genes, but not FXR target genes, were increased in the livers of mice exposed to the highest dose. Taken together, these data support a causal relationship between TDCPP exposure and male sex-specific metabolic disruption, and future studies will investigate the role of PXR and sex hormones to determine the mechanistic underpinnings of TDCPP-induce metabolic derangements.
EHS Core Center Affiliation: University of Kentucky, CARES Center
Joseph Romano, Ph.D., University of Pennsylvania
Abstract: In this webinar, Romano will introduce ComptoxAI – a toolkit for artificial intelligence research in computational toxicology. ComptoxAI includes a large graph database of toxicology-related biomedical knowledge, a suite of information retrieval tools, advanced machine learning models, educational documentation, and tools for programmatic access to the knowledge base. He will showcase ComptoxAI’s capabilities through:
- A tour of its information retrieval functionality.
- Reviewing the results of a recent study in which he used ComptoxAI’s knowledge base along with graph machine learning to significantly outperform state-of-the-art QSAR modeling for predicting toxic outcomes.
ComptoxAI is entirely open-access and under active development, and community involvement is encouraged.
EHS Core Center Affiliation: University of Pennsylvania, CEET Center