Antiandrogenic Activity Research Articles

Removal of oxidative stress and genotoxic activities during drinking water production by ozonation and granular activated carbon filtration

BackgroundBioanalytical tools have been shown to be useful in drinking water quality assessments. Here, we applied a panel of in vitro bioassays to assess the treatment efficiency of two pilot-scale treatments: ozonation and granular activated carbon (GAC) filtration at a drinking water treatment plant (DWTP). The pilot-scale systems were studied alongside a full-scale treatment process consisting of biological activated carbon (BAC) filtration, UV disinfection, and monochloramine dosing. Both systems were fed the same raw water treated with coagulation/flocculation/sedimentation and sand filtration. The endpoints studied were oxidative stress (Nrf2 activity), genotoxicity (micronuclei formations), aryl hydrocarbon receptor (AhR) activation, as well as estrogen receptor (ER) and androgen receptor (AR) activity.ResultsNrf2, AhR, and ER activities and genotoxic effects were detected in the incoming raw water and variability was observed between the sampling events. Compared to most of the samples taken from the full-scale treatment system, lower Nrf2, AhR, and ER bioactivities as well as genotoxicity were observed in all samples from the pilot-scale systems across all sampling events. The most pronounced treatment effect was a 12-fold reduction in Nrf2 activity and a sixfold decrease in micronuclei formations following ozonation alone. GAC filtration alone resulted in sevenfold and fivefold reductions in Nrf2 activity and genotoxicity, respectively, in the same sampling event. Higher bioactivities were detected in most samples from the full-scale system suggesting a lack of treatment effect. No androgenic nor anti-androgenic activities were observed in any sample across all sampling events.ConclusionsUsing effect-based methods, we have shown the presence of bioactive chemicals in the raw water used for drinking water production, including oxidative stress, AhR and ER activities as well as genotoxicity. The currently used treatment technologies were unable to fully remove the observed bioactivities. Ozonation and GAC filtration showed a high treatment efficiency and were able to consistently remove the bioactivities observed in the incoming water. This is important knowledge for the optimization of existing drinking water treatment designs and the utilization of alternative treatment technologies.

Toxicity and endocrine-disrupting potential of PM2.5: Association with particulate polycyclic aromatic hydrocarbons, phthalate esters, and heavy metals

The adverse effects of fine atmospheric particulate matter with aerodynamic diameters of ≤2.5 μm (PM2.5) are closely associated with particulate chemicals. In this study, PM2.5 samples were collected from highway and industry sites in Hangzhou, China, during the autumn and winter, and their cytotoxicity and pulmonary toxicity and endocrine-disrupting potential (EDP) were evaluated in vitro and in vivo; the particulate polycyclic aromatic hydrocarbons (PAHs), phthalate esters (PAEs), and heavy metals were then characterized. The toxicological results suggested that the PM2.5 from highway site induced higher cytotoxicity (cell viability inhibition, intracellular oxidative stress, and cell membrane injury) and pulmonary toxicity (inflammatory response (IR) and oxidative stress (OS)) than the samples from industry site, while the PM2.5 from industry site exhibited higher EDP (estrogenic and anti-androgenic activity). The cytotoxicity and pulmonary toxicity of PM2.5 in the winter were higher than those in the autumn, while no seasonal difference in the endocrine-disrupting potential was observed (p > 0.05). The Pearson correlation analysis between the biological effects and particulate chemicals revealed that the PM2.5-induced inflammatory response and oxidative stress were closely associated with the particulate PAHs and heavy metals (Pearson correlation coefficients: rIR, PAHs = 0.822–0.988, rIR, heavy metals = 0.895–0.971, rOS, PAHs = 0.843–0.986, and rOS, heavy metals = 0.887–0.933), while particulate di (2-ethylhexyl)phthalate (DEHP) substantially contributed to the EDP of PM2.5 (rEDP, DEHP = 0.981). This study indicated that the toxicity and EDP of PM2.5 could vary with the surrounding environment and season, which was closely associated with the variations of particulate chemicals. Further studies are needed to clarify the associations between the harmful effects of PM2.5 and other contributing factors.

