September 19, 2022
Purpose
Fluorinated chemistries have been heavily scrutinized due their long half-lives and reported bioactivity. Several compounds have been shown to be modulators of ligand-activated nuclear receptors. This includes agonists for peroxisome proliferator-activated receptor alpha (PPARα), a key regulator of lipid metabolism regulating genes and associated with liver hypertrophy and tumorigenicity in rodents. Additionally, fluorinated compounds have been found to activate estrogen receptor alpha (ERα), which controls key physiological functions including development and maintenance of normal sexual and reproductive functions. However, fluorinated chemistries represent a wide umbrella of chemistries, and it has been recently suggested that there are classes of fluorinated chemistries that are biologically inert (fluoroinerts). Our client developed several fluorinated molecules and wanted to assess their potential liver and endocrine toxicity, as well as effects on PPARα and ERα modulation.
Method
- Conduct range-finding experiments to assess the effects of the compounds on cytotoxicity and viability in liver and epithelial cell lines.
- Treat liver and epithelial cell lines with a sub-cytotoxic compound dose and analyze ERα modulation (epithelial) and PPARα induction (liver) with gene expression biomarkers.
Results
- The compound set had a range of cytotoxicity in the cell lines, with some exhibiting no cytotoxicity.
- Some compounds were found to induce PPARα and/or alter endocrine function.
Client Value
Based on the data provided the client was able to narrow the list of candidate compounds to move forward rapidly and in a cost-efficient manner.