- Membrane and Nuclear Initiated Estrogenic Regulation of Homeostasis. [Journal Article]
- SSteroids 2019 Jun 20; :108428
- Reproduction and energy balance are inextricably linked in order to optimize the evolutionary fitness of an organism. With insufficient or excessive energy stores a female is liable to suffer complic…
Reproduction and energy balance are inextricably linked in order to optimize the evolutionary fitness of an organism. With insufficient or excessive energy stores a female is liable to suffer complications during pregnancy and produce unhealthy or obesity-prone offspring. The quintessential function of the hypothalamus is to act as a bridge between the endocrine and nervous systems, coordinating fertility and autonomic functions. Across the female reproductive cycle various motivations wax and wane, following levels of ovarian hormones. Estrogens, more specifically 17β-estradiol (E2), coordinate a triumvirate of hypothalamic neurons within the arcuate nucleus (ARH) that govern the physiological underpinnings of these behavioral dynamics. Arising from a common progenitor pool of cells, this triumvirate is composed of the kisspeptin (Kiss1ARH), proopiomelanocortin (POMC), and agouti related/neuropeptide Y (AgRP) neurons. Although the excitability of these neuronal subpopulations is subject to genomic and rapid estrogenic regulation, kisspeptin neurons are the most sensitive, reflecting their integral function in female fertility. Based on the premise that E2 coordinates autonomic functions around reproduction, we will review the recent findings on the synaptic interactions between Kiss1, AgRP and POMC neurons and how the rapid membrane-initiated and intracellular signaling cascades activated by E2 in these neurons are critical for control of homeostatic functions supporting reproduction.
- In vitro assessment of effects of persistent organic pollutants on the transactivation of estrogen receptor α and β (ERα and ERβ) from the Baikal seal (Pusa sibirica). [Journal Article]
- EEEcotoxicol Environ Saf 2019 Jun 19; 181:463-471
- To assess the effect of exposure to persistent organic pollutants (POPs) on the estrogen receptor (ER) signaling pathway in Baikal seals (Pusa sibirica), we investigated the molecular characterizatio…
To assess the effect of exposure to persistent organic pollutants (POPs) on the estrogen receptor (ER) signaling pathway in Baikal seals (Pusa sibirica), we investigated the molecular characterizations and functions of two Baikal seal ER (bsER) isoforms, bsERα and bsERβ. The bsERα and bsERβ cDNA clones isolated have an open reading frame of 595 and 530 amino acid residues, respectively. The tissue distribution analyses of bsER mRNAs showed that bsERα transcripts were primarily found in the ovary and uterus, and bsERβ in the muscle in wild Baikal seals. The immunofluorescence staining assay showed that 17β-estradiol (E2) treatment promoted the nuclear translocation of in vitro-expressed bsERα. Transient transfection of bsERα in U2OS cells enhanced the transcription of pS2, an ER target gene of E2. We then measured bsER-mediated transactivation potencies of POPs in an in vitro reporter gene assay system, in which a bsERα or bsERβ expression vector was transfected into COS-1 cells. For comparison, transactivation potencies of POPs on mouse ERs (mERα and mERβ) were also evaluated in the same manner. Results showed significant dose-dependent responses of bsERs and mERs when treated with p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE). bsERs and mERs showed no response when exposed to polychlorinated biphenyls (PCBs) or 2,3,7,8-tetrachlorodibenzo-p-dioxin. Comparison of the dose-response curves of DDTs across species (bsERs vs. mERs) showed that bsERα had a response similar to mERα, but bsERβ was less sensitive than mERβ. Comparing the lowest observable effective concentrations of p,p'-DDT (2.8 μM) and p,p'-DDE (10 μM) for in vitro bsERα-mediated transactivation with their hepatic concentrations in wild Baikal seals indicated that some individuals accumulated these compounds at levels comparable to the effective concentrations, suggesting the potential disruption of the bsERα signaling pathway in the wild population by these compounds. Co-transfection experiments with bsER and the aryl hydrocarbon receptor (AHR) suggested that high accumulation of estrogenic compounds exerts a synergistic effect with dioxin-like congeners on ER signaling through AHR activation in the wild seal population.
