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Estimating the Bioaccumulation Potential of Per- and Polyfluoroalkyl Substances (PFAS) across Species by Integrative in Silico Approaches
Citation:
Cheng, W., J. Doering, C. LaLone, AND C. Ng. Estimating the Bioaccumulation Potential of Per- and Polyfluoroalkyl Substances (PFAS) across Species by Integrative in Silico Approaches. SETAC North America, Fort Worth, TX, November 15 - 19, 2020. https://doi.org/10.23645/epacomptox.13241546
Impact/Purpose:
Per and polyfluoroalkyl substances (PFAS) are a group of chemicals that have been widely used in industrial and consumer products and found in the environment. It is known that these substances can bioaccumulate, however there are limited data regarding their ability bioaccumulate across the diversity of species. PFAS are known to interact with certain proteins in mammals thought to be involved in their bioaccumulation potential. Therefore, understanding if these proteins are found in other organisms can provide an initial indication of whether PFAS have the potential to interact with the protein in another species and bioaccumulate. The US EPA Sequence Alignment to Predict Across Species Susceptibility tool (SeqAPASS) was used in this initial study to understand how and if PFAS are likely to interact with the liver fatty acid binding protein in other species to inform follow up cross species bioaccumulation studies. Advanced molecular modeling computational techniques were then used to understand species differences in binding affinity to 9 PFAS.
Description:
Per and polyfluoroalkyl substances (PFAS) are a diverse group of chemicals that have been widely used in industrial and consumer products for decades. Recent estimates suggest there are thousands of PFAS that have been registered and/or produced. However, many of these PFASs have limited information available about their bioaccumulation potential and toxic effects. The data are even more sparse across species, preventing effective ecological risk assessment. Given the vast number of PFAS and our limited resources, reliable and cost-effective in silico approaches to predict the behavior of PFAS across species would be beneficial. Studies have shown that interactions between PFAS and proteins such as serum albumin and liver-type fatty acid binding protein (LFABP) are critical factors contributing to their bioaccumulation potential across species. Here, a complementary evaluation with the US Environmental Protection Agency’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool (https://seqapass.epa.gov/seqapass/), and a multi-step molecular modeling workflow, previously applied to PFAS-LFABP interaction prediction, was employed to evaluate potential differences across a human, rat, chicken, zebrafish, rainbow trout, fathead minnow and Japanese medaka. The interactions between wild-type and 9 PFAS were critically compared. The sequence-based comparisons from SeqAPASS predicted similar bioaccumulation potential to PFAS between humans and vertebrates when comparing primary amino acid sequences and critical amino acids identified from previous work. The tool also identified potentially important individual residues (i.e., F50, A54, T81, T93, and N97) that were predicted as different between human LFABP and those in other taxa. When comparing whole-sequence wild-type LFABP across species, human LFABP had comparable PFAS binding affinity to all other species (p > 0.05) except Japanese medaka and fathead minnow (p < 0.05), both of which indicated significantly weaker binding affinities than human for some PFAS ligands. This pipeline highlights how structural considerations with predicted binding affinities enhance understanding of PFAS bioaccumulation potential beyond the sequence alone. The molecular modeling workflow was also used to evaluate single residue mutations to the human LFABP structure based on individual amino acids that were hypothesized to explain species differences from one species to another from SeqAPASS. These mutations did not significantly change predicted binding affinity, with the exception of a significant difference (p < 0.05) after human LFABP mutation, F50V, for PFNA. Our study provides valuable insights into PFAS bioaccumulation potential across species.
URLs/Downloads:
DOI: Estimating the Bioaccumulation Potential of Per- and Polyfluoroalkyl Substances (PFAS) across Species by Integrative in Silico Approaches