We tested 200 pesticides, including some of their isomers and metabolites, for agonism and antagonism to two human estrogen receptor (hER) subtypes, hERalpha and hERbeta, and a human androgen receptor (hAR) by highly sensitive transactivation assays using Chinese hamster ovary cells. The test compounds were classified into nine groups: organochlorines, diphenyl ethers, organophosphorus pesticides, pyrethroids, carbamates, acid amides, triazines, ureas, and others. These pesticides were tested at concentrations < 10-5 M. Of the 200 pesticides tested, 47 and 33 showed hER- and hERbeta-mediated estrogenic activities, respectively. Among them, 29 pesticides had both hERalpha and hERbeta agonistic activities, and the effects of the organochlorine insecticides beta-benzene hexachloride (BHC) and delta-BHC and the carbamate insecticide methiocarb were predominantly hERbeta rather than hERalpha agonistic. Weak antagonistic effects toward hERalpha and hERbeta were shown in five and two pesticides, respectively. On the other hand, none of tested pesticides showed hAR-mediated androgenic activity, but 66 of 200 pesticides exhibited inhibitory activity against the transcriptional activity induced by 5alpha-dihydrotestosterone. In particular, the antiandrogenic activities of two diphenyl ether herbicides, chlornitrofen and chlomethoxyfen, were higher than those of vinclozolin and p,p -dichlorodiphenyl dichloroethylene, known AR antagonists. The results of our ER and AR assays show that 34 pesticides possessed both estrogenic and antiandrogenic activities, indicating pleiotropic effects on hER and hAR. We also discussed chemical structures related to these activities. Taken together, our findings suggest that a variety of pesticides have estrogenic and/or antiandrogenic potential via ER and/or AR, and that numerous other manmade chemicals may also possess such estrogenic and antiandrogenic activities.

A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.

[1] Two large-scale cross-hole pumping tests were conducted at depths of 191-226 m and 662-706 m in deep boreholes at the Mizunami Underground Research Laboratory (MIU) construction site in central Japan. During these two tests, induced groundwater responses were monitored at many observation intervals at various depths in different boreholes at the site. We analyze the two cross-hole pumping tests using transient hydraulic tomography (THT) based on an efficient sequential successive linear estimator to compute the hydraulic conductivity (K) and specific storage (S s ) tomograms, as well as their uncertainties in three dimensions. The equivalent K and S s estimates obtained using asymptotic analysis treating the medium to be homogeneous served as the mean parameter estimates for the 3-D stochastic inverse modeling effort. Results show several, distinct, high K and low S s zones that are continuous over hundreds of meters, which appear to delineate fault zones and their connectivity. The THT analysis of the tests also identified a low K zone which corresponds with a known fault zone trending NNW and has been found to compartmentalize groundwater flow at the site. These results corroborate well with observed water level records, available fault information, and coseismic groundwater level responses during several large earthquakes. The successful application of THT to cross-hole pumping tests conducted in fractured granite at this site suggests that THT is a promising approach to delineate large-scale K and S s heterogeneities, fracture connectivity, and to quantify uncertainty of the estimated fields.

No abstract

Background: An increasing number of studies are reporting the existence of polybrominated diphenyl ethers (PBDEs) and their hydroxylated (HO) and methoxylated (MeO) metabolites in the environment and in tissues from wildlife and humans. oBjective: Our aim was to characterize and compare the agonistic and antagonistic activities of principle PBDE congeners and their HO and MeO metabolites against human nuclear hormone receptors. Methods: We tested the hormone receptor activities of estrogen receptor α (ERα), ERβ, androgen receptor (AR), glucocorticoid receptor (GR), thyroid hormone receptor α 1 (TRα 1 ), and TRβ 1 against PBDE congeners BDEs 15, 28, 47, 85, 99, 100, 153, and 209, four para-HO-PBDEs, and four para-MeO-PBDEs by highly sensitive reporter gene assays using Chinese hamster ovary cells. results: Of the 16 compounds tested, 6 and 2 showed agonistic activities in the ERα and ERβ assays, respectively, and 6 and 6 showed antagonistic activities in these assays. 4´-HO-BDE-17 showed the most potent estrogenic activity via ERα/β, and 4´-HO-BDE-49 showed the most potent anti estrogenic activity via ERα/β. In the AR assay, 13 compounds showed antagonistic activity, with 4´-HO-BDE-17 in particular inhibiting AR-mediated transcriptional activity at low concentrations in the order of 10 -8 M. In the GR assay, seven compounds, including two HO-PBDEs and two MeO-PBDEs, showed weak antagonistic activity. In the TRα 1 and TRβ 1 assays, only 4-HO-BDE-90 showed weak antagonistic activity. conclusions: Taken together, these results suggest that PBDEs and their metabolites might have multiple endocrine-disrupting effects via nuclear hormone receptors, and para-HO-PBDEs, in particular, possess more potent receptor activities compared with those of the parent PBDEs and corresponding para-MeO-PBDEs. key words: androgen receptor, brominated diphenyl ether, Chinese hamster ovary cells, estrogen receptor, glucocorticoid receptor, reporter gene assay, thyroid hormone receptor.