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Exposure of androgen mimicking environmental chemicals enhances proliferation of prostate cancer (LNCaP) cells by inducing AR expression and epigenetic modifications
2021
Singh, Vipendra Kumar | Pal, Rajesh | Srivastava, Priyansh | Misra, Gauri | Shukla, Yogeshwer | Sharma, Pradeep Kumar
Exposure to environmental endocrine disrupting chemicals (EDCs) is highly suspected in prostate carcinogenesis. Though, estrogenicity is the most studied behavior of EDCs, the androgenic potential of most of the EDCs remains elusive. This study investigates the androgen mimicking potential of some common EDCs and their effect in androgen-dependent prostate cancer (LNCaP) cells. Based on the In silico interaction study, all the 8 EDCs tested were found to interact with androgen receptor with different binding energies. Further, the luciferase reporter activity confirmed the androgen mimicking potential of 4 EDCs namely benzo[a]pyrene, dichlorvos, genistein and β-endosulfan. Whereas, aldrin, malathion, tebuconazole and DDT were reported as antiandrogenic in luciferase reporter activity assay. Next, the nanomolar concentration of androgen mimicking EDCs (benzo[a]pyrene, dichlorvos, genistein and β-endosulfan) significantly enhanced the expression of AR protein and subsequent nuclear translocation in LNCaP cells. Our In silico studies further demonstrated that androgenic EDCs also bind with epigenetic regulatory enzymes namely DNMT1 and HDAC1. Moreover, exposure to these EDCs enhanced the protein expression of DNMT1 and HDAC1 in LNCaP cells. These observations suggest that EDCs may regulate proliferation in androgen sensitive LNCaP cells by acting as androgen mimicking ligands for AR signaling as well as by regulating epigenetic machinery. Both androgenic potential and epigenetic modulatory effects of EDCs may underlie the development and growth of prostate cancer.
Показать больше [+] Меньше [-]In vitro differential responses of rat and human aryl hydrocarbon receptor to two distinct ligands and to different polyphenols
2020
Doan, T.Q. | Connolly, L. | Igout, A. | Müller, M. | Scippo, M.L.
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and several other environment/food-borne toxic compounds induce their toxicity via the aryl hydrocarbon receptor (AhR). AhR is also modulated by various endogenous ligands e.g. highly potent tryptophan (Trp)-derivative FICZ (6-formylindolo[3,2-b]carbazole) and natural ligands abundant in the human diet e.g. polyphenols. Therefore, evaluating AhR species-specific responses is crucial for understanding AhR physiological functions, establishing risk assessments, and exploring the applicability of AhR mediators in drug and food industry towards human-based usages. We studied AhR transactivation of FICZ/TCDD in vitro in a time-dependent and species-specific manner using dioxin responsive luciferase reporter gene assays derived from rat (DR-H4IIE) and human (DR-HepG2) hepatoma cells. We observed for the first time that FICZ potency was similar in both cell lines and was 40 times higher than TCDD in DR-HepG2 cells. Depleting Trp-derivative endogenously produced ligands by using culture medium without Trp, resulted in 3-fold higher AhR activation upon adding FICZ in DR-H4IIE cells, in contrast to DR-HepG2 cells which revealed a fast degradation of FICZ induction from 10 h post-exposure to complete disappearance after 24 h. Seven polyphenols and a mixture thereof, chosen based on commercially recommended doses and adjusted to human realistic exposure, caused rat and human species-specific AhR responses. Two isoflavones (daidzein and genistein) induced rat AhR synergistic effects with FICZ and/or TCDD, while quercetin, chrysin, curcumin, resveratrol, and the mixture exerted a strong inhibitory effect on the human AhR. Strikingly, resveratrol and quercetin at their realistic nanomolar concentrations acted additively in the mixture to abolish human AhR activation induced by various TCDD concentrations. Taken together, these results illustrate the species-specific complexity of AhR transcriptional activities modulated by various ligands and highlight the need for studies of human-based approaches.
Показать больше [+] Меньше [-]Associations of maternal soy product consumption and urinary isoflavone concentrations with neonatal anthropometry: A prospective cohort study
2021
Chen, Yao | Li, Tao | Ji, Honglei | Wang, Xin | Sun, Xiaowei | Miao, Maohua | Wang, Yan | Wu, Qian | Liang, Hong | Yuan, Wei
Isoflavones (ISOs) are naturally occurring endocrine-disrupting compounds. Few human studies have evaluated the effects of ISO exposure on neonatal anthropometry. This study aimed to examine the associations of maternal soy product consumption and urinary ISO concentrations, including genistein, daidzein, glycitein, and equol, with neonatal anthropometry, based on a Chinese cohort study. In Shanghai-Minhang Birth Cohort Study, pregnant women at 12–16 weeks of gestation were recruited, and they completed a structured questionnaire to assess soy product consumption during pregnancy. They also provided a single spot urine sample for the ISO assay. Neonatal anthropometric indices (birth weight; arm, waist, and head circumference; and triceps, back, and abdominal skinfold thickness) were measured at birth. Multivariable linear regression analysis was performed among the 1188 mother-infant pairs to examine the associations between maternal soy product consumption and neonatal anthropometry. The same statistical model was applied to examine the associations between maternal ISO exposure and neonatal anthropometry among 480 mother-infant pairs. Neonate girls born to mothers who “sometimes” and “frequent” consumed soy products had 169.1 g (95% confidence interval [CI], −68.9–407.1) and 256.5 g (95% CI, 17.1–495.8) higher birth weight, respectively, than those born to mothers who “never” consumed soy products during pregnancy. We observed consistent associations between higher maternal urine ISO concentrations and increased anthropometric indices (birth weight, arm and waist circumference, and triceps and abdominal skinfold thickness) in neonate girls, while no association was observed among boys. The findings suggested that maternal dietary ISO intake during pregnancy is associated with fetal development in a sex-specific pattern. In addition, follow-up studies are required to evaluate whether the observed changes in anthropometric indices at birth are associated with health conditions later in life.
