Chronic Exposure to Climbazole Induces Oxidative Stress and Sex Hormone Imbalance in the Testes of Male Zebrafish.

As the main active ingredient for the treatment of fungal infections, climbazole (CBZ) is commonly used in a variety of personal care products. After its use, CBZ enters the receiving environment directly or indirectly through domestic sewage. Its concentration can be up to several nanograms per liter in surface water. So far, the effects of CBZ on the reproductive system of female zebrafish have been systematically studied, but the potential toxicity mechanism of CBZ on male zebrafish still needs to be further explored. In this study, adult male zebrafish were exposed to CBZ at concentrations of 0.1, 10, and 1000 µg·L-1 for 28 days, and their testes were collected for histological, mass-spectrometry-based metabolomics, and biochemical analyses. We found that CBZ caused a significantly abnormal metabolism of purine and glutathione and triggered oxidative stress in zebrafish testes, thereby inducing testicular cell apoptosis. In addition, CBZ could inhibit the synthesis of essential sex hormones in the testis and thus reduce the sperm production. The conclusions of this study fill the data gap on the reproductive toxicity of CBZ to male zebrafish and highlight the ecotoxicological application of untargeted metabolomics in the biomarker discovery.

Sex-tailored pharmacology and COVID-19: Next steps towards appropriateness and health equity.

Making gender bias visible allows to fill the gaps in knowledge and understand health records and risks of women and men. The coronavirus disease 2019 (COVID-19) pandemic has shown a clear gender difference in health outcomes. The more severe symptoms and higher mortality in men as compared to women are likely due to sex and age differences in immune responses. Age-associated decline in sex steroid hormone levels may mediate proinflammatory reactions in older adults, thereby increasing their risk of adverse outcomes, whereas sex hormones and/or sex hormone receptor modulators may attenuate the inflammatory response and provide benefit to COVID-19 patients. While multiple pharmacological options including anticoagulants, glucocorticoids, antivirals, anti-inflammatory agents and traditional Chinese medicine preparations have been tested to treat COVID-19 patients with varied levels of evidence in terms of efficacy and safety, information on sex-targeted treatment strategies is currently limited. Women may have more benefit from COVID-19 vaccines than men, despite the occurrence of more frequent adverse effects, and long-term safety data with newly developed vectors are eagerly awaited. The prevalent inclusion of men in randomized clinical trials (RCTs) with subsequent extrapolation of results to women needs to be addressed, as reinforcing sex-neutral claims into COVID-19 research may insidiously lead to increased inequities in health care. The huge worldwide effort with over 3000 ongoing RCTs of pharmacological agents should focus on improving knowledge on sex, gender and age as pillars of individual variation in drug responses and enforce appropriateness.

The Effect of Metformin vs Placebo on Sex Hormones in Canadian Cancer Trials Group MA.32.

BACKGROUND: Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo. METHODS: We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models. RESULTS: 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone. CONCLUSION: Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.

Sex Disparities in COVID-19 Severity and Outcome: Are Men Weaker or Women Stronger?

The coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health issue which has profound effects on most aspects of societal well-being, including physical and mental health. A plethora of studies globally have suggested the existence of a sex disparity in the severity and outcome of COVID-19 patients, mainly due to mechanisms of virus infection, immune response to the virus, development of systemic inflammation, and consequent systemic complications, particularly thromboembolism. Epidemiological data report a sex difference in the severity of COVID-19, with a more favorable course of the disease in women compared to men regardless of age, although the rate of SARS-CoV-2 infection seems to be similar in both sexes. Sex hormones, including androgens and estrogens, may not only impact virus entry and load, but also shape the clinical manifestations, complications, and ultimately the outcome of the disease. The current review comprehensively summarizes the current literature on sex disparities in susceptibility and outcome of COVID-19 as well as the literature underpinning the pathophysiological and molecular mechanisms, which may provide a rationale to a sex disparity. These mechanisms include sex hormone influence on factors that facilitate virus entry and priming, immune and inflammatory response, as well as coagulation and thrombosis diathesis. Based on present evidence, women appear to be relatively protected from COVID-19 because of a more effective immune response and a less pronounced systemic inflammation, with consequent moderate clinical manifestations of the disease, together with a lesser predisposition to thromboembolism. Conversely, men appear to be particularly susceptible to COVID-19 because of a less effective immune response with consequent severe clinical manifestations of the disease, together with a greater predisposition to thromboembolism. In the elderly, generally characterized by the phenomenon of inflammaging, sex disparities in overall mortality following SARS-CoV-2 infection are even more palpable as elderly men appear to be more prone to severe COVID-19 because of a greater predisposition to infections, a weaker immune defense, and an enhanced thrombotic state compared to women. The information revealed from the review highlights potential novel therapeutic approaches employing the administration of hormonal or antihormonal therapy in combination with antiviral drugs in COVID-19 patients.

