The endocrine disrupting alkylphenols and 4,4'-DDT interfere with estrogen conversion and clearance by mouse liver...

Endocrine disrupting chemicals (EDCs) are ubiquitous compounds known for negative impacts on reproductive functions and for increasing cancer risk. EDCs are believed to cause the harmful effects in part through their inappropriate low-affinity binding to steroid receptors and other possible non-receptor mediated paradigms, however there is a need to further elucidate other mechanisms involving the direct and indirect impact of EDCs on reproductive functions. We examined the metabolism of 17β-estradiol (E2) and estrone (E1) by cell-free hepatic cytosol in the presence of alkylphenols (nonylphenol/NP and 4-tert-octylphenol/tOP), Dichlorodiphenyltrichloroethane (4,4'-DDT) and other EDCs. Tandem liquid chromatography mass spectrometry was utilized to quantitatively assess the impact of each EDC on estrogen clearance, inter-conversions and downstream metabolism by mouse liver cytosol. The results revealed that NP and tOP (0.1-3μg/mL) significantly reduced the hepatic cytosol clearance and biotransformation of estrogens with inclination for accumulating E2, the stronger estrogen form, than E1. Alkylphenols also caused up to a 34-fold increase in the E2/E1 ratio possibly by suppressing the hepatic E2→E1 conversion by 17β-hydroxysteroid dehydrogenase (17βHSD) types 2, 4 while displaying a weaker inhibition of E1→E2 conversion by type 1, 17βHSD. On the other hand, the pesticide 4,4'-DDT was a weaker inhibitor of clearance of estrogens by the cytosol preparations when compared to alkylphenols, whereas chemicals such as phthalates and atrazine were ineffective. Our data suggest that exposure to NP, tOP and DDT can indirectly increase the estrogenic load by suppressing the hepatic clearance of estrogens and by elevating the E2/1 ratio and could therefore increase the risk of reproductive lesions.