- Transcriptomic points-of-departure from short-term exposure studies are protective of chronic effects for fish exposed to estrogenic chemicals. [Journal Article]
- TAToxicol Appl Pharmacol 2019 Jun 18; :114634
- Resource limitations often require risk assessors to extrapolate chronic toxicity from acute tests using assessment factors. Transcriptomic dose-response analysis following short-term exposures may p…
Resource limitations often require risk assessors to extrapolate chronic toxicity from acute tests using assessment factors. Transcriptomic dose-response analysis following short-term exposures may provide a more reliable and biologically-based alternative for estimating chronic toxicity. Here, we demonstrate that transcriptomic dose-response analysis in fish following short-term exposure to endocrine disrupting chemicals (EDCs) provides estimates of chronic toxicity that may be used as protective points-of-departure (POD) for risk assessment. The benchmark dose (BMD) method was used on publicly available datasets (n = 5) to determine transcriptomic PODs in fish exposed to three EDCs (bisphenol A, ethinylestradiol, and diethylstilbesterol). To test for potential bias related to data processing, our analysis compared the effect of different normalization, filtering, and BMD-grouping methods on the transcriptomic PODs. The resulting PODs were then compared to the empirically-derived chronic LOEC of each substance. Normalization and filtering methods had limited impact on the final PODs. However, we found that PODs derived from ontology- or pathway-based gene grouping methods were highly variable, whereas PODs from grouping methods that focused on the most responsive genes were more stable and provided POD estimates that were most similar to the chronic LOEC. Overall, 72% of transcriptomic PODs were within 1 order of magnitude of the chronic LOEC, regardless of data analysis method. When our recommended analysis approach was applied, the concordance improved to 100%. These results suggest that toxicogenomic dose-response analysis has the potential to be a protective decision-support tool for compounds with chronic toxicity, such as EDCs.
- Circaea Mollis Siebold & Zucc. Prevents Bone Loss in a Mouse Postmenopausal Osteoporosis Model by Promoting of Osteoblast Differentiation (P06-130-19). [Journal Article]
- CDCurr Dev Nutr 2019; 3(Suppl 1)
- CONCLUSIONS: EECM enhanced the differentiation of osteoblasts via osteogenic markers and modulated RANK/RANKL signaling via an elevation of OPG from osteoblasts in vitro and in vivo. Therefore, EECM may be effective in preventing bone loss and offers a promising alternative for the nutritional management of postmenopausal osteoporosis.
- Long-time qingyan formula extract treatment exerts estrogenic activities on reproductive tissues without side effects in ovariectomized rats and via active ER to ERE-independent gene regulation. [Journal Article]
- AAging (Albany NY) 2019 Jun 19
- The reproductive tissues are negatively influenced by estrogens in hormone therapy. Qingyan formula ethanol extract (QYFE)'s estrogenic effects and safety on reproductive tissues after long-term admi…
The reproductive tissues are negatively influenced by estrogens in hormone therapy. Qingyan formula ethanol extract (QYFE)'s estrogenic effects and safety on reproductive tissues after long-term administration and its mechanism via estrogen receptor (ER) pathway haven't been studied. Here, we characterized its estrogenic effects using ovariectomized rats together with in vitro studies for further molecular characterization. Ovariectomized rats were treated with QYFE at doses of 0.7, 1.4, and 2.8g/kg for 12 weeks. The results showed QYFE has a potent estrogenic activity, as indicated by restoring the disappeared estrous cycle, antagonizing the atrophy of uterus, vagina and mammary gland, and the estrogen decline in circulation caused by ovariectomy. In addition, QYFE upregulated ERα and ERβ expressions and had a less stimulatory effect on PCNA and ki-67 antigen in reproductive tissues compared with estradiol valerate. QYFE components can bind to ERα and ERβ, significantly increased ERα/β-ERE luciferase reporter gene expression, upregulated the expressions of ERs, PR and pS2 in MCF-7 cells at protein and gene level. All these activities were significantly inhibited by the ER antagonist ICI182,780. QYFE's estrogenic activity maybe mediated by stimulating biosynthesis of estrogen and increasing the quantity of ERs in target tissue and via active ER to ERE-independent gene regulation.
