Structural conservation of peroxisome proliferator-activated receptor isoforms reveals potential of perfluorooctanesulfonic acid to disrupt mammalian and avian lipid signaling

Lipid metabolism and transport are essential physiological processes necessary to survival and daily function. Impairment of lipid transport and metabolism through factors such as dietary alterations or exposure to some exogenous chemicals can lead to deleterious health outcomes in individuals and populations. For example, in birds, lipid metabolism is critical throughout their life cycle, including reproduction, migration, and overwintering. Nuclear receptor signaling, including peroxisome proliferator-activated receptor (PPAR) signaling, plays a major role in avian lipid metabolism, and PPAR transcripts vary throughout the annual cycle. Perfluorooctanesulfonic acid (PFOS), a ubiquitous and persistent environmental contaminant causes PPAR-mediated changes in hepatic lipid metabolism, including steatosis, in some vertebrate species, primarily mammals. However, the evidence for changes in PPAR signaling and downstream lipidomic effects is mixed and inconclusive in birds. Grounded in an adverse outcome pathway (AOP) perspective within a taxonomic domain of applicability (tDOA) approach, we utilized the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool to help assess the degree of cross-species conservation of proteins in several key steps in PFOS-PPAR signaling. Overall, the proteins in these pathways had high structural similarity between mammalian and avian taxa, suggesting a potential susceptibility of avian PPAR-mediated lipid metabolism to PFOS. However, receptor susceptibility does not necessarily cause downstream adverse physiological outcomes. Differences in avian and mammalian physiology and gene expression, nuclear receptor crosstalk, and downstream protein sequences may all contribute to the taxonomically disparate body of evidence of PFOS triggering PPAR-mediated steatosis in different vertebrate species.