Statin therapy and sex hormones.

Current guidelines recommend statin therapy for all adult patients with coronary artery disease irrespective of sex. Over recent years, some concerns have been raised concerning the effects of statins on endogenous steroid hormones synthesis. The aim of this review was to summarize the effects of statins on endogenous sex hormones in order to clarify their role and safety in different clinical settings. Results suggest that HMG-CoA inhibitors may slightly impair adrenal and/or gonadal steroid hormone production. In men, statins do not cause any clinically-relevant harmful effects on erectile function and spermatogenesis and, in women, statins have beneficial effects in treatment of polycystic ovary syndrome (PCOS). Additional research is needed to provide specific clinical recommendations concerning this topic.

High resolution effect-directed analysis of steroid hormone (ant)agonists in surface and wastewater quality monitoring.

Monitoring of chemical water quality is extremely challenging due to the large variety of compounds and the presence of biologically active compounds with unknown chemical identity. Previously, we developed a high resolution Effect-Directed Analysis (EDA) platform that combines liquid chromatography with high resolution mass spectrometry and parallel bioassay detection. In this study, the platform is combined with CALUX bioassays for (anti)androgenic, estrogenic and glucocorticoid activities, and the performance of the platform is evaluated. It appeared to render very repeatable results, with high recoveries of spiked compounds and high consistency between the mass spectrometric and bioassay results. Application of the platform to wastewater treatment plant effluent and surface water samples led to the identification of several compounds contributing to the measured activities. Eventually, a workflow is proposed for the application of the platform in a routine monitoring context. The workflow divides the platform into four phases, of which one to all can be performed depending on the research question and the results obtained. This allows one to make a balance between the effort put into the platform and the certainty and depth by which active compounds will be identified. The EDA platform is a valuable tool to identify unknown bioactive compounds, both in an academic setting as in the context of legislative, governmental or routine monitoring.

Unexpected Observations: Probiotic Administration Greatly Aggravates the Reproductive Toxicity of Perfluorobutanesulfonate in Zebrafish.

The present study exposed adult zebrafish to 0, 10, and 100 µg/L perfluorobutanesulfonate (PFBS) with or without dietary supplement of probiotic Lactobacillus rhamnosus. Interaction between probiotic and PFBS on sex endocrine and reproduction was investigated. It was striking to find that PFBS and probiotic coexposures almost ceased the fecundity, which was accompanied by disturbances in sex hormones and oocyte maturation in females. In contrast, probiotic additive efficiently antagonized the estrogenic activity of PFBS in males. For the first time, this study reported that probiotic heavily depended on sex to modulate the endocrine disruption and reproductive toxicity of aquatic pollutants.

Curcumin: a phytochemical modulator of estrogens and androgens in tumors of the reproductive system.

Curcumin (Cur) is an active derivative extracted from turmeric which exerts a wide range of interactions with biomolecules through complex signaling pathways. Cur has been extensively shown to possess potential antitumor properties. In addition, there is growing body of evidence suggesting that Cur may exert potential anti-estrogen and anti-androgen activity. In vitro and in vivo studies suggest that anticancer properties of Cur against tumors affecting the reproductive system in females and males may be underlied by the Cur-mediated inhibition of androgen and estrogen signaling pathways. In this review we examine various studies assessing the crosstalk between Cur and both androgen and estrogen hormonal activity. Also, we discuss the potential chemopreventive and antitumor role of Cur in the most prevalent cancers affecting the reproductive system in females and males.