Extensive rain events have a more substantial impact than advanced effluent treatment on the endocrine-disrupting activity in an effluent-dominated small river

Wastewater treatment plants (WWTPs) remain an important primary source of emission for endocrine-disrupting compounds in the environment. As an advanced wastewater treatment process, ozonation is known to reduce endocrine-disrupting activity. However, it remains unclear to which extend improved wastewater treatment may reduce the endocrine-disrupting activity in the receiving water body. The present study investigated possible factors for the endocrine-disrupting activity in a small receiving water body, the Wurm River (North-Rhine Westphalia, Germany), up- and downstream of a local WWTP. The cell-based reporter gene CALUX® assay was applied to identify the endocrine-disrupting activity in the water, sediment, and suspended particulate matter. The water phase and the effluent sampling were primarily driven by applying the full-scale effluent ozonation (sampling campaigns in June 2017 and March 2019). In contrast, the sediment sampling aimed to compare the particle-bound endocrine-disrupting activity during dry (June 2017) and rainy summer (June 2018) seasons. The water phase showed low to moderate estrogenic/antiandrogenic activity. Advanced effluent treatment by ozonation led to a complete reduction of the endocrine-disrupting activity according to the limit of detection of the CALUX® assays. The suspended particulate matter originated from the water phase of the second sampling campaign revealed antiandrogenic activity only. Sediments at the sampling sites along the local WWTP revealed higher estrogenic and antiandrogenic activity after extensive rain events and were not affected by the ozonated effluent. Fluctuation patterns of the endocrine-disrupting activity in sediments were in line with fluctuated concentrations of polycyclic aromatic hydrocarbons. Rainwater overflow basin release was suggested as a vector for particle-bound and dissolved endocrine-disrupting activity in the receiving water body. The present study underlined the necessity for monitoring both water and sediment phases to achieve reliable profiling of the endocrine-disrupting activity. The receptor-mediated CALUX® assays were proven to be suitable for investigating the endocrine-disrupting activity distribution in different river compartments and WWTP effluents.

Exposure to Atrazine through gestation and lactation period led to impaired sexual maturation and subfertility in F1 male rats with congenital deformities in F2 progeny

Several scientific reports suggest perturbed reproductive and developmental defects associated with environmental exposure to Atrazine (ATR). ATR has been associated with altered endocrine and reproductive functioning in-vivo exposed during the critical window of development. Thus, the present study investigates the effect of ATR exposure on F1–F2 male progeny exposed through gestation and lactation. F0 dams administered with ATR at doses 2, 10, 70, and 100 mg/kg b. wt/day from gestation day 6 to postnatal day 21. The F1 male rats were monitored for sexual maturation and subjected to fertility assessment on PND75. Delayed testicular descent was observed in 10, 70, and 100 mg/kg b. wt/day ATR dose with significantly lower serum testosterone, sperm count, and motility with testicular defects in F1 male. Expression of Androgen receptor (AR), Estrogen receptors (ER α and ER β), StAR, Aromatase, and INSL-3 were upregulated at all doses indicating estrogenic/anti-androgenic activity of ATR. Fertility assessment revealed subfertility in F1 males with high (%) pre- and post-implantation loss at 10, 70, and 100 mg/kg b. wt/day dose as compared to control. Further, F2 fetuses exhibited congenital disabilities viz. decreased weight, crown-rump length, and anogenital distance with several other morphological deformities. To conclude, ATR exerted estrogenic and/or anti-androgenic activity with fetotoxic effects through the male germline.

Passive sampling and in vitro assays to monitor antiandrogens in a river affected by wastewater discharge

Pharmaceuticals and personal care products, antibiotics, estrogens, and antiandrogens are found widely in aquatic environments. Monitoring studies by sampling surface water and effluents of wastewater treatment plants (WWTPs) have been conducted recently to monitor antiandrogens, which, along with estrogens, cause endocrine disruption. However, few studies have investigated antiandrogenic activity (AA) combined with a chemical analyses of emerging antiandrogens. Therefore, we analyzed the presence and persistence of 12 types of antiandrogens, atrazine, and carbamazepine using grab sampling and polar organic chemical integrative sampler (POCIS) along a river affected by WWTP discharges. Water and sediment samples were collected from the WWTP effluent (WW), as well as upstream (US) and downstream (DS) of the WWTP. We detected only tebuconazole, triclosan, propiconazole, and fluconazole during the two sampling campaigns in 2016 and 2017. Grab sampling of the site WW detected tebuconazole (7–77 ng/L), propiconazole (5–47 ng/L), and fluconazole (6–45 ng/L). However, the concentrations in the river water were below the detection limits. Nevertheless, fluconazole and triclosan were detected by POCIS in the site WW (45.7 and 26.8 ng/L, respectively) and all river samples ranges of 0.3–9.3 and 2.4–3.7, respectively. This detection was attributed to the limit of quantification of POCIS being lower than that of grab sampling. Nilutamide and triclosan were detected in the river sediment, suggesting that their concentrations in the water column were at least partly attenuated through sediment sorption. We also observed AA by analyzing POCIS extracts with the yeast androgen screen assay. The highest AA was found in the site WW and it was still observable several kilometers downstream of the point of discharge despite decreasing. Therefore, the WWTP effluent was most likely contributor to the persistent AA in the river.