- Hepatic steroid sulfatase critically determines estrogenic activities of conjugated equine estrogens in human cells in vitro and in mice. [Journal Article]
- JBJ Biol Chem 2019 Jun 19
- Conjugated equine estrogens (CEEs), whose brand name is Premarin, are widely used as a hormone-replacement therapy (HRT) drug to manage postmenopausal symptoms in women. Extracted from pregnant mare …
Conjugated equine estrogens (CEEs), whose brand name is Premarin, are widely used as a hormone-replacement therapy (HRT) drug to manage postmenopausal symptoms in women. Extracted from pregnant mare urine, CEEs are composed of nearly a dozen estrogens existing in an inactive sulfated form. To determine whether the hepatic steroid sulfatase (STS) is a key contributor to the efficacy of CEEs in HRT, we performed estrogen responsive element (ERE) reporter gene assay, real-time PCR, and UPLC/MS-MS to assess the STS-dependent and inflammation-responsive estrogenic activity of CEEs in HepG2 cells and human primary hepatocytes. Using liver-specific STS-expressing transgenic mice, we also evaluated the effect of STS on the estrogenic activity of CEEs in vivo. We observed that CEEs induce activity of the ERE reporter gene in an STS-dependent manner and that genetic or pharmacological inhibition of STS attenuates CEE estrogenic activity. In hepatocytes, inflammation enhanced CEE estrogenic activity by inducting STS gene expression. The inflammation-responsive estrogenic activity of CEEs, in turn, attenuated inflammation through the anti-inflammatory activity of the active estrogens. In vivo, transgenic mice with liver-specific STS expression exhibited markedly increased sensitivity to CEE-induced estrogenic activity in the uterus resulting from increased levels of liver-derived and circulating estrogens. Our results reveal an critical role of hepatic STS in mediating the hormone- replacing activity of CEEs. We propose that caution needs to be applied when Premarin is used in patients with chronic inflammatory liver diseases, because such patients may have heightened sensitivity to CEEs due to the inflammatory induction of STS activity.
- Safety and Efficacy Assessment of Isoflavones from Pueraria (Kudzu) Flower Extract in Ovariectomised Mice: A Comparison with Soy Isoflavones. [Journal Article]
- IJInt J Mol Sci 2019 Jun 12; 20(12)
- Numerous Foods with Function Claims that contain the extract of Pueraria flower (kudzu) isoflavones (PFI) are available in the Japanese market. These are labelled with function claims of reducing vis…
Numerous Foods with Function Claims that contain the extract of Pueraria flower (kudzu) isoflavones (PFI) are available in the Japanese market. These are labelled with function claims of reducing visceral fat. However, these foods have not undergone proper safety assessment such as the evaluation of their oestrogenic activity and effects on drug-metabolising enzymes (cytochrome P-450: CYP) in the liver. This study evaluated the estrogenic effect and the hepatic CYP activity and mRNA expression in normal female mice as a safety assessment of PFI (Experiment 1). In addition, the bone mineral density and visceral fat weight in ovariectomised mice (OVX) compared to soy isoflavones (SI) was evaluated to assess the efficacy of PFI (Experiment 2). OVX control fed a control diet, OVX fed a PFI diet (the recommended human intake of PFI), OVX fed a PFI20 diet (20- times the recommended PFI), OVX fed an SI diet (the recommended human intake of SI), and OVX fed an SI20 diet (20 -times the recommended intake of SI) for 28 days in Experiment 2. Body, liver, and visceral fat weights were not affected by the PFI, PFI20, SI, or SI20 diets. The hepatic CYP1A and CYP3A activities were elevated by the SI20 treatment. Ovariectomy-induced bone loss was inhibited by the SI20 treatment, but not by the PFI20 treatment. These results suggest that (1) PFI intake in human doses had no oestrogenic properties and did not affect CYP activity in the liver; (2) there was no evidence that PFI affects the amount of visceral fat in OVX mice.
