Levels Of Aromatase Activity Research Articles

Review on Natural Agents as Aromatase Inhibitors: Management of Breast Cancer.

Breast cancer is a prevalent type of cancer that is typically hormone-dependent, caused by estrogen. Aromatase inhibitors are frequently utilised in the treatment of hormonereceptor- positive breast cancer because they prevent the enzyme aromatase from converting androgens to estrogens. Natural medicines with aromatase inhibitory characteristics have attracted interest as potential alternatives or complementary therapy to manufactured medications. This review discusses the function of natural agents as aromatase inhibitors in treating breast cancer. A variety of natural compounds have been investigated for their capacity to inhibit aromatase activity and lower estrogen levels. These agents include resveratrol from red wine and grapes, curcumin from turmeric extract and green teahigh in catechins, and other flavonoids such as genistein, luteolin and quercetin. It has been demonstrated that by decreasing estrogen synthesis, they can slow the growth of breast cancer cells that are dependent on estrogen. However, the clinical evidence supporting their efficacy and safety in breast cancer treatment is inadequate. More research is required to investigate the therapeutic potential of natural medicines, such as aromatase inhibitors, in treating breast cancer. The clinical trials are required to assess their efficacy, appropriate doses, and potential interactions with other therapies. In conclusion, natural aromatase inhibitory drugs are promising adjuncts in the treatment of hormone receptor-positive breast cancer. Their clinical value and safety profile, however, require additional investigation.

Integrating fecal metabolomics and gut microbiome to reveal the mechanism of Schisandra chinensis-Acorus tatarinowii Schott treatment in Alzheimer’s disease rats

BackgroundSchisandra chinensis (Turcz.) Baill (Schisandraceae) and Acorus tatarinowii Schott (Araceae Juss) (Sc-At) are two traditional Chinese medicinal herbs that are widely used in the treatment of neurological disorders such as insomnia. In our previous study, we found that Sc-At could improve the therapeutic efficacy of Alzheimer’s disease by affecting aromatase activity and estrogen levels, among other pathways. Material and methodsIn this study, first, the ameliorative effect of Sc-At on cognitive dysfunction in Alzheimer’s disease model rats was verified by Y-maze test together with Elisa assay. Second, fecal untargeted metabolomics analysis was performed using a UPLC-Q-TOF/MS-based metabolomics approach. 16S rDNA sequencing was utilized to screen the differential flora between groups, and linear discriminantan alysis effect size (LEfSe) was used to find the target flora. Finally, Spearman correlation analysis was combined to find the relationship between differential flora and differential metabolites in feces. Results(1) The results of Y-maze test and Elisa assay indicated that Sc-At could improve the cognitive dysfunction of AD model rats. (2) Metabolomics results showed that fecal metabolite levels were significantly different from those of rats in the blank group, and 18 potential biomarkers in feces were screened, mainly affecting linoleic acid metabolism, steroid hormone biosynthesis, sphingomyelin metabolism, riboflavin metabolism, etc. The 16S rDNA results showed that the abundance and diversity of intestinal flora in AD rats were destroyed, and the Sc-At treatment was able to reverse these changes. (3) Spearman’s correlation analysis showed a significant correlation between differential metabolites in feces and intestinal flora, further suggesting that Sc-At treats Alzheimer’s disease through the gut-brain axis. ConclusionsIn this study, we explored the mechanism of Sc-At in the treatment of Alzheimer’s disease by integrating fecal untargeted metabolomics and 16S rDNA gene sequencing, and the results showed that Sc-At exerts therapeutic effects on Alzheimer’s disease by improving the intestinal flora and related metabolic pathways.