Comparative transcriptomic analysis reveals reproductive impairments caused by PCBs and OH-PCBs through the dysregulation of ER and AR signaling

Reports have highlighted the presence of PCBs and their metabolites, OH-PCBs, in human serum as well as their endocrine-disrupting effects on reproductive function through direct interactions with the androgen receptor (AR) and estrogen receptor (ER). However, the molecular mechanisms directly linking the actions of PCBs and OH-PCBs on the AR and ER to induce reproductive impairment remain poorly understood. In this study, we characterized the cellular response to PCBs and OH-PCBs acting on AR and ER transactivation at the transcriptome level coupled with bioinformatics analysis to identify the downstream pathways of androgen and estrogen signaling that leads to reproductive dysfunction. We first confirmed the agonistic and antagonistic effects of several PCBs and OH-PCBs on AR- and ER-mediated reporter gene activity using the androgen-responsive LNCaP and estrogen-responsive MCF-7 cell lines, respectively. Anti-estrogenic activity was not detected among the tested compounds; however, we found that in addition to anti-androgenic and estrogenic activity, PCB 28 and PCB 138 exhibited androgenic activity, while most of the tested OH-PCBs showed a synergistic effect on DHT-mediated transactivation of the AR. Bioinformatics analysis of transcriptome profiles from selected PCBs and OH-PCBs revealed various pathways that were dysregulated depending on their agonistic, antagonistic, or synergistic effects. The OH-PCBs with estrogenic activity affected pathways including vitamin metabolism and calcium transport. Other notable dysregulated pathways include cholesterol transport in response to androgenic PCBs, thyroid hormone metabolism in response to anti-androgenic PCBs, and antioxidant pathways in response to androgen-synergistic OH-PCBs. Our results demonstrate that PCBs and OH-PCBs directly alter specific pathways through androgen- or estrogen-mediated signaling, thereby providing additional insights into the mechanisms by which these compounds cause reproductive dysfunction.

Anti-androgenic compounds in breast milk and cryptorchidism among Norwegian boys in the HUMIS birth cohort

The prevalence of cryptorchidism has increased over the past decades, yet its origins remain poorly understood. Testis descent is dependent on androgens and likely affected by endocrine disrupting compounds (EDCs), targeting the androgen receptor (AR). We investigated the association between anti-androgenic activity, not derived from natural hormones, in maternal breast milk and impaired testis descent among boys. We performed a case-control study based on 199 breast milk samples from 94 mothers of cryptorchid boys and 105 random non-cryptorchid boys participating in the Norwegian HUMIS (Human Milk Study) cohort. For each participant, apolar, and polar fractions were extracted, and combined to reconstitute a mixture. Anti-androgenic activity was measured in all three fractions using the human cell-based in vitro anti-AR CALUX® assay and expressed in μg of flutamide equivalent, a well-known antiandrogen. Results from fraction analyses were compared among boys with cryptorchidism and controls using multiple logistic regression, controlling for appropriate confounders identified using a directed acyclic graph. Children's daily exposure to anti-androgenic EDCs through breastfeeding was estimated to 78 μg flutamide eq./kg of body weigh/day. The activity was higher in the polar fraction (1.48 ± 1.37 μg flutamide eq./g of milk) mainly representing non-persistent chemicals, in contrast to other fractions. However, the activity in the polar extracts was decreased when in mixtures with the apolar fraction, indicating synergistic interactions. No significant difference in the activity was observed according to cryptorchid status for polar, apolar or mixed breast milk fractions. The study showed anti-androgenic activity in nearly all human milk samples, and at levels higher than the advisory threshold. However, no significant association was observed between cryptorchidism and antiandrogenic activity measured in either polar, apolar, or mixture fractions derived from breast milk.

