Background:Atherosclerotic cardiovascular disease has become the leading cause of death worldwide, and environmental pollutants are increasingly recognized as risk factors for atherosclerosis. Liver X receptors (LXRs) play a central role in atherosclerosis; however, LXR activity of organic pollutants and associated potential risk of atherosclerosis have not yet been characterized.Objectives:This study aimed to explore whether LXR-antagonistic chemicals are present in indoor house dust and, if so, to characterize this activity in relation to changes in macrophages in vitro and cardiovascular disease indicators in vivo in an atherosclerosis ApoE−/− mouse model.Methods:We used a His-LXRα-pull-down assay and a nontarget high-resolution mass spectrometry method to screen house dust collected from Chinese homes for LXRα- and LXRβ-antagonist activity. A chemical identified in this manner was assessed for its ability to induce cholesterol efflux and foam cell formation in RAW264.7 macrophages, to down-regulate the expression of two LXR-dependent genes, ABCA1 and ABCG1, and finally to induce atherosclerotic lesions in vivo using an ApoE−/− mouse model.Results:We identified the flame retardants triphenyl phosphate (TPHP) and 2-ethylhexyl diphenyl phosphate (EHDPP) in house dust samples and demonstrated their ability to antagonize LXRs. The potency of TPHP was similar to that of the LXR-antagonist SR9238. TPHP could also inhibit cholesterol efflux and promote foam cell formation in RAW264.7 macrophages and mouse peritoneal macrophages and significantly promoted atherosclerotic lesion formation in the ApoE−/− mouse model.Conclusions:We found LXR-antagonist chemicals in environmental samples of indoor dust from Chinese homes. One of the chemicals, TPHP, was able to promote the development of atherosclerotic lesions in the ApoE−/− mouse model. These results highlight the need to assess the LXR-antagonist activities of pollutants in future environmental management programs. https://doi.org/10.1289/EHP5039
Since triphenyl phosphate (TPhP) elicits both antiestrogenic activities via blocking the estrogen receptor (ER) and estrogenic activity by elevating 17β-estradiol (17β-E2) synthesis, its adverse effect on female reproduction is uncertain. In this study, we exposed Japanese medaka to TPhP at 131, 363, and 1773 ng/L for 100 days following hatching. TPhP significantly induced ovary retardation in all exposure groups (incidence: from 11.9 to 37.8%) and reduced egg production by 38.9 and 50.9% in the 363 and 1773 ng/L exposure groups, respectively. Vitellogenin (vtg) transcription was significantly downregulated by 35.4–57.4% after TPhP exposure, explaining the ovary retardation. Considering that 17β-E2 was only significantly decreased in the 1773 ng/L exposure group, ER antagonism could be the dominant contributor to the inhibition of vtg transcription and female reproductive toxicity of TPhP. As 4-hydroxyphenyl diphenyl phosphate, a metabolite of TPhP, was detected in livers with similar concentration [68.4–1237 ng/g lipid weight (lw)] to that of TPhP (485–1594 ng/g lw) and elicited medaka ER antagonistic activity (50% inhibitory concentration = 78.1 μM), TPhP and its metabolite should both contribute to the reproductive inhibition. We demonstrate that TPhP at environmentally relevant concentrations is toxic to female reproduction, which poses an ecological risk to wild fish at the population level.
Background: Abnormal placental development may result in adverse pregnancy outcomes and metabolic diseases in adulthood; however, it remains unknown whether and how xenobiotics affect human placentation. Objectives: This study aimed to screen and identify placentation-disrupting chemicals in commonly used organophosphate flame retardants (OPFRs) and, if identified, to investigate potential adverse effects on placentation in relation to adverse pregnancy outcomes and metabolic disorder in offspring in mice. Methods: We devised a high-throughput immunofluorescence screening assay based on human trophoblast organoids and used it to screen OPFRs that inhibit the proliferation of organoids. One identified chemical was assessed for its effects on placentation by evaluating villous cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts using immunofluorescence and a mitochondrial stress test after 2 d of exposure. A 10-d exposure study was further performed to observe the dynamic effect of the OPFR on the structure of the organoids. RNA-sequencing and western blotting experiments were performed to explore the associated pathways, and a potential binding protein was identified by immunoprecipitation and in vitro kinase activity assays. Animal studies were performed to determine whether the findings in organoids could be replicated in mice and to observe adverse pregnancy outcomes. Results: The proliferation of organoids exposed to three aryl-OPFRs was significantly lower than the proliferation of control organoids. Further analysis demonstrated that one such chemical, 2-ethylhexyl-diphenyl phosphate (EHDPP), disrupted placentation in organoids. Mechanistically, EHDPP interfered with insulin-like growth factor 1 receptor (IGF1R) to inhibit aerobic respiration. Mice exposed to EHDPP at a physiological human concentrations exhibited immature and mature placental disorders, which correlated with fetal growth restriction, implantation failure, stillbirth, and impaired glucose tolerance. Conclusions: The human trophoblast organoid model showed that the commonly used OPFRs disrupted placentation via IGF1R, indicating that its use may contribute to adverse pregnancy outcomes and metabolic disorders in offspring. https://doi.org/10.1289/EHP10273
2-Ethylhexyl diphenyl phosphate (EHDPP) has been detected in wild fish with high concentrations, which may pose a risk in the embryo development considering its potential maternal transfer. In this study, EHDPP was demonstrated to elicit antagonistic activity to medaka retinoic acid receptor (mRAR) and retinoic X receptor (mRXR) with 50% inhibitory concentration of 18 and 36 μM, respectively. After adult female medaka were exposed to EHDPP at 156, 405, and 1161 ng/L for 35 days, the embryonic EHDPP concentrations (364−4824 ng/g lipid weight (lw)) were higher than those in the maternal tissues (15.0−4166 ng/g lw), showing notable maternal transfer. The embryonic concentration of EHDPP decreased limitedly during 1-2 day post-fertilization (dpf, the main developmental window of eye) but then decreased sharply after 2 dpf. The transcript abundance of cyp26a1 was inhibited and subsequent increasing embryonic alltrans RA level was observed in embryos, showing RAR/RXR antagonistic activity. These results may specifically contribute to the increased eye deformity incidences in all exposure groups (up to 8.0%; 51/637) relative to the control (1.0%, 7/733). The response behavior of the larvae to light stimulation was impaired in a dose-dependent manner, demonstrating a vision disorder. Because such developmental toxicities were observed at the environmental level, EHDPP may pose a threat to the survival of wild larvae and therefore a population risk for wild fish.
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