Aromatase Enzyme Activity and Liver Receptor Homolog-1 Levels in Gestational Diabetes Mellitus

Background: Gestational diabetes mellitus (GDM) is one of the prediabetes conditions in which high blood sugar levels and body weight increase during pregnancy. The underlying molecular and biochemical mechanisms of GDM are poorly defined. Introduction: Aromatase enzyme activity is responsible for the conversion of androgens to estrogens and has a share in the regulation of body fat distribution and liver receptor homolog-1 (LRH-1), which plays a critical role in cholesterol transport, acid homeostasis, and steroidogenesis in GDM patients. This study aims to determine the levels of aromatase enzyme and LRH-1 in GDM patients and to investigate the relationship between the levels of aromatase enzyme and LRH-1 and the levels of insulin, HbA 1c and total cholesterol. Method: This prospective cross-sectional study was conducted over eleven months (September 2020 to July 2021). The study population was selected at Harran University Teaching and Research Hospital. The study included 32 GDM patients and 32 healthy pregnants. The automated assay measured serum fasting blood glucose, HbA1c, and insulin levels (AVIDA 1800 Chemistry System; Siemens). Aromatase enzyme activity and LRH-1 levels were determined by using a commercial enzyme-linked immunosorbent assay (ELISA) kit. Result: Aromatase activity decreased in GDM patients while LRH1 increased. Significant differences in means levels of fasting blood glucose (p=0.11), insulin (p= 0.001) and HbA1c (p= 0.001) between the patients and control groups. There was a significant negative correlation between the levels of aromatase and insulin (r=-370, p =0.037). In addition, a positive significant correlation coefficient (r=0.645, p=0.001) was found between HbA1c and total cholesterol among the patients' group. Conclusion: Our findings indicate that there is a negative relationship between aromatase activity and insulin levels. Aromatase and LRH 1 may play a role in the pathogenesis of GDM, and the use of LRH-1 agonists in treating the disease may be considered an alternative treatment in the future. However, additional studies are required to reveal the possible functions of these two proteins in GDM with their mechanisms.

Male subclinical hypogonadism and late-onset hypergonadotrophic hypogonadism: mechanisms, endothelial function, and interplay between reproductive hormones, undercarboxylated osteocalcin, and endothelial dysfunction

Background Pathogenesis and endothelial function in subclinical hypogonadism (SCH) remain unclear. Undercarboxylated osteocalcin (ucOC) participates in atherosclerosis and reproduction. We explored the underlying mechanisms and interplay of endothelial dysfunction, unOC and reproductive hormones in SCH and primary late-onset hypogonadism (LOH). Methods In the SCH, LOH, and healthy eugonadal male groups, we measured serum unOC, calculated luteinizing hormone/testosterone (LH/T), LH.T product, and estradiol/T (E/T) as indicators of impaired Leydig cells, androgen sensitivity index (ASI), and aromatase activity, respectively (LH set-point regulators), and assessed flow-mediated dilation of the brachial artery (FMD%), carotid-intima media thickness (CIMT), and aortic stiffness (AS). Results ↑LH/T, ↑ASI, ↓aromatase activity, normal T, follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) levels, ↑unOC, and enhanced atherosclerotic markers (↓FMD%, ↑CIMT, ↑AS) are characteristics of SCH. Testosterone was positively correlated with FMD% in SCH. The independent predictors were: SHBG and LH for FMD% and CIMT, respectively, and LH/T, ucOC, FSH, estradiol, and E/T ratio for AS in the LOH group; and LH for FMD% & AS and LH and LH/T for CIMT in all study subjects. Conclusions SCH is a distinct clinical entity characterized by impaired androgen sensitivity and aromatase activity, compensatory elevated unOC, endothelial dysfunction, and anti-atherogenic role of testosterone.

