Carbon chain length of perfluoroalkylated carboxylic acids determines inhibitory strength on gonadal 38-hydroxysteroid dehydrogenases in humans, rats, and mice

Perfluoroalkylated carboxylic acids (PFCAs) are a subclass of man-made chemicals that have been widely used in industrial production and consumer products. As a result, PFCAs have been found to accumulate in the environment and bioaccumulate in organisms, leading to potential health and environmental impacts. This study investigated the inhibition of 11 PFCAs on gonadal 38-hydroxysteroid dehydrogenases in humans, rats, and mice. We observed a V-shaped inhibition pattern against human granulosa (KGN) cell 38-HSD2 starting from C9 (half -maximal inhibitory concentration, IC50, 100.8 mu M) to C11 (8.92 mu M), with a V-shaped turn. The same V-shaped inhibition pattern was also observed for PFCAs against rat testicular 38-HSD1 from C9 (IC50, 50.43 mu M) to C11 (6.60 mu M). Mouse gonadal 38-HSD6 was insensitive to the inhibition of PFCAs, with an IC50 of 50.43 mu M for C11. All of these PFCAs were mixed inhibitors of gonadal 38-HSDs. Docking analysis showed that PFCAs bind to the nicotinamide adenine dinucleotide (NAD+)/steroid binding sites of these enzymes and bivariate correlation analysis showed that molecular length determines the inhibitory pattern of PFCAs on these enzymes. In conclusion, the carbon chain length determines the inhibitory strength of PFCAs on human, rat, and mouse gonadal 38-HSDs, and the inhibitory strength of PFCAs against human and rat 38-HSD enzymes shows V-shaped turn.