ABSTRACT
The production of chlorinated paraffins (CPs) has risen in the past two decades due to their versatile industrial applications. Consequently, CPs are now widely detected in human food sources, the environment, and in human matrices such as serum, the placenta and breast milk. This raises concern about prenatal and postnatal exposure. While some studies suggest that certain short-chained CPs (SCCPs) may have endocrine disrupting properties, knowledge about potential endocrine disrupting potential of medium- (MCCP) and long-chained CPs (LCCPs) remains relativity sparse. Here, we used a panel of in vitro assays to investigate seven pure CPs and two technical mixtures of CPs. These varied in chain length and, chlorination degree. The in vitro panel covered androgen, estrogen, and retinoic acid receptor activities, transthyretin displacement, and steroidogenesis. One of the SCCPs inhibited androgen receptor (AR) activity. All SCCPs induced estrogen receptor (ER) activity. Some SCCPs and MCCPs increased 17ß-estradiol levels in the steroidogenesis assay, though not consistently across all substances in these groups. SCCPs exhibited the most pronounced effects in multiple in vitro assays, while the tested LCCPs showed no effects. Based on our results, some CPs can have endocrine disrupting potential in vitro. These findings warrant further examinations to ensure that CPs do not cause issues in intact organisms, including humans.
Subject(s)
Hydrocarbons, Chlorinated , Paraffin , Humans , Paraffin/toxicity , Paraffin/analysis , Hydrocarbons, Chlorinated/toxicity , Hydrocarbons, Chlorinated/analysis , Environmental Monitoring/methods , Estrogens , ChinaABSTRACT
A suite of in vitro assays and in silico models were evaluated to identify which best detected the endocrine-disrupting (ED) potential of 10 test chemicals according to their estrogenic, androgenic and steroidogenic (EAS) potential compared to the outcomes from ToxCast. In vitro methods included receptor-binding, CALUX transactivation, H295R steroidogenesis, aromatase activity inhibition and the Yeast oestrogen (YES) and Yeast androgen screen (YAS) assays. The impact of metabolism was also evaluated. The YES/YAS assays exhibited a high sensitivity for ER effects and, despite some challenges in predicting AR effects, is a good initial screening assay. Results from receptor-binding and CALUX assays generally correlated and were in accordance with classifications based on ToxCast assays. ER agonism and AR antagonism of benzyl butyl phthalate were abolished when CALUX assays included liver S9. In silico final calls were mostly in agreement with the in vitro assays, and predicted ER and AR effects well. The efficiency of the in silico models (reflecting applicability domains or inconclusive results) was 43-100%. The percentage of correct calls for ER (50-100%), AR (57-100%) and aromatase (33-100%) effects when compared to the final ToxCast call covered a wide range from highly reliable to less reliable models. In conclusion, Danish (Q)SAR, Opera, ADMET Lab LBD and ProToxII models demonstrated the best overall performance for ER and AR effects. These can be combined with the YES/YAS assays in an initial screen of chemicals in the early tiers of an NGRA to inform on the MoA and the design of mechanistic in vitro assays used later in the assessment. Inhibition of aromatase was best predicted by the Vega, AdmetLab and ProToxII models. Other mechanisms and exposure should be considered when making a conclusion with respect to ED effects.
Subject(s)
Androgens , Endocrine Disruptors , Androgens/metabolism , Androgens/pharmacology , Estrogens/pharmacology , Aromatase , Saccharomyces cerevisiae/metabolism , Receptors, Androgen/metabolism , Estrone , Endocrine Disruptors/chemistryABSTRACT
This study was carried out to provide the evidence with respect to the adverse potential of chlorpropham, a representative carbamate ester herbicide product, on the endocrine system by using in vitro testing methods in accordance with the Organization for Economic Cooperation and Development Test Guideline No. 458 (22Rv1/MMTV_GR-KO human androgen receptor [AR] transcriptional activation assay) and a bioluminescence resonance energy transfer-based AR homodimerization assay. Results revealed that chlorpropham had no AR agonistic effects, but it was determined to be a true AR antagonist without intrinsic toxicity against the applied cell lines. In the mechanism of chlorpropham-induced AR-mediated adverse effects, chlorpropham suppressed cytoplasmic AR translocation to the nucleus by inhibiting the homodimerization of the activated ARs. This suggests that chlorpropham exposure caused endocrine-disrupting effects through its interactions with human AR. Additionally, this study might help identify the genomic pathway of the AR-mediated endocrine-disrupting potential of N-phenyl carbamate herbicides.