Targeting the Unfolded Protein Response in Hormone-Regulated Cancers.

Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One of these is the unfolded protein response (UPR), a highly conserved signaling pathway that is mounted in response to endoplasmic reticulum (ER) stress. Recent work showed that steroid hormones, in particular estrogens and androgens, regulate the canonical UPR pathways in breast cancer (BCa) and prostate cancer (PCa). In addition, UPR has pleiotropic effects in advanced disease and development of therapy resistance. These findings implicate the UPR pathway as a novel target in hormonally regulated cancers in the clinic. Here, we review the potential therapeutic value of recently developed small molecule inhibitors of UPR in hormone regulated cancers.

Natural Compounds in Sex Hormone-Dependent Cancers: The Role of Triterpenes as Therapeutic Agents.

Sex hormone-dependent cancers currently contribute to the high number of cancer-related deaths worldwide. The study and elucidation of the molecular mechanisms underlying the progression of these tumors was a double-edged sword, leading to the expansion and development of new treatment options, with the cost of triggering more aggressive, therapy resistant relapses. The interaction of androgen, estrogen and progesterone hormones with specific receptors (AR, ER, PR) has emerged as a key player in the development and progression of breast, ovarian, prostate and endometrium cancers. Sex hormone-dependent cancers share a common and rather unique carcinogenesis mechanism involving the active role of endogenous and exogenous sex hormones to maintain high mitotic rates and increased cell proliferation thus increasing the probability of aberrant gene occurrence and accumulation highly correlated with abnormal cell division and the occurrence of malignant phenotypes. Cancer related hormone therapy has evolved, currently being associated with the blockade of other signaling pathways often associated with carcinogenesis and tumor progression in cancers, with promising results. However, despite the established developments, there are still several shortcomings to be addressed. Triterpenes are natural occurring secondary metabolites biosynthesized by various pathways starting from squalene cyclization. Due to their versatile therapeutic potential, including the extensively researched antiproliferative effect, these compounds are most definitely a cornerstone in the research and development of new natural/semisynthetic anticancer therapies. The present work thoroughly describes the ongoing research related to the antitumor activity of triterpenes in sex hormone-dependent cancers. Also, the current review highlights both the biological activity of various triterpenoid compounds and their featured mechanisms of action correlated with important chemical structural features.

Migraine: navigating the hormonal minefield.

Migraine affects 959 million people worldwide,1 with the highest prevalence being in women of childbearing age. The interplay between female hormones and migraine can be a challenging area to navigate since issues relating to pregnancy, contraception and the menopause are often out of the neurology comfort zone. This review aims to help the neurologist to manage women with migraine, from menarche to menopause.

Indirect Comparisons of Efficacy between Combination Approaches in Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Network Meta-analysis.