Показать больше [+] Меньше [-]Embryonic exposure to genistein induces anxiolytic and antisocial behavior in zebrafish: persistent effects until the adult stage
2022
Menegasso, Aloma Santin | Fortuna, Milena | Soares, Suelen Mendonça | Maffi, Victoria Costa | Mozzato, Mateus Timbola | Barcellos, Leonardo José Gil | Rossato-Grando, Luciana Grazziotin
Genistein is a phytoestrogen, which is structurally similar to 17β-estradiol. It is present in plants, food, and as a contaminant in effluents. In this article, we demonstrate the effects of embryonic exposure to three different concentrations of genistein (10 μg/L, 40 μg/L, and 80 μg/L) which is similar to those found in effluents. Zebrafish eggs were exposed during the first 72 h post-fertilization (hpf). Heart rate was evaluated at 48 hpf and mortality rate was assessed during the first 72 hpf. The light/dark (LDT) and open field (OFT) behavioral tests were applied to the larvae (6 dpf), and the novel tank (NTT), social preference (SPT), light-dark (LDT), and sexing tests were performed on adult fish (90 dpf). Embryonic exposure to genistein caused anxiolytic-like behavior in both larvae and adult animals. In adult stage, we observed an increase in locomotor activity and antisocial behavior in the concentration of 40 μg/L. There was an increase in the mortality rate in all concentrations when compared to the control and an increase in heart rate at the concentration of 80 μg/L. Exposure to 10 μg/L generated a higher frequency of females when compared to the control group. Our results show that exposure to genistein during the embryonic phase brings damage in the short and long term as it increases the mortality rate and leads to behavioral disorders both in the larval stage, with perpetuation until adult stage. The anxiolytic-like effect and less social interaction are effects that harm fish survival.
Показать больше [+] Меньше [-]In vitro estrogenic, cytotoxic, and genotoxic profiles of the xenoestrogens 8-prenylnaringenine, genistein and tartrazine
2021
Nasri, Atefeh | Pohjanvirta, Raimo
Phytoestrogens have been widely praised for their health-promoting effects, whereas synthetic environmental estrogens are considered a toxicological risk to human health. The aim of this study was therefore to compare in vitro the estrogenic, cytotoxic, and genotoxic profiles of three common estrogen-like endocrine-disrupting chemicals: the phytoestrogens 8-prenylnaringenine (8-PN) and genistein and the synthetic xenoestrogen tartrazine. As assessed by a yeast bioreporter assay and estrogen-dependent proliferative response in human mammary gland adenocarcinoma cell line (MCF-7), 8-PN showed the highest estrogen-like activity of the three compounds, followed by tartrazine and genistein. After 24-h incubation on MCF-7 cells, all three compounds exhibited low cytotoxicity in the lactate dehydrogenase assay and no genotoxicity in the micronucleus assay. These results demonstrate that 8-PN, genistein and tartrazine possess variable estrogenic activity but display little cellular toxicity in short-term tests in vitro. No difference between phytoestrogens and a synthetic xenoestrogen could be established.
Показать больше [+] Меньше [-]Distribution of six anticancer drugs and a variety of other pharmaceuticals, and their sorption onto sediments, in an urban Japanese river
2017
Azuma, Takashi | Arima, Natsumi | Tsukada, Ai | Hirami, Satoru | Matsuoka, Rie | Moriwake, Ryogo | Ishiuchi, Hirotaka | Inoyama, Tomomi | Teranishi, Yusuke | Yamaoka, Misato | Ishida, Mao | Hisamatsu, Kanae | Yunoki, Ayami | Mino, Yoshiki
The distributions of 31 pharmaceuticals grouped into nine therapeutic classes, including six anticancer drugs, were investigated in the waters and sediments of an urban river in Japan. The coefficients of sorption (logK d) to the river sediments were also determined from the results of a field survey and laboratory-scale experiment. Three anticancer drugs—bicalutamide, doxifluridine, and tamoxifen—were detected in the river sediments at maximum concentrations of 391, 392, and 250 ng/kg, respectively. In addition, the transformation products of psychotropic carbamazepine (2-hydroxy carbamazepine, acridine, and acridone) were detected in the range of 108 ng/kg (2-hydroxy carbamazepine) to 2365 ng/kg (acridine), and the phytoestrogen glycitein was detected in the range of N.D. to 821 ng/kg. The logK d values of the targeted pharmaceuticals in river sediments in the field survey ranged from 0.5 (theophylline) to 3.3 (azithromycin). These results were in accord with those of the laboratory-scale sorption experiment. To the best of our knowledge, this is the first report of the detection of the anticancer drugs bicalutamide and tamoxifen, the transformation products of carbamazepine (2-hydroxy carbamazepine, acridine, and acridone), and the phytoestrogen genistein in river sediments.
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