Local aromatase activity alterations in breast cancer tissues: A potential way of decision support for clinicians

Background and aimsIt is becoming evident that local estrogen exposure is important in postmenopausal breast cancer patients. The microenvironment is established by breast stromal cells based on communication with tumor cells that is essential to cancer development, invasion, and metastasis. Here we investigated aromatase activity levels in both tumor and matched stromal tissues by showing their impact on the manufacturing of local estrogen and tumor progression in cases of invasive ductal carcinoma (IDC). MethodsTumor (T) and tumor-associated stroma (TAS) neighboring tissues were acquired from each postmenopausal patient, diagnosed with IDC, and categorized as luminal A (n = 20). The control group was formed from tumor-free breast tissue samples (N, n = 12). A microsomal-based technique was created to compare breast tissue aromatase activities using liquid chromatography – mass spectrometry. FindingsWe observed that the TAS tissues have the highest aromatase activities (p < 0.05). High progesterone receptor (PR) intensity levels were found to be decreasing the activity level in these tissues significantly (p < 0.05). Tumor tissue specific aromatase activity levels of postmenopausal patients' were tend to be lower compared to healthy premenopausal subjects' (3 fold, p < 0.001). In addition low activity in tumor tissues were associated with low grade and late stage cancers. ConclusionsEarly detection and personalized therapy is essential for postmenopausal breast cancer patients. Together, our in-house tandem mass spectrometry technique has the potential for further development and standardization for the measurement of aromatase activity and may assist clinicians decide on therapy policies for postmenopausal IDC patients which could be an invaluable asset for precise and specific evaluation.

The effect of adipocyte-macrophage crosstalk in obesity-related breast cancer.

Adipose tissue is the primary source of many pro-inflammatory cytokines in obesity. Macrophage numbers and pro-inflammatory gene expression are positively associated with adipocyte size. Free fatty acid and tumor necrosis factor-α involve in a vicious cycle between adipocytes and macrophages aggravating inflammatory changes. Thereby, M1 macrophages form a characteristic 'crown-like structure (CLS)' around necrotic adipocytes in obese adipose tissue. In obese women, CLSs of breast adipose tissue are responsible for both increase in local aromatase activity and aggressive behavior of breast cancer cells. Interlinked molecular mechanisms between adipocyte-macrophage-breast cancer cells in obesity involve seven consecutive processes: Excessive release of adipocyte- and macrophage-derived inflammatory cytokines, TSC1-TSC2 complex-mTOR crosstalk, insulin resistance, endoplasmic reticulum (ER) stress and excessive oxidative stress generation, uncoupled respiration and hypoxia, SIRT1 controversy, the increased levels of aromatase activity and estrogen production. Considering elevated risks of estrogen receptor (E2R)-positive postmenopausal breast cancer growth in obesity, adipocyte-macrophage crosstalk is important in the aforementioned issues. Increased mTORC1 signaling in obesity ensures the strong activation of oncogenic signaling in E2Rα-positive breast cancer cells. Since insulin and insulin-like growth factors have been identified as tumor promoters, hyperinsulinemia is an independent risk factor for poor prognosis in breast cancer despite peripheral insulin resistance. The unpredictable effects of adipocyte-derived leptin-estrogen-macrophage axis, and sirtuin 1 (SIRT1)-adipose-resident macrophage axis in obese postmenopausal patients with breast cancer are unresolved mechanistic gaps in the molecular links between the tumor growth and adipocytokines.

Abstract SY01-01: Endocrine resistance in metastatic breast cancer: Mechanisms and new therapeutic strategies

Abstract SY01-01: Endocrine resistance in metastatic breast cancer: Mechanisms and new therapeutic strategies

Toxicological analysis of triadimefon on endocrine disruption and oxidative stress during rare minnow (Gobiocypris rarus) larvae development.

Triadimefon (TDF) is a systemic wide-spectrum antifungal compound that is widely used in agriculture to inhibit fungal growth on various crops. Since previous studies focused on the embryo and adult life stages in the investigation of ecological impact, here we investigated the long-term effects of TDF (1, 10, 100μg/L) on rare minnow during its larvae development. TDF caused an anti-estrogenic effect by decreasing vitellogenin (VTG) and CYP19a mRNA level, and inhibiting the aromatase activity and VTG levels after a 3, 6, 10, or 14-day exposure in rare minnow larvae. TDF also disturbed the endocrine disruption by regulating the transcription of estrogen receptors ERα, ERβ1 and ERβ2, CYP1a, CYP11, CYP17, steroidogenic acute regulator (STAR), doublesex and mab-3 related transcription factor (DMRT1), gonadotropin-releasing hormone (GnRH2), GnRH3, GnRHR1A, and GnRHR1B. Furthermore, TDF induced the accumulation of reactive oxygen species (ROS) and the activity of antioxidant proteins glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT), and significantly increased the transcriptions of stress response genes P53, growth arrest and DNA damage-inducible 45 alpha (Gadd45α), and COX1, suggested that TDF might cause oxidative stress during larvae development. The changes in transcript and biological levels represented the potential adaptive or compensatory responses to impaired oxidative stress and endocrine system after TDF exposure in rare minnow during its larvae development.