CONTEXT: There have been substantial changes in the management of men with metastatic hormone-sensitive prostate cancer (mHSPC) over the past 5 yr, with upfront combination therapies replacing androgen-deprivation therapy (ADT) alone. A range of therapies have entered the space with no clear answer regarding their comparative efficacy. OBJECTIVE: To perform a systematic review and network meta-analysis to characterise the comparative efficacy of combination approaches in men with mHSPC. EVIDENCE ACQUISITION: We searched multiple databases and abstracts of major meetings up to June 2019 for randomised trials of patients receiving first-line therapy for metastatic disease, a combination of ADT and one (or more) of taxane-based chemotherapy, and androgen receptor-targeted therapies. The primary endpoint was overall survival (OS) and we evaluated progression-free survival as a secondary outcome. We performed subgroup analysis based on the volume of disease. EVIDENCE SYNTHESIS: We found seven trials that met our eligibility criteria using either docetaxel, abiraterone acetate, enzalutamide, or apalutamide in combination with ADT. All agents in combination with ADT were shown to be superior to ADT alone; enzalutamide + ADT had the lowest absolute hazard ratio compared with ADT only (hazards ratio 0.53, 95% confidence interval 0.37-0.75), and an estimated 76.9% probability that it is the preferred treatment to prolong OS compared with other combination treatments, or with ADT alone. Enzalutamide appeared to have better OS compared with docetaxel in men with low-volume disease, but there was no difference in other comparisons. CONCLUSIONS: Combination therapy with any of docetaxel, abiraterone acetate, enzalutamide, or apalutamide provides a significant OS benefit when compared with ADT alone. We did not identify significant differences in OS between different combination therapies. Subtle differences between these options provide clinicians considerable flexibility when selecting options for individual patients. PATIENT SUMMARY: Many men with metastatic, hormone-sensitive prostate cancer should be managed with upfront combination therapy instead of androgen-deprivation therapy alone. Clinicians may consider many factors during the decision-making process, and thus management should be tailored for patients individually.

An expanded toxicological profile of tetramethyl bisphenol F (TMBPF), a precursor for a new food-contact metal packaging coating.

Tetramethyl bisphenol F (TMBPF) has been shown to impart unique physical properties critical for high performance of epoxy can coatings without the estrogenic activity concerns associated with other bisphenols. To further characterize the toxicological profile of TMBPF, additional endocrine-related endpoints including in vitro aromatase inhibition and steroidogenesis assays, and in vivo androgen agonism/antagonism were performed. Systemic toxicity was also assessed by a repeat dose 90-day dietary toxicity study followed by 28-day recovery period. TMBPF did not inhibit aromatase activity, and induced estradiol and testosterone at highest non-cytotoxic concentrations (10 µM) in the steroidogenesis assay. In the Hershberger assay, TMBPF showed no androgenic activity at any dose and equivocal anti-androgenic activity at the highest dose (1000 mg/kg-bw/d). In a 90-day dietary toxicity study with 28-day recovery period, observations including changes in clinical pathology, absolute and relative organ weights, and microscopic findings are discussed. In this current study, the no observed adverse effect level was considered to be 750 mg/kg-bw/d for female rats and 1000 mg/kg-bw/d for male rats with no biologically significant changes to endocrine endpoints at any dose level. Our findings provide further evidence that TMBPF is a low-toxicity substance with a toxicology profile distinct from some other bisphenols.

Ameliorative Effects of Hydromethanolic Extract of Citrullus lanatus (Watermelon) Rind on Semen Parameters, Reproductive Hormones and Testicular Oxidative Status Following Nicotine Administration in Male Wistar Rats.

The present study examines the possible ameliorative effects of the hydromethanolic extract of Citrullus lanatus rind (HECL) on some reproductive function and oxidative indices of the testes in male Wistar rats following administration of nicotine. Twenty male rats were assigned into four groups: Group A to D of five rats each. Group A served as control and received 2ml/kg body weight of 10% extract vehicle; Group B received 1mg/kg body weight of nicotine; Group C were co-administered 1mg/kg body weight nicotine and 500 mg/kg body weight of HECL and Group D received only 500mg/kg body weight of HECL. The drugs and extracts were administered orally to the rats for 42days; blood samples were collected by direct cardiac puncture for determination of serum concentrations of testosterone, Follicle Stimulating Hormone and Luteinizing Hormone. The testes were also harvested for determination of semen parameters: motility, morphology, viability and count and testicular tissue processed for superoxide dismutase and malondialdehyde concentration. Compared to Group A control rats, administration of HECL significantly increased sperm count and reproductive hormone concentrations amongst Group B rats (p<0.05). Treatment with nicotine caused a significant reduction in the levels of all reproductive hormones with significant diminution of some sperm parameters: motility, morphology and viability; and decrease in superoxide dismutase and increase in malondialdehyde concentration amongst Group B rats compared to Group A control rats (p<0.05). Co-administration of HECL with nicotine to Group C rats apparently reversed the effects of nicotine resulting in significant increases in sperm count and the reproductive hormones concentration as compared to Group A control rats (p<0.05). Amongst Group D rats, the extract also caused a significant increase in superoxide dismutase concentration and a significant decrease in malondialdehyde concentration compared with the Group A control rats (p<0.05). The findings suggest that the hydromethanolic extract of Citrullus lanatus rind possibly ameliorates the deleterious effects of nicotine on some reproductive indices in male Wistar rats.

