Evaluation of estrogenic activity at low doses of bisphenol A using a novel in vivo detection method

Abstract

Bisphenol A (BPA) have been used to manufacture polycarbonate plastic and reported to exhibit endocrine-disrupting effects via estrogenic action in animals. There are concerns that BPA has low-dose, adverse effects that could be detected at doses lower than the NOAEL. However, the low-dose effects of BPA cannot be detected in guideline-confirming toxicity tests such as the uterotrophic bioassay, which is an in vivo screening method for detecting the estrogenic activity of chemicals. Therefore, these effects, including their authenticity, have not been fully clarified and the debate about them is ongoing. Here, we tried to develop a novel, highly sensitive, screening method for estrogen-like chemicals using in vivo bioluminescence imaging of estrogen-responsive reporter (E-Rep) mice. First, we compared the detection sensitivity between two endpoints (bioluminescence and uterine weight) within the same E-Rep mouse using 17α-ethinylestradiol (a reference estrogen) and bazedoxifene acetate (a selective estrogen receptor modulator), and demonstrated that the method using bioluminescence as an endpoint provides higher detection sensitivity than the uterotrophic bioassay. Moreover, the method using bioluminescence of E-Rep mice could detect the estrogenic effects of BPA at doses below the NOAEL. Our results suggested that in vivo bioluminescence imaging using E-Rep mice was extremely useful for screening estrogen-like chemicals. Our method could greatly facilitate resolution of questions associated with low-dose effects of estrogen-like chemicals, including BPA.