POLYMORPHISM OF CYTOCHROME P450, SUPERFAMILY19, POLYPEPTIDE 1 GENE AND RELATED TO AROMATASE ENZYME ACTIVITY IN ACROMEGALY IRAQI PATIENTS

Objective: The objective of the present work was to investigate the association between aromatase enzyme activity and polymorphisms, rs2236722, in exon 2 of cytochrome P450 (CYP), superfamily19, polypeptide 1 (CYP19A1gene) in patients with active acromegaly.Methods: A total of 120 males and females (age 20-60 years) were enrolled in this study, 60 patients with active acromegaly who have attended the National Diabetes Centre and and Specialist Center for endocrinology and diabetes, Baghdad, from December 2015 to June 2016 and 60 healthy individuals with matches as a control group. From the whole blood, genomic DNA was extracted to perform genotyping analysis and single-nucleotide polymorphism, rs2236722, in the CYP19A1 gene using multiplex polymerase chain reaction technique, and serum aromatase levels were determined using a solid-phase enzyme-linked immunosorbent assay based on sandwich method.Results: The results show that the aromatase activity levels of patients were a highly significant decrease when contrasted with healthy control groups in both sexes (p≤0.01), and there were summarized positive results of an allele in single-nucleotide polymorphism, rs2236722, were highly significant in TT allele when contrasted with healthy control groups. While revealed that there was non-significant difference in TC allele when contrasted with healthy control groups (p&gt;0.01).Conclusion: we conclude that there was associated between CYP19A1 gene polymorphism (rs2236722) with aromatase activity and related to acromegaly patients.

Androgênios e mama

Breast cancer (BCAA) is one of the most frequent malignancies in women in several countries, which excessive exposure to oestrogens is one of the main risk factors. The ovaries are the main source of endogenous estrogen production; however, at menopause this production sessate and extra‐gonadal synthesis, especially in ectomesenchymal cells from adipose tissue, turns the main source of estrogen production, since these cells express aromatase, an enzyme that converts androgens to estrogens. Supported by strong clinical evidence androgen replacement has been recommended for the relief of symptoms caused by female syndrome of androgen insufficiency, such as fatigue, mood swings and depression; Furthermore, experimental studies have suggested the possibility of protection of androgen replacement against BCA. In these studies, acting through their receptors, testosterone showed antiproliferative, proapoptotic and inhibited the activity of estrogen receptors and growth of mammary tumors; Clinical evidence also support the protective role of androgens in the breast. However, studies indicate that this protective role depends on the level of aromatase activity; for instance, testosterone can exert a direct inhibitory effect on tumor growth by binding to its receptor, but have an indirect effect by stimulating its conversion to oestrogens by aromatase. Obesity and insulin, as well as multiple other factors, some of which are independent risk factors for BCA, may result in overexpression of aromatase, resulting in increased localized production of estrogens, which are inducible factors of BCA. Studies on the administration of testosterone in women are scarce and controversial, and there are no studies that provide data in terms of long‐term use of safety. Thus, in this review we intend to show how androgens act in the breast. Given the current evidence, the use of androgens in women with risk factors for breast cancer is not recommended.

Estrogen Receptor Alpha Distribution and Expression in the Social Neural Network of Monogamous and Polygynous Peromyscus.