A pilot study of glyphosate, and preterm birth among blacks and whites

BACKGROUND AND AIM: Glyphosate was first registered as an herbicide in the United States in 1974. It has since been linked to birth defects in animal models. Additionally, in vitro studies suggest that glyphosate has anti-androgenic and anti-estrogenic activities including the ability to interfere with aromatase activity. One observational human study found a statistically significant correlation between higher maternal glyphosate levels and shortened gestational length. However, no studies have investigated potential race-disparities in gestational glyphosate exposure or effects. METHODS: A nested case control pilot study enrolled 26 women with a preterm birth (37 weeks completed gestation) and 26 term births matched by race from a larger cohort study. Second trimester urine samples, collected at 18-22 weeks of gestation, were analyzed for specific-gravity corrected glyphosate using liquid chromatography-tandem mass spectrometry. Logistic regression was used to estimate the association between gestational urinary glyphosate concentrations and preterm birth, adjusted for age, race, body mass index, season of specimen collection, education level and reported organic food consumption. RESULTS:Geometric mean glyphosate concentrations were 0.07 ng/mL (95% CI: 0.04-0.13) for preterm and 0.06 ng/mL for term births (95% CI: 0.03-0.10). Fewer term whites (n=4, 31%) were in the middle (range: 0.04-0.11 ng/mL) and highest (range: 0.17-1.25 ng/mL) tertiles of glyphosate exposure than term Blacks (n=7, 54%), although the difference was not statistically significant (p=0.43). Higher urinary glyphosate was associated with lower odds of preterm birth (odds ratio=0.75, 95% confidence interval 0.16-3.68), adjusted for covariates, although also not statistically significant. The odds varied by race, with OR=0.60 (95% CI: 0.11-3.4) among whites and OR=1.40 (95% CI: 0.28-7.02) among Blacks, although the interaction was not statistically significant. CONCLUSIONS:Glyphosate exposure varied by maternal race with elevated exposure in Blacks. There was no association found between urinary glyphosate levels and preterm birth, suggesting that glyphosate may not be a preterm birth risk factor. KEYWORDS: Glyphosate, Pregnancy Outcomes, Risk Assessment, Exposure assessment-biomarkers of exposure

Antimicrobial activity, bioactive constituents, and functional groups in aqueous methanol extract of Polyalthia longifolia (Sonn.) thwaites leaves

Background: Polyalthia longifolia is an ornamental plant with various applications in traditional medicine. There is a need to identify its bioactive compounds to justify its medicinal use. Objectives: In this study, the functional groups and bioactive compounds in aqueous methanol extract of P. longifolia leaves and its antimicrobial potential were investigated. Materials and Methods: Bioactive constituents of the extract were assayed with gas chromatography-mass spectrometry (GC-MS) and functional groups by Fourier transform infra-red (FT-IR), while its phytochemical screening and antimicrobial activity were investigated in vitro using standard protocols. Results: Qualitative phytochemical screening showed the presence of therapeutically important phytochemicals, namely, alkaloids, steroidal and cardiac glycosides, saponins, triterpenes, steroids, phytosterols, resins, phenols, flavonoids, tannins, and diterpenes. The extract showed promising bactericidal and fungicidal properties against the test organisms. Staphylococcus aureus was the most resistant of all the test organisms, while other test organisms were significantly inhibited by the extract in a concentration-dependent fashion. FT-IR analysis showed different characteristic peak values confirming the presence of important functional groups, namely, alcohol, alkane, ester, alkene, nitro compounds, amine, carboxylic acid, aromatics, and alkyl halide in the extract. GC-MS analysis identified 25 bioactive compounds in the leave extract. Some of these compounds include 2-methoxy-4-vinylphenol, copaene, aromadendrene, alpha-curcumene, caryophyllene oxide, palmitic acid methyl ester, cis-Z-alpha-Bisabolene epoxide, phytol, alpha-Santoline alcohol, and linolenic acid ethyl ester reportedly possessing antimicrobial, antioxidant, antigenotoxic, antiproliferative, anti-inflammatory, anticarcinogenic, cardio-protective, insecticidal, pesticidal, nematicidal, antiandrogenic, antiviral, and analgesic activities. Conclusion: This study underscores the vast therapeutic importance of P. longifolia leaves as an important source of potentially useful bioactive principles.

Computer Based Screening of Selected Phytoconstituents from Cyperus Rotundus Linn. Against 5 α Reductase Enzyme

Hirsutism is a condition of unwanted, male-pattern terminal hair growth in women. Electro epilation, laser treatment, intense pulsed light therapy, eflornithine cream, and oral antiandrogen medications are the various allopathic therapeutics have been employed for treatment of Hirsutism. However, a significant number of patients experience discomfort with reported procedures. Cyperus Rotundus Linn. have reported for its anti-androgenic activity effective against Hirsutism disorder. The main objective of present investigation is to screen the selected phytoconstituents of stated plant against 5 α Reductase Enzyme. In this study Cyperene, humulen, β- selinene, campholenic aldehyde, and α-pinene were docked with 5 α Reductase Enzyme using PyRx 0.8.Autodock and binding energies were obtained. The present investigation concludes that the molecular docking analysis of selected phytoconstituents with 5 α reductase enzyme shows good interaction. The binding affinity of Humulen is higher than others whereas campholenic aldehyde showed lowest affinity amongst all other constituents. Further studies need to be performed at laboratory level to support results of computational screening of present investigation.