Reproductive Indices and Oxidative Stress Biomarkers of Male Wistar Rats Prenatally Exposed to Cigarette Smoke.

The negative influence of cigarette smoking on developing fetus is well documented but reports of prenatal cigarette smoking on male reproductive hormones are controversial. However, shortened anogenital distance (AGD) has been established to be an indicator of potential male infertility. We therefore investigated the effects of prenatal exposure to passive cigarette smoke on AGD, reproductive hormones and oxidative stress biomarkers of Wistar rats. Female rats were randomly divided into two groups (n=5) and cohabited with male. Group 1 was exposed to smoke from an idling cigarette from day 1 of gestation till parturition, while Group 2 served as control (no-exposure). Morphometric variables of the litters were recorded on postnatal day 1 (PND1) and at 6th week postnatal life. The male offspring were then sacrificed by cervical dislocation. Testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were analysed using ELISA. Serum levels of Catalase, sodium dismutase (SOD), malondialdehyde (MDA), lipid profile and liver function biomarkers were examined spectrophotometrically.  On PND1, crown rump length and total body length of rats prenatally exposed to cigarette smoke were significantly shorter. Significantly shorter AGD and crown rump length were also observed at 6th week. Testosterone, LH and FSH were not significantly affected.  Cigarette smoke exposure significantly decreased Catalase and SOD while MDA increased. Liver function biomarkers, HDL and LDL were not affected but serum levels of total cholesterol and triglyceride significantly increased. The observed decline in AGD and precipitation of oxidative stress by intrauterine cigarette smoke exposure may predispose to male infertility at adulthood.

A combined FSTRA-shotgun proteomics approach to identify molecular changes in zebrafish upon chemical exposure.

The fish short-term reproduction assay (FSTRA) is a common in vivo screening assay for assessing endocrine effects of chemicals on reproduction in fish. However, the current reliance on measures such as egg number, plasma vitellogenin concentration and morphological changes to determine endocrine effects can lead to false labelling of chemicals with non-endocrine modes- of-action. Here, we integrated quantitative liver and gonad shotgun proteomics into the FSTRA in order to investigate the causal link between an endocrine mode-of-action and adverse effects assigned to the endocrine axis. Therefore, we analyzed the molecular effects of fadrozole-induced aromatase inhibition in zebrafish (Danio rerio). We observed a concentration-dependent decrease in fecundity, a reduction in plasma vitellogenin concentrations and a mild oocyte atresia with oocyte membrane folding in females. Consistent with these apical measures, proteomics revealed a significant dysregulation of proteins involved in steroid hormone secretion and estrogen stimulus in the female liver. In the ovary, the deregulation of estrogen synthesis and binding of sperm to zona pellucida were among the most significantly perturbed pathways. A significant deregulation of proteins targeting the transcriptional activity of estrogen receptor (esr1) was observed in male liver and testis. Our results support that organ- and sex-specific quantitative proteomics represent a promising tool for identifying early gene expression changes preceding chemical-induced adverse outcomes. These data can help to establish consistency in chemical classification and labelling.

Endocrinology of Transgender Medicine.