In microtine and dwarf hamsters low levels of estrogen receptor alpha (ERα) in the bed nucleus of the stria terminalis (BST) and medial amygdala (MeA) play a critical role in the expression of social monogamy in males, which is characterized by high levels of affiliation and low levels of aggression. In contrast, monogamous Peromyscus males display high levels of aggression and affiliative behavior with high levels of testosterone and aromatase activity. Suggesting the hypothesis that in Peromyscus ERα expression will be positively correlated with high levels of male prosocial behavior and aggression. ERα expression was compared within the social neural network, including the posterior medial BST, MeA posterodorsal, medial preoptic area (MPOA), ventromedial hypothalamus (VMH), and arcuate nucleus in two monogamous species, P. californicus and P. polionotus, and two polygynous species, P. leucopus and P. maniculatus. The results supported the prediction, with male P. polionotus and P. californicus expressing higher levels of ERα in the BST than their polygynous counter parts, and ERα expression was sexually dimorphic in the polygynous species, with females expressing significantly more than males in the BST in both polygynous species and in the MeA in P. leucopus. Peromyscus ERα expression also differed from rats, mice and microtines as in neither the MPOA nor the VMH was ERα sexually dimorphic. The results supported the hypothesis that higher levels of ERα are associated with monogamy in Peromyscus and that differential expression of ERα occurs in the same regions of the brains regardless of whether high or low expression is associated with social monogamy. Also discussed are possible mechanisms regulating this differential relationship.

Abstract CN07-02: Obesity, inflammation, and breast cancer

Abstract Obesity is a risk factor for the development of several malignancies including hormone receptor–positive breast cancer in postmenopausal women and has been associated with an increased risk of recurrence and reduced survival. Chronic inflammation increases the risk of multiple tumor types. A link between obesity, breast inflammation and hormone receptor-positive breast cancer was previously unknown. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures (CLS). Estrogen synthesis is catalyzed by aromatase, which is encoded by CYP19. We found increased numbers of CLS, activation of the NF-kappaB transcription factor, increased levels of pro-inflammatory mediators and elevated aromatase levels in the mammary glands of obese mice. These preclinical findings raised the possibility that the obesity-inflammation-aromatase axis is important for breast carcinogenesis. Importantly, these findings have now been translated to women. Breast tissue was obtained from women who underwent surgery. CLS of the breast (CLS-B) were found in approximately 50% of patient samples. The severity of breast inflammation correlated with both body mass index and adipocyte size. Menopause is an independent determinant of CLS-B. Consistent with our preclinical findings, increased NF-κB binding activity, increased levels of pro-inflammatory mediators and elevated aromatase expression and activity were found in the inflamed breast tissue of overweight and obese women. Collectively, our results suggest that the obesity-inflammation-aromatase axis is present in the breast tissue of most overweight and obese women and is likely to contribute to the increased risk of hormone receptor-positive breast cancer. The discovery of the connection between obesity, breast inflammation and changes in the expression of genes linked to breast cancer provides a mechanistic rationale for the development of behavioral, dietary and pharmacological strategies to reduce the risk of breast cancer. Non-invasive biomarkers of adipose inflammation are needed to both identify at-risk individuals and monitor the efficacy of interventions aimed at attenuating inflamed adipose tissue. Recent progress in the development of blood biomarkers of breast adipose inflammation will be reviewed. Citation Format: Andrew J. Dannenberg. Obesity, inflammation, and breast cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN07-02.