Vinclozolin-induced mouse penile malformation and “small testis” via miR132, miR195a together with the Hippo signaling pathway

Vinclozolin (VCZ) is a fungicide with antiandrogen activity. Exposure to VCZ in maternal uterus may cause uterine, ovarian and testicular damage, hypospadias and prostate abnormality in the offspring. Hippo pathway, which is highly conservative and may be activated by miR132 and miR195a, can control organ size and tissue regeneration, and participate in injury and deformity. In the present study, VCZ was found to have caused penile malformation in the male offspring and also induced “small testis” when it was administered to the pregnant mice orally at a dose of 400 mg kg−1 day−1 on Days 12–18 of gestation. At 1, 3 and 7 weeks of age, VCZ could increase miR132, Mst1, Sav1, phosphorylated Yes-associated protein (pYap) and pLats, and decrease Yap in offspring penises and testes. Besides, it could also raise miR195a both in the testes of 1, 7-week and in the penises of all the three ages. In addition, we found the levels of some cyclin (Ccn) genes elevated in the testes, the expression of the androgen receptor (Ar) gene dereased and Jnks changed in the penises of offspring aged 1, 3 and 7 weeks. The results suggest that that gestational VCZ exposure could not only increase miR132 and miR195a in penises and testes of the offspring, but also activate Hippo pathway and down-regulate Ar. These may directly inhibit cell proliferation, accelerate cell death by up-regulating the expression of some Ccns, and ultimately lead to penile and testicular damage and malformations in the offspring.

Response to Androgens and Androgen Receptor Antagonists in the Presence of Cytokines in Prostate Cancer.

Simple SummaryProstate cancer is the most frequently diagnosed non-cutaneous tumor in men in the Western world. Therapy for non-organ confined prostate cancer includes anti-androgens such as bicalutamide, enzalutamide and darolutamide. The androgen receptor is expressed during tumor initiation and progression. Androgen receptor could be activated by interleukins, which are produced by blood cells and adjacent stroma. These cytokines may affect response of tumor cells to anti-androgenic drugs, which are commonly used in prostate cancer therapy. There are several experimental studies showing an effect of anti-cytokine therapies in prostate cancer. However, the clinical translation is limited and more clinical trials are needed to improve action of anti-androgens in prostate cells which are stimulated by cytokines. Non-steroidal anti-androgens have a major role in the treatment of non-localized prostate cancer. Interleukins are involved in the regulation of many cellular functions in prostate cancer and also modify cellular response to anti-androgens. A specific role of selected IL is presented in this review. IL-8 is a cytokine expressed in prostate cancer tissue and microenvironment and promotes proliferation and androgen receptor-mediated transcription. In contrast, IL-1 displays negative effects on expression of androgen receptor and its target genes. A subgroup of prostate cancers show neuroendocrine differentiation, which may be in part stimulated by androgen ablation. A similar effect was observed after treatment of cells with IL-10. Another cytokine which is implicated in regulation of androgenic response is IL-23, secreted by myeloid cells. Most studies on androgens and IL were carried out with IL-6, which acts through the signal transducer and activator of the transcription (STAT) factor pathway. IL-6 is implicated in resistance to enzalutamide. Activation of the STAT-3 pathway is associated with increased cellular stemness. IL-6 activation of the androgen receptor in some prostate cancers is associated with increased growth in vitro and in vivo. Molecules such as galiellalactone or niclosamide have an inhibitory effect on both androgen receptor and STAT-3 pathways.

Novel daidzein molecules exhibited anti-prostate cancer activity through nuclear receptor ERβ modulation, in vitro and in vivo studies

Eight novel ERβ selective daidzein analogues (NCE1-8) were synthesized and their anti-cancer activity was evaluated by in vitro and in vivo methods. Cytotoxicity study, Receptor binding studies, Luciferase assay, cMYC & Cyclin D1 expression and Caspase 3, 8 & 9 activities were measured to ascertain the anticancer activity and mechanism. Uterotropic, anti-androgenic and anti-tumour activities were performed in rodents. The results revealed that NCEs produced anti-prostate cancer activity in DU145, LNCaP and PC3 cell lines and 50% more active than genistein. NCEs was significantly down-regulated cMYC & Cyclin D1 genes and elevated caspase 3 & 9 levels and did not show any difference in uterotropic, anti-androgenic activities. The tumour weight was also reduced. The NCE 1 and 2 have shown ERβ selectivity in receptor binding studies. Daidzein with methyl substitution at R or R1 position exhibited more ERβ selectivity and could be considered as lead molecules for anti-prostate cancer activity.

