The in vivo developmental toxicity of diethylstilbestrol (DES) in rat evaluated by an alternative testing strategy
Adam, Aziza Hussein Bakheit ; Zhang, Mengying ; Haan, Laura H.J. de; Ravenzwaay, Bennard van; Louisse, Jochem ; Rietjens, Ivonne M.C.M. - \ 2019
Archives of Toxicology 93 (2019)7. - ISSN 0340-5761 - p. 2021 - 2033.
Developmental toxicity - Diethylstilbestrol - Estrogen receptor alpha (ERα) - Physiologically based kinetic modelling - Reverse dosimetry
In the present study, we evaluated an alternative testing strategy to quantitatively predict the in vivo developmental toxicity of the synthetic hormone diethylstilbestrol (DES). To this end, a physiologically based kinetic (PBK) model was defined that was subsequently used to translate concentration–response data for the in vitro developmental toxicity of DES, obtained in the ES-D3 cell differentiation assay, into predicted in vivo dose–response data for developmental toxicity. The previous studies showed that the PBK model-facilitated reverse dosimetry approach is a useful approach to quantitatively predict the developmental toxicity of several developmental toxins. The results obtained in the present study show that the PBK model adequately predicted DES blood concentrations in rats. Further studies revealed that DES tested positive in the ES-D3 differentiation assay and that DES-induced inhibition of the ES-D3 cell differentiation could be counteracted by the estrogen receptor alpha (ERα) antagonist fulvestrant, indicating that the in vitro ES-D3 cell differentiation assay was able to mimic the role of ERα reported in the mode of action underlying the developmental toxicity of DES in vivo. In spite of this, combining these in vitro data with the PBK model did not adequately predict the in vivo developmental toxicity of DES in a quantitative way. It is concluded that although the EST qualifies DES as a developmental toxin and detects the role of ERα in this process, the ES-D3 cell differentiation assay of the EST apparently does not adequately capture the processes underlying DES-induced developmental toxicity in vivo.
Towards a generic physiologically based kinetic model to predict in vivo uterotrophic responses in rats by reverse dosimetry of in vitro estrogenicity data
Zhang, Mengying ; Ravenzwaay, Bennard van; Fabian, Eric ; Rietjens, Ivonne M.C.M. ; Louisse, Jochem - \ 2018
Archives of Toxicology 92 (2018)3. - ISSN 0340-5761 - p. 1075 - 1088.
17β-estradiol - Bisphenol A - In vitro–in vivo extrapolation - Physiologically based kinetic modelling - Reverse dosimetry - Uterotrophic assay
Physiologically based kinetic (PBK) modelling-based reverse dosimetry is a promising tool for the prediction of in vivo developmental toxicity using in vitro concentration–response data. In the present study, the potential of this approach to predict the dose-dependent increase of uterus weight in rats upon exposure to estrogenic chemicals was assessed. In vitro concentration–response data of 17β-estradiol (E2) and bisphenol A (BPA) obtained in the MCF-7/BOS proliferation assay, the U2OS ER-CALUX assay and the yeast estrogen screen (YES) assay, were translated into in vivo dose–response data in rat, using a PBK model with a minimum number of in vitro and in silico determined parameter values. To evaluate the predictions made, benchmark dose (BMD) analysis was performed on the predicted dose–response data and the obtained BMDL10 values were compared with BMDL10 values derived from data on the effects of E2 and BPA in the uterotrophic assay reported in the literature. The results show that predicted dose–response data of E2 and BPA matched with the data from in vivo studies when predictions were made based on YES assay data. The YES assay-based predictions of the BMDL10 values differed 3.9-fold (E2) and 4.7- to 13.4-fold (BPA) from the BMDL10 values obtained from the in vivo data. The present study provides the proof-of-principle that PBK modelling-based reverse dosimetry of YES assay data using a minimum PBK model can predict dose-dependent in vivo uterus growth caused by estrogenic chemicals. In future studies, the approach should be extended to include other estrogens.