Carbon-chain length dictates per- and polyfluorinated substance potency as inhibitors of human and rat 11β-hydroxysteroid dehydrogenase 1

Per - and polyfluorinated substances (PFAS) are synthetic, long-lasting contaminants that persist in the environment. However, it is still unknown whether these chemicals can inhibit the activity of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in humans and rats to disrupt glucocorticoid metabolism. Eighteen PFAS (11 carboxylic acids and 7 sulfonic acids) were used to analyze their inhibition on human and rat 11β-HSD1 activity. Eight of the eleven PFAS carboxylic acids (from C7 to C14) gradually inhibited human 11β-HSD1 with the increase of carbon-chain length (inhibitory potency was C4-C6 < C7 < C8 < C9 < C10 < C11 < C12 < C13 < C14). The IC 50 values of perfluoroheptanoic acid (C7) and perfluorotetradecanoic acid (C14) were 100.4 and 10.33 μM, respectively. Perfluorooctanesulfonic acid (PFOS, C8) from 7 sulfonic acids can significantly inhibit human 11β-HSD1. The carbon-chain length, carbon atom number, fluorine atom number, molecular weight, rotatable bonds, boiling point, and melting point, pKa, apolar desolvation, and polar desolvation, and LogP were negatively correlated with IC 50 values to inhibit human 11β-HSD1 (the higher the number, the lower the IC 50 value, thus, stronger inhibition). On the contrary, LogS, Gibbs free energy, and lowest binding energy were positively correlated with IC 50 values. All these chemicals bind to steroid binding site of human 11β-HSD1 as competitive or mixed inhibitors. Only perfluorononanoic acid (C9, IC 50  = 128.2 μM) and perfluorodecanoic acid (C10, 68.21 μM) markedly inhibited rat 11β-HSD1. In conclusion, PFAS show structure-dependent inhibition on human 11β-HSD1 and they increase inhibitory potency with the increase in carbon-chain length, and rat enzyme is less sensitive to the inhibition of these chemicals.