Disruption of Estrogenic and Androgenic Bioactivities in Human Fetuses Exposed to Maternal Smoking

Endocrine disruptors (EDs) interfere with hormonal signalling and, given that multiple developmental processes are hormone-driven, the prenatal period is a window of increased sensitivity. Maternal smoking is a real-life model of in utero exposure to a complex mixture of EDs. Cigarette smoke contains of >7,000 pollutants, including polycyclic aromatic hydrocarbons (PAHs), which are AhR ligands and cross-talk with the estrogen receptor (ER) system. Prenatal exposure to cigarette smoke is associated with adverse outcomes, including intrauterine growth restriction and increased risk of metabolic syndrome later in life. We aimed to evaluate ED effects associated with smoke exposure in human fetuses. Fetal tissues (plasma, n=48; placenta, n=30; liver, n=29) from elective terminations of normally progressing pregnancies, ranging from 10 to 20 gestation weeks, were collected (SAFeR and FEGO studies: REC 15/NS/0123, REC 04/S0802/21). PAHs and PAH-like compounds were extracted from placenta and fetal liver. Bioactivity levels in plasma, placenta and liver extracts were determined using ER and androgen receptor (AR) transactivation reporter gene assays. PAH burden was evaluated using the AhR-responsive DRhp-CALUX assay. Smoke exposure was associated with a 1.3-fold increase in plasma estrogenic activity. The developmental trajectory of androgenic activity was altered in plasma of smoke-exposed fetuses, with significant anti-androgenic activity in older fetuses (>16 weeks of gestation). In males, plasma androgenic activity was positively associated with testes weight and anogenital distance. In contrast, placentas from smoking mothers had significantly increased androgenic potential. Furthermore, AhR-like activity was 2.9-fold higher in smoke-exposed placentas compared to controls, and 2.3-fold higher in female compared to male fetal livers. Overall, all bioactivity levels were higher in placentas compared to fetal liver. Prenatal exposure to cigarette smoke is associated with higher placental AhR activation, indicative of increased xenotoxicants burden. We also report that smoke-exposed fetuses showed increased circulating estrogenic activity and disrupted androgenic potential, across 10-20 weeks of gestation, in both fetal plasma and placenta. This demonstrates that EDs present in cigarette smoke are able to interfere with hormonal signalling and alter dynamic endocrine activity profiles, which are critical to ensure appropriate, sex-specific, development. These ED effects are likely to disturb placental function and reprogramme fetal development and thus impacting on life-long health.

Characterisation of (anti-)progestogenic and (anti-)androgenic activities in surface and wastewater using high resolution effectdirected analysis

The quality of surface waters is threatened by pollution with low concentrations of bioactive chemicals, among which those interfering with steroid hormone systems. Induced by reports of anti-progestogenic activity in surface waters, a two-year four-weekly survey of (anti-)progestogenic activity was performed at three surface water locations in the Netherlands that serve as abstraction points for the production of drinking water. As certain endogenous and synthetic progestogenic compounds are also potent (anti-)androgens, these activities were also investigated. Anti-progestogenic and anti-androgenic activities were detected in the majority of the monitoring samples, sometimes in concentrations exceeding effect-based trigger values, indicating the need for further research. To characterize the compounds responsible for the activities, a high resolution Effect-Directed Analysis (hr-EDA) panel was combined with PR and AR CALUX bioassays, performed in agonistic and antagonistic modes. The influent and effluent of a domestic wastewater treatment plant (WWTP) were included as effluent is a possible emission source of active compounds. As drivers for androgenic and progestogenic activities several native and synthetic steroid hormones were identified in the WWTP samples, namely androstenedione, testosterone, DHT, levonorgestrel and cyproterone acetate. The pesticides metolachlor and cyazofamid were identified as contributors to both the anti-progestogenic and anti-androgenic activities in surface water. In addition, epiconazole contributed to the anti-progestogenic activities in the rivers Rhine and Enclosed Meuse. This study showed the strength of hr-EDA for the identification of bioactive compounds in environmental samples and shed light on the drivers of (anti-)progestogenic and (anti-)androgenic activities in the aquatic environment.

