Activation of the estrogen receptor by human serum extracts containing mixtures of perfluorinated alkyl acids from pregnant women.

Humans are exposed to a wide variety of perfluorinated alkyl acids (PFAAs). Several studies have found xenoestrogenic activity of single PFAAs. Studies on mixture effects of the PFAAs are however sparse. In the present study, we aimed to determine the xenoestrogenic activity in human serum extracts containing mixtures of PFAAs. Recently we developed a method to extract the PFAAs from human serum with simultaneous removal of endogenous hormones and interfering steroid metabolites. We used this method to extract the PFAAs from serum of 397 Danish nulliparous pregnant women followed by analysis of estrogen receptor (ER) transactivation using MVLN cells carrying an estrogen response element luciferase reporter vector. Using 17β-estradiol (E2) concentration-transactivation curves, we calculated the estradiol equivalents (EEQ) for the extracts containing the PFAAs. Fifty-two percent of the PFAA serum extracts agonized the ER transactivation, and 46% enhanced the E2-induced ER transactivation. We found positive linear concentration-response associations between the ER transactivation and the PFAA serum levels. For the relatively few PFAA extracts that antagonized the ER in the presence of 24 pM E2 (n=38, 10%), we found inverse linear associations between the ER transactivation and the PFAA serum levels. The results indicated that the serum extracts induced the ER in a non-monotonic concentration dependent manner. The median EEQ of the extracts containing the PFAAs corresponds to the effect of 0.5pg E2 per mL serum. In conclusion, we observed that most of the extracts containing the PFAA mixtures from pregnant women's serum agonized the ER and enhanced the E2-induced effects in non-monotonic concentration-dependent manners.