Modulation of estradiol synthesis and aromatase activity in human choriocarcinoma JEG-3 cells exposed to tetrabromobisphenol A

The goal of the present study was to investigate the impact of tetrabromobisphenol A (TBBPA) on human choriocarcinoma-derived placental JEG-3 cells in vitro. We determined the effect of this compound on estradiol secretion, aromatase protein expression and activity in vitro in the JEG-3 cell line. We assessed the ability of TBBPA to increase intracellular levels of cAMP as well as its effect on cell viability and proliferation. Our results indicated that TBBPA, at a wide range of concentrations (1×10−8–5×10−5M), significantly induced estradiol secretion by JEG-3 cells compared to that of controls after 24, 48 or 72h of exposure. This effect was accompanied by an increase in the aromatase protein expression in JEG-3 cells treated with 100nM and 10μM of TBBPA for 24h. Additionally, in our study, we confirmed that TBBPA-induced changes in aromatase protein expression were associated with the up-regulation of aromatase activity and cAMP levels. No tested doses of TBBPA inhibited JEG-3 cell proliferation, except for the highest dose of 100μM, which had a toxic effect on cell viability at all time points. The present study clearly indicates that TBBPA alters JEG-3 cells estrogen synthesis due to its action on CYP19 protein expression and thus this compound may interfere with normal placental development during early pregnancy.

Age-dependent and age-independent effects of testosterone in male quail

Various studies in rodents recently concluded that puberty should be considered as a second period of organization of brain and behavior and that action of sex steroids at that time is long lasting and possibly permanent. We tested this notion in male Japanese quail that had been castrated before 3weeks post-hatch by analyzing whether a similar treatment with exogenous testosterone initiated at 3, 5 or 7weeks post-hatch has a differential influence on the development of testosterone-dependent morphological, behavioral and neural characteristics that are known to be sexually differentiated. The growth of the androgen-dependent cloacal gland was significantly faster when testosterone treatment was initiated later in life indicating that the target tissue is not ready to fully respond to androgens at 3weeks post-hatch. The three groups of birds nevertheless developed a gland of the same size typical of intact sexually mature birds. When adults, all birds expressed copulatory behavior with the same frequencies and latencies and they displayed the same level of aromatase activity and of vasotocinergic innervation in the preoptic area as gonadally intact males despite the fact that they had been treated with testosterone for different durations starting at different ages. Surprisingly, the frequency of cloacal sphincter contractions, a measure of appetitive sexual behavior, was significantly higher when testosterone treatment had been initiated later. Together these data provide no clear evidence for an organizational action of testosterone during sexual maturation of male quail but additional experiments should investigate whether estrogens have such an action in females.

Abstract PL05-02: Obesity, inflammation and breast cancer

Abstract More than 40,000 women in the U.S. die each year of metastatic breast cancer. Notably, obese postmenopausal women are at increased risk of developing hormone receptor (HR)-positive breast cancer. Approximately two-thirds of breast cancer patients have tumors that express estrogen receptors and require estrogen for tumor growth. Estrogens are synthesized from androgens in a reaction catalyzed by cytochrome P450 aromatase (aromatase), encoded by the CYP19 gene. After menopause, peripheral aromatization in adipose tissue is largely responsible for estrogen production. The increased breast cancer risk in obese postmenopausal women has been attributed, in part, to elevated levels of circulating estrogen related to both increased adipose tissue and elevated aromatase expression. Given the epidemic of overweight and obese subjects in the U.S., there is a pressing need to develop mechanism-based strategies to reduce the cancer risk among this sector of the population. Chronic inflammation increases the risk of multiple tumor types. A link between obesity, breast inflammation and HR-positive breast cancer was previously unknown. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue, characterized by macrophages surrounding dead adipocytes forming crown-like structures (CLS). Recently, we found increased numbers of CLS, activation of the NF-κB transcription factor, increased levels of pro-inflammatory mediators including PGE2 and elevated aromatase levels in the mammary glands of obese mice. In vitro models were utilized to demonstrate the importance of COX-2-derived PGE2 for the induction of aromatase. These preclinical findings raised the possibility that the obesity-inflammation-aromatase axis is important for breast carcinogenesis. Importantly, these findings have now been translated to women. Breast tissue was obtained from women who underwent surgery. CLS of the breast (CLS-B) were found in nearly 50% of patient samples. The severity of breast inflammation, defined as the CLS-B index, correlated with both body mass index and adipocyte size. Consistent with our preclinical findings, increased NF-κB binding activity, increased levels of pro-inflammatory mediators and elevated aromatase expression were found in the inflamed breast tissue of overweight and obese women. Notably, levels of COX-2 and PGE2 correlated with levels of aromatase and the progesterone receptor, an estrogen receptor-α regulated gene. The discovery of the connection between obesity, breast inflammation and changes in the expression of genes linked to breast cancer provides a mechanistic rationale for the development of behavioral, dietary and pharmacological strategies to reduce the risk of breast cancer. Recently conducted caloric restriction experiments provide proof-of-principle evidence that obesity-related mammary gland inflammation including related molecular changes can be reversed. Moreover, treatment with celecoxib, a selective COX-2 inhibitor, suppressed both the elevated levels of PGE2 and aromatase activity found in the mammary glands of obese mice. A clinical trial is underway in an attempt to translate these promising preclinical findings. Citation Format: Andrew J. Dannenberg. Obesity, inflammation and breast cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr PL05-02.