A Literature Review of the Pharmacokinetics, Pharmacodynamics, and Possible Uses of Spironolactone

Spironolactone (SL) is an antimineralocorticoid derived from progesterone, and was therefore developed as a diuretic for hypertension and edema treatment (Kolkhof & Barfacker, 2017). As a prodrug, its effects are largely mediated by its metabolites, 7α-thiomethylspironolactone and canrenone (Janowski et al., 1996), which are ultimately eliminated through the urine (Abshagen et al., 1977). Later on, it was discovered that SL also exhibits moderate antiandrogenic activity due to its structural similarity to progesterone (Menard, 2004), allowing it to be used as an off-label treatment for hyperandrogenism and its associated symptoms, such as hirsutism and acne (Voegli et al., 2009). As researchers continue to elucidate the role of mineralocorticoid receptors in cognition and behaviour, new possibilities for SL as an anxiolytic may also emerge in the future (Otte et al., 2007). With all that being said, SL’s sexual side-effects, especially in males, continue to limit the various applications of this multi-use drug.

Glass-bottled drinking water: a time capsule to study the historic presence of hazardous chemicals using effect-based methods

BackgroundContamination of drinking water by hazardous chemicals can be associated with human health risks. Recent studies using effect-based in vitro methods have demonstrated that a large part of the observed toxic effects are caused by unknown chemicals. In this study, we have used a panel of effect-based methods to study the presence of chemical contaminants in a unique material; glass-bottled Swedish tap water collected during the 1990s. These water samples were compared to drinking water from the same source waters and drinking water facilities, yet collected about 25 years later, in 2020.ResultsSamples were concentrated by solid phase extraction and evaluated for the following activities; estrogen receptor activity, androgen receptor activity, antiandrogenic activity, aryl hydrocarbon receptor activity, and oxidative stress response. We observed aryl hydrocarbon receptor activities in almost all studied samples and estrogen receptor activity in three out of ten studied samples. No activities were observed for androgen receptor activity, antiandrogenic activity or oxidative stress response. In general, observed activities were more frequent and higher in the water samples collected during the 1990s as compared to the corresponding samples collected in 2020.ConclusionsThis study demonstrates that it is possible to conduct an effect-based evaluation of the presence of hazardous chemicals in drinking water, with as small starting volume as 330 mL, by using miniaturized bioassays. Further, by comparing the glass-bottled water samples with newly collected water samples from the same drinking water treatment facilities, our results indicate that the presence of aryl hydrocarbon receptor and estrogen receptor activating compounds in the drinking water has decreased over the approximately quarter of a century that is separating the two sampling occasions. This difference could be due to improved raw water quality and/or improved treatment efficiency in the treatment plants.

A Review on Serenoa serrulata: A Potential Medicinal Plant for Prostatic Diseases

Background: Prostatic diseases which include prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer are the benign or malignant disorders that affect the prostate. Phytotherapies have been adopted as the alternative treatment/ management option especially for BPH since the current modern methods of treatment presents a lot of adverse effects.
 Methodology: The literature was searched using different databases including Medline/PubMed, Cochrane library, Scopus, Proquest library, Embase, EBooks and Google Scholar for relevant records for a period from 1988 to 2018 to identify all the published articles of S. serrulata regarding treatment of prostatic diseases. The key search terms were Serenoa serrulata, S. repens, Saw palmetto, Prostate cancer treatment with Serenoa serrulata, treatment of Benign Prostatic Hyperplasia with Serenoa serrulata, phytochemicals of Serenoa serrulata, ethnobotanical uses of Serenoa serrulata, toxicity of Serenoa serrulata, pharmacological activities of Serenoa serrulata and also traditional management and treatment of prostatic diseases using Serenoa serrulata and also clinical trials on treatment of prostatic diseases with Serenoa serrulata. The retrieved articles were reviewed, synthesized and analyzed qualitatively. The reference list of the retrieved articles was also reviewed and synthesized. The original research articles which reported an investigation of S. serrulata of any study design, original published research articles, any time of publication and grey literature (conference papers, reported articles, academic thesis) were included. The articles whose full texts were not freely available by the time of search and those without clear information about methodology and study design were excluded.
 Results: This review reported that Serenoa serrulata belonging to the Arecaceae family commonly known as saw palmetto is used traditionally for treating prostatic disease conditions and other infertility conditions in both men and women. Phytochemical screening of hexanic and ethanolic extracts of S. serrulata comprised of free fatty acids and phytosterols which together contribute to their antiprostatic activities. These extracts of S. serrulata exhibited antiandrogenic, anti-inflammatory and anti-proliferative activities through inhibition of both isoenzymes 5α- reductase and inhibition of binding of dihydrotestosterone (DHT) to the cytosolic androgen receptors. This is a similar mechanism exhibited by finasteride and Tamsulosin both antiprostatic conventional drugs though the plant phytochemicals do not interfere with PSA secretion. S. serrulata has also been reported to be non-toxic in both non clinical and clinical trial studies. The medicinal plants reported by this review to be used in combination include; stinging nettle (Urtica dioca), Zingiber officinalis, Echinacea angustifolia and pumpkin (Cucurbita pepo). The antiprostatic conventional drugs reported include finasteride and Tamsulosin.
 Conclusion and Recommendation: The results showed that S. serrulata is effective in treating prostatic diseases. The potency and safety is improved when used in combination with Urtica dioca, Cucurbita pepo, Zingiber officinalis and Echinacea angustifolia as compared with anti-prostatic conventional drugs Finasteride and Tamsulosin alone. The plant combination has also been shown to have improvement in the quality of life and as well enhancing the synergy of Finasteride and Tamsulon and their adverse effects. Effective medicinal plant combinations should be formulated into products and integrated into the usual treatment for prostatic diseases.