Subject(s)
Chlorpropham , Herbicides , Humans , Chlorpropham/metabolism , Chlorpropham/toxicity , Herbicides/toxicity , Herbicides/metabolism , Receptors, Androgen , Androgens , Carbamates/toxicity , Endocrine SystemABSTRACT
Bisphenol A (BPA) is a high production volume chemical with a broad application spectrum. As an endocrine disrupting chemical, mainly by modulation of nuclear receptors (NRs), BPA has an adverse impact on organisms and is identified as a substance of very high concern under the European REACH regulation. Various BPA substitution candidates have been developed in recent years, however, information concerning the endocrine disrupting potential of these substances is still incomplete or missing. In this study, we intended to investigate the endocrine potential of BPA substitution candidates used in environmentally relevant applications such as thermal paper or epoxy resins. Based on an extensive literature and patent search, 33 environmentally relevant BPA substitution candidates were identified. In order to evaluate the endocrine potential of the BPA replacements, a screening cascade consisting of biochemical and cell-based assays was employed to investigate substance binding to the NRs estrogen receptor α and ß, as well as androgen receptor, co-activator recruitment and NR-mediated reporter gene activation. In addition, a computational docking approach for retrospective prediction of receptor binding was carried out. Our results show that some BPA substitution candidates, for which so far no or only very few data were available, possess a substantial endocrine disrupting potential (TDP, BPZ), while several substances (BPS, D-8, DD70, DMP-OH, TBSA, D4, CBDO, ISO, VITC, DPA, and DOPO) did not reveal any NR binding.
Subject(s)
Benzhydryl Compounds/chemistry , Phenols/chemistry , Endocrine Disruptors , Receptors, Androgen , Retrospective StudiesABSTRACT
BACKGROUND: Surface waters receive a variety of organic pollutants via wastewater discharge, and sediment represents a sink for hydrophobic contaminants. In this study, we used in vitro yeast-based reporter gene assays and a Bacillus subtilis Rec-assay to examine the occurrence of endocrine disrupting activities and genotoxic potentials in samples collected from three Taiwanese rivers. Levels of 51 polycyclic aromatic hydrocarbons (PAHs) in muscles of fish captured from same rivers were also analyzed to assess in vivo pollution of PAHs. RESULTS: Antagonist activities for androgen receptor and retinoid X receptor (RXR) were detected in river water extracts at environmentally relevant concentrations., and sediment extracts exhibited RXR agonist, RXR antagonist, and genotoxic potentials concurrently. Σ16 PAHs in fish muscles ranged from 44.9-242.4 ng g- 1 dry weight, representing 38 to 59% of the total 51 PAHs concentrations, and methylated PAHs of low molecular weight PAHs were often detected as well. CONCLUSION: Taiwanese river sediment samples concomitantly exhibited RXR disrupting potentials and genotoxic activities, whereas RXR agonist and antagonist activities were simultaneously detected in several dry-season sediment extracts. PAH levels in fish muscles were categorized as minimally polluted by aromatic compounds, nonetheless, the presence of methylated PAHs in muscles samples may be of concern owing to the higher toxic potentials than their parent compounds.
ABSTRACT
Endocrine disrupting potentials were assessed for sediment samples collected near Hebei Spirit oil spill (HSOS) site, between December 2007 and January 2012. For comparison, major crude oil (CO) of HSOS, or its weathered form were assessed. Both raw extracts (REs) and their fractionated samples were tested using H295R and MVLNluc bioassays. In H295R cells, REs of crude and weathered oil (WO), and nine of 14 sediments significantly increased E2 levels, which were correlated with the concentrations of PAHs. Steroidogenic disruption potentials of the sediments generally decreased over time. Among silica fractions of all REs, aromatic hydrocarbons (F2) and polar compounds (F3) caused greater E2 levels. While, in MVLN cell bioassay, only three of 14 sediment REs showed estrogen receptor binding potencies, and no temporal trend was observed. In conclusion, oil spill can cause endocrine disruption in the affected ecosystem through steroidogenic alteration for years, and such potencies attenuate over time.