Effect of land use on pollution status and risk of fish endocrine disruption in small farmland ponds

To study whether the intensity of agricultural activities affects pesticides loads in pond environment, a large number of Belgian farmland ponds were surveyed in spring 2004. Temporal distribution of pollutants was also investigated over restricted survey ponds sampled three times round year 2007. Sedentary pond Prussian carp juveniles were also captured to determine their brain aromatase activity (AA) and plasma vitellogenin (VTG) levels. Heavy metal distribution was also examined in various pond matrices. Amongst the pesticides analysed, only herbicides were detected. Contamination of pond water by atrazine was frequently observed during spring 2004, while isoproturon and glyphosate were detected round year 2007. Levels of herbicides were inversely related to the distance of ponds to crop field, and values peaked in April or October. Absence of endocrine disruptors in pond water was confirmed by lack of modulation in VTG and AA in male fish. Heavy metals were present in all the pond matrices, but overall contamination levels were low. The results demonstrated that Belgian ponds were mainly contaminated by herbicides and that pond sedentary fish were not affected by endocrine disruptors. They also demonstrated a marked effect of land-use intensity on herbicide pollution which can be mitigated by an adjustment of the buffer zones.

Biochemical and molecular mechanisms for the association between obesity, chronic Inflammation, and breast cancer

Upper body obesity is a risk factor for postmenopausal breast cancer and is related to an aggressive tumor phenotype and a poor prognosis regardless of menopausal status. After the menopause, the major mechanism for the association with disease risk is elevated estrogen production by adipose tissue, due to a high level of aromatase activity: these hormone-dependent tumors express both estrogen and progesterone receptors. Other important biological factors of risk include leptin and adiponectin, adipokines with opposing endocrine and paracrine activities, and obesity-related hyperinsulinemia. Chronic inflammation of the breast adipose tissue, which occurs in some obese women and is indicated by the accumulation of macrophages around dead adipocytes ("crown-like structures"), rather than adiposity per se, may prove to be the pathological lesion responsible for both local aromatase induction, and enhanced invasiveness and metastatic capacity through biological mechanisms that involve leptin, tumor necrosis factor-α, and insulin. A causal association between obesity in premenopausal women and breast cell epithelial-mesenchymal transition, perhaps with the participation of the Wnt signaling pathway, and aggressive hormone-independent breast cancer is suggested by a number of experimental and clinical studies.

Abstract SY01-03: The obesity-inflammation connection: Implications for breast carcinogenesis.