Enhanced Disrupting Effect of Benzophenone-1 Chlorination Byproducts to the Androgen Receptor: Cell-Based Assays and Gaussian Accelerated Molecular Dynamics Simulations

Benzophenone-1 (BP-1), one of the commonly used ultraviolet filters, has caused increasing public concern due to frequently detected residues in environmental and recreational waters. Its susceptibility to residual chlorine and the potential to subsequently trigger endocrine disruption remain unknown. We herein investigated the chlorination of BP-1 in swimming pool water and evaluated the endocrine disruption toward the human androgen receptor (AR). The structures of monochlorinated (P1) and dichlorinated (P2) products were separated and characterized by mass spectrometry and 1H-1H NMR correlation spectroscopy. P1 and P2 exhibited significantly higher antiandrogenic activity in yeast two-hybrid assays (EC50, 6.13 μM and 9.30 μM) than did BP-1 (12.89 μM). Our 350 ns Gaussian accelerated molecular dynamics simulations showed the protein dynamics in a long-time scale equilibrium, and further energy calculations revealed that although increased hydrophobic interactions are primarily responsible for enhanced binding affinities between chlorinated products and the AR ligand binding domain, the second chloride in P2 still hinders the complex motion because of the solvation penalty. The mixture of BP-1-P1-P2 elicited additive antiandrogenic activity, well fitted by the concentration addition model. P1 and P2 at 1 μM consequently downregulated the mRNA expression of AR-regulated genes, NKX3.1 and KLK3, by 1.7-9.1-fold in androgen-activated LNCaP cells. Because chlorination of BP-1 occurs naturally by residual chlorine in aquatic environments, our results regarding enhanced antiandrogenic activity and disturbed AR signaling provided evidence linking the use of personal care products with potential health risks.

Effects of neonatal exposure to methoxychlor on corpus luteum in gilts: A transcriptomic analysis.

This study investigated the effects of neonatal exposure to methoxychlor (MXC), a synthetic organochlorine used as an insecticide with estrogenic, antiestrogenic, and antiandrogenic activities, on luteal function in pigs. Piglets were injected subcutaneously with MXC (20 μg/kg body weight) or corn oil (control) between postnatal Days 1 and 10 (N = 5/group). Corpora lutea from sexually mature gilts were examined for luteal steroid and prostaglandin concentrations and processed for total RNA isolation and subsequent RNA sequencing. Intra-luteal concentrations of androstenedione and prostaglandin E2 were greater, while that of estrone was lower when compared to control. Fifty-three differentially expressed (DE) microRNAS (miRNAs) (p-adjusted <.05 and log2(fold change) ≥.5) and 359 DE genes (p-adjusted <.05 and log2(fold change) ≥1) were identified in luteal tissue in response to neonatal MXC treatment. MXC was found to affect the expression of genes related to lipogenesis, steroidogenesis, membrane transport, immune response, cell signaling and adhesion. These results suggest an earlier onset of structural luteolysis in pigs caused by MXC actions in neonates. Since negative correlation analysis showed the potential interactions of miRNAs with specific messenger RNAs, we propose that these miRNAs are potential mediators of the long-term MXC effect on the CL function in pigs.