Human-Based Exposure Levels of Perfluoroalkyl Acids May Induce Harmful Effects to Health by Disrupting Major Components of Androgen Receptor Signalling In Vitro

Abstract

Perfluoroalkyl acids (PFAAs) are detectable in human blood. PFAA exposure may contribute to androgen receptor (AR)related health effects such as prostate cancer (PCa). In Norway and Sweden, exposures to PFAAs and PCa are very real concerns. In vitro studies conventionally do not investigate PFAA-induced AR disruption at human blood-based concentrations, thus limiting application to human health. We aim to determine the endocrine disrupting activity of PFAAs based upon human exposure levels, on AR transactivation and translocation. PFAAs (PFOS, PFOA, PFNA, PFDA, PFHxS, and PFUnDA) were tested at concentrations ranging from 1/10 × to 500 × relative to human blood based upon the exposure levels observed in a Scandinavian population. Translocation was measured by high content analysis (HCA) and transactivation was measured by reporter gene assay (RGA). No agonist activity (translocation or transactivation) was detected for any PFAAs. In the presence of testosterone, AR translocation increased following exposure to PFOS 1/10 × and 100 ×, PFOA 1/10 ×, and PFNA 1 × and 500 × (P < 0.05). In the presence of testosterone, PFOS 500 × antagonised AR transactivation, whereas PFDA 500 × increased AR transactivation (P < 0.05). PFAAs may contribute to AR-related adverse health effects such as PCa. PFAAs can disrupt AR signalling via two major components: translocation and transactivation. PFAAs which disrupt one signalling component do not necessarily disrupt both. Therefore, to fully investigate the disruptive effect of human exposure-based contaminants on AR signalling, it is imperative to analyse multiple molecular components as not all compounds induce a disruptive effect at the same level of receptor signalling.

Effects of Defined Mixtures of Persistent Organic Pollutants (POPs) on Pre-lethal Cytotoxicity in the Human A-498 Kidney Cell Line In Vitro

“…In pGIP/neo: STC-1 enteroendocrine cells a reduction is seen with total mixture, submixtures, and their combinations. However, an effect on CN has been noted with the Cl mixture alone at concentrations starting at 1x (McComb et al 2019). This indicates that the cytotoxic effects of individual classes of compounds can be masked within the total mixture by combinatorial or antagonist effects.…”

“…This low cytotoxicity when CN is taken in consideration is in agreement with previous observations with the same mixture. Indeed, in a U-2 OS cell line expressing a fluorescently tagged human androgen receptor, no effect on CN was noted at concentrations up to 500x after 6 h (McComb et al 2019). In HepG2 liver cells no effect on CN was seen for concentrations up to 1000x (Wilson et al 2016).…”

Divergent molecular responses of greater amberjack (Seriola dumerili) to acute salinity stress revealed by comparative transcriptome analysis

“…141 (4), 401-429. doi: 10.1016/j.cbpb.2005.01.013 Vij, S., Purushothaman, K., Sridatta, P. S. R., and Jerry, D. R. (2020). Transcriptomic analysis of gill and kidney from Asian seabass (Lates calcarifer) acclimated to different salinities reveals pathways involved with euryhalinity.…”

Assessing the chemical-induced estrogenicity using in silico and in vitro methods

“…The selection of this set of POPs was based on recent studies that warned about the endocrine disruptive potential of these chemicals and their mixtures (McComb et al, 2020;Shannon et al, 2019;Yadav et al, 2021). Moreover, their demonstrated presence in water, food, blood, and breast milk, arouses great interest in their analysis (Berntsen et al, 2017;Collet et al, 2020;Doan et al, 2020;Thomsen et al, 2010).…”