Abstract Obesity is a risk factor for the development of several malignancies including hormone receptor-positive breast cancer in postmenopausal women and has been associated with an increased risk of recurrence and reduced survival. Chronic inflammation increases the risk of multiple malignancies. A link between obesity, breast inflammation and hormone receptor-positive breast cancer was previously unknown. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue, characterized by macrophages surrounding dead adipocytes forming crown-like structures (CLS). The synthesis of estrogen is catalyzed by aromatase, which is encoded by CYP19. Recently, we found increased numbers of CLS, activation of the NF-κB transcription factor, increased levels of pro-inflammatory mediators (TNF-α, IL-1β, PGE2) and elevated aromatase levels and activity in the mammary glands of obese mice. These preclinical findings raised the possibility that the obesity→inflammation →aromatase axis is important for breast carcinogenesis. Importantly, these findings have now been translated to women. Breast tissue was obtained from women who underwent mastectomy. CLS of the breast (CLS-B) were found in nearly 50% of patient samples. The severity of breast inflammation, defined as the CLS-B index, correlated with both body mass index and adipocyte size. Consistent with our preclinical findings, increased NF-κB binding activity, increased levels of pro-inflammatory mediators and elevated aromatase expression and activity were found in the inflamed breast tissue of overweight and obese women. Collectively, these results suggest that the obesity→inflammation →aromatase axis is present in the breast tissue of most overweight and obese women and is likely to contribute to the increased risk of hormone receptor-positive breast cancer. The presence of CLS-B may be a biomarker of increased breast cancer risk or poor prognosis. The discovery of the connection between obesity, breast inflammation and changes in the expression of genes linked to breast cancer provides a mechanistic rationale for the development of behavioral, dietary and pharmacological strategies to reduce the risk of breast cancer. Recently conducted preclinical experiments provide proof-of-principle evidence that obesity-related mammary gland inflammation can be rapidly reversed with caloric restriction. Citation Format: Andrew J. Dannenberg. The obesity-inflammation connection: Implications for breast carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY01-03. doi:10.1158/1538-7445.AM2013-SY01-03

A computational model to predict rat ovarian steroid secretion from in vitro experiments with endocrine disruptors.

A finely tuned balance between estrogens and androgens controls reproductive functions, and the last step of steroidogenesis plays a key role in maintaining that balance. Environmental toxicants are a serious health concern, and numerous studies have been devoted to studying the effects of endocrine disrupting chemicals (EDCs). The effects of EDCs on steroidogenic enzymes may influence steroid secretion and thus lead to reproductive toxicity. To predict hormonal balance disruption on the basis of data on aromatase activity and mRNA level modulation obtained in vitro on granulosa cells, we developed a mathematical model for the last gonadal steps of the sex steroid synthesis pathway. The model can simulate the ovarian synthesis and secretion of estrone, estradiol, androstenedione, and testosterone, and their response to endocrine disruption. The model is able to predict ovarian sex steroid concentrations under normal estrous cycle in female rat, and ovarian estradiol concentrations in adult female rats exposed to atrazine, bisphenol A, metabolites of methoxychlor or vinclozolin, and letrozole.

Investigation of aromotase inhibition by several dietary vegetables in human non-small cell lung cancer cell lines

Objective: In this study we have investigated the effect of extracts obtained from well-known vegetable diets consumed commonly in Mediterranean and Aegean regions of Turkey on the expression of aromatase at protein, mRNA and activity levels in human non–small cell lung cancer cellsPC-3 and PC-14 cell lines. Method: For this purpose, cytotoxicity was determined by using crystal violet stain. In vivo and in vitro aromatase activity was determined flourometrically. The expression of aromatase in protein and mRNA levels was detected by Western blotting using anti-hCYP19 and reverse transcriptasepolymerase chain reaction using suitable primers, respectively. Result: Extracts obtained from Laurus nobilis, Mentha piperita, Crocus sativus reduced aromatase activity 32%, 44%, 36% and 42%, 32%, 56% in PC-14 and PC-3 cell lines, respectively, no significant changes were observed in protein and mRNA levels. Whereas extract obtained from Allium porrum decreased aromatase activity and mRNA level only in PC-14 cell lines by 52% and 2,5-fold, respectively, without significant influence on aromatase protein level. Conclusion: The results obtained in this study have shown that Laurus nobilis, Mentha piperita, Crocus sativus and Allium porrum do contain effective aromatase inhibitors. Therefore, further studies investigating the content of these vegetables are necessary to understand the potential role and mechanism of action of these foods in reducing the risk of non-small cell lung carcinomas.