- Estrogenic Compounds or Adiponectin Inhibit Cyclic AMP Response to Human Luteinizing Hormone in Mouse Leydig Tumor Cells. [Journal Article]
- BBiology (Basel) 2019 Jun 11; 8(2)
- Mouse Leydig Tumor cells (mLTC), transiently expressing cAMP-dependent luciferase, were used to study the influence of sexual steroids and of adiponectin (ADPN) on the cAMP response to luteinizing ho…
Mouse Leydig Tumor cells (mLTC), transiently expressing cAMP-dependent luciferase, were used to study the influence of sexual steroids and of adiponectin (ADPN) on the cAMP response to luteinizing hormones (LH). While testosterone and progesterone had no significant effect, several molecules with estrogenic activity (17β-estradiol, ethynylestradiol, and bisphenol A) provoked a decrease in intracellular cyclic AMP accumulation under 0.7 nM human LH stimulation. Adiponectin exhibited a bimodal dose-effect on LH response: synergistic between 2-125 ng/mL and inhibitory between 0.5-5 µg/mL. In brief, our data indicate that estrogens and ADPN separately exert rapid (<1 h) inhibitory and/or synergistic effects on cAMP response to LH in mLTC-1 cells. As the inhibitory effect of each estrogenic molecule was observed after only 1-h preincubation, it might be mediated through the G protein-coupled estrogen receptor (GPER) membrane receptor, but this remains to be demonstrated. The synergistic effect with low concentrations of ADPN with human Luteinizing Hormone (hLH) was observed with both fresh and frozen/thawed ADPN. In contrast, the inhibitory effect with high concentrations of ADPN was lost with frozen/thawed ADPN, suggesting deterioration of its polymeric structure.
- Nonylphenol causes shifts in microbial communities and nitrogen mineralization in soil microcosms. [Journal Article]
- EEEcotoxicol Environ Saf 2019 Jun 15; 181:395-403
- The aims of this work was to investigate, in soil microcosms, the effects on soil microbial community structure and function of increasing concentrations of 4-Nonylphenol (NP). The lasts is a product…
The aims of this work was to investigate, in soil microcosms, the effects on soil microbial community structure and function of increasing concentrations of 4-Nonylphenol (NP). The lasts is a product of degradation of NPEOs (Nonylphenol polyethoxylates) with a known toxic and estrogenic capacity able to disrupt animal's hormonal systems. The effect of increasing concentrations of NP (0, 10, 30, 90, and 270 mg NP kg-1 of dry soil) in soil microcosms in three sampling dates (28, 56, and 112 days) over soil microbial activity and function were assessed. Soil microbial activity was estimated by microbial ATP content, and both bacterial and fungal communities composition were estimated using the terminal restriction fragment length polymorphism technique (T-RFLP). Abundance of ammonia-oxidizing bacteria (AOB) was estimated by qPCR of gene encoding for the bacterial ammonia-monoxygenase (amoA). Changes in biologically mediated soil properties were also assessed, namely water-soluble NH+4, NO-2 and NO-3 content, the two last allowing the assessment of mineralization rates. NP-spiking had some unexpected impacts on microbial community structure and functions, since (i) impacted both bacterial and fungal communities structure at the highest NP concentration tested, bacterial communities were resistant to lower concentrations, while fungal communities were increasingly impacted until the end of the incubation at day 112; (ii) no community structure resilience was observed in bacteria at the highest NP concentration nor for fungi at any concentration; (iii) microbial activity decreased with NP after 28 and 56 d, but increased in the last sampling at the highest concentrations tests, coupled to an enrichment in AOB taxa after 56 and 112 days, that at least partly explain also explain the observed speed up of nitrification rates.
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- Benzyl butyl phthalate (BBP) triggers the migration and invasion of hemangioma cells via upregulation of Zeb1. [Journal Article]
- TVToxicol In Vitro 2019 Jun 15
- Hemangioma (HA) are tumors formed by hyper-proliferation of vascular endothelial cells. As a potential endocrine disrupting chemical (EDC), benzyl butyl phthalate (BBP) can mimic estrogen to disturb …
Hemangioma (HA) are tumors formed by hyper-proliferation of vascular endothelial cells. As a potential endocrine disrupting chemical (EDC), benzyl butyl phthalate (BBP) can mimic estrogen to disturb the estrogenic signals. Our present study investigated the potential roles of phthalates on the progression of HA and found that 100 nM BBP can significantly trigger the migration and invasion of HA cells, which was evidenced by the results that BBP can induce the expression of matrix metalloproteinase (MMPs) and vimentin. Further, BBP can increase the expression of Zeb1, one powerful transcription factor for cell migration and invasion. Targeted inhibition of Zeb1 blocked BBP induced cell migration. Mechanistically, BBP can increase the mRNA stability of Zeb1 via suppression of miR-655. Further, BBP can enhance the protein stability of Zeb1 via upregulation of ataxia telangiectasia mutated (ATM). Collectively, our present study revealed that BBP can trigger the migration and invasion of HA cells via upregulation of Zeb1.