Gender-affirming treatment of transgender people requires a multidisciplinary approach in which endocrinologists play a crucial role. The aim of this paper is to review recent data on hormonal treatment of this population and its effect on physical, psychological, and mental health. The Endocrine Society guidelines for transgender women include estrogens in combination with androgen-lowering medications. Feminizing treatment with estrogens and antiandrogens has desired physical changes, such as enhanced breast growth, reduction of facial and body hair growth, and fat redistribution in a female pattern. Possible side effects should be discussed with patients, particularly those at risk for venous thromboembolism. The Endocrine Society guidelines for transgender men include testosterone therapy for virilization with deepening of the voice, cessation of menses, and increases of muscle mass and facial and body hair. Owing to the lack of evidence, treatment of gender nonbinary people should be individualized. Young people may receive pubertal suspension, consisting of GnRH analogs, later followed by sex steroids. Options for fertility preservation should be discussed before any hormonal intervention. Morbidity and cardiovascular risk with cross-sex hormones is unchanged among transgender men and unclear among transgender women. Sex steroid-related malignancies can occur but are rare. Mental health problems such as depression and anxiety have been found to reduce considerably following hormonal treatment. Future studies should aim to explore the long-term outcome of hormonal treatment in transgender people and provide evidence as to the effect of gender-affirming treatment in the nonbinary population.

Resistance of primary breast cancer cells with enhanced pluripotency and stem cell activity to sex hormonal stimulation and suppression.

Female sex steroid hormones have a fundamental role in breast cancer. Meanwhile, current evidence supports the contribution of breast cancer stem cells in carcinogenesis, metastasis, and resistance to cytotoxic chemotherapy. Nevertheless, the interaction between breast cancer stem cells with sex hormones or key hormonal antagonists remains elusive. OBJECTIVE: To investigate the effect of diverse sex hormonal stimulation and suppression regimens on the proliferation of a primary human breast cancer cells with stem cell activity. METHODS: Cells were exposed to estradiol, progesterone, letrozole, ulipristal acetate, or a combination of ulipristal acetate-letrozole, continually for 6 months. Additionally, nanoparticle-linked letrozole and ulipristal acetate formulations were included in a subsequent short-term exposure study. Phenotypic, pathologic, and functional characteristics of unexposed cells were investigated. RESULTS: The proliferation of breast cancer cells was comparable among all hormonal stimulation and suppression groups (P= 0.8). In addition, the nanoparticle encapsulated hormonal antagonists were not able to overcome the observed resistance of cells. Cell characterization showed a mesenchymal-like phenotype overexpressing three master pluripotency markers (Oct 4, SOX2, and Nanog), and 92% of cells were expressing ALDH1A1. Notably, the CD44 high/CD24 low cell population presented only 0.97%-5.4% over repeat analyses. Most cells lacked the expression of mesenchymal markers; however, they showed differentiation into osteogenic and adipogenic lineages. Upon transfer to serum-free culture, the long-term maintained mesenchymal-like cancer cells showed remarkable morphologic plasticity as they switched promptly into an epithelial-like phenotype with significant mammosphere formation capacity (P= 0.008). CONCLUSION: Breast cancer cells can develop a pluripotent program with enhanced stemness activity that may together contribute to universal resistance to sex hormonal stimulation or deprivation. Isolation and characterization of patient-derived breast cancer stem cells in large clinical studies is therefore crucial to identify new targets for endocrine therapies, potentially directed towards stemness and pluripotency markers. Such direction may help overcoming endocrine resistance and draw attention to breast cancer stem cells' behaviour under endogenous and exogenous sex hormones throughout a woman's reproductive life.

A Novel Action of Endocrine-Disrupting Chemicals on Wildlife; DDT and Its Derivatives Have Remained in the Environment.

Huge numbers of chemicals are released uncontrolled into the environment and some of these chemicals induce unwanted biological effects, both on wildlife and humans. One class of these chemicals are endocrine-disrupting chemicals (EDCs), which are released even though EDCs can affect not only the functions of steroid hormones but also of various signaling molecules, including any ligand-mediated signal transduction pathways. Dichlorodiphenyltrichloroethane (DDT), a pesticide that is already banned, is one of the best-publicized EDCs and its metabolites have been considered to cause adverse effects on wildlife, even though the exact molecular mechanisms of the abnormalities it causes still remain obscure. Recently, an industrial raw material, bisphenol A (BPA), has attracted worldwide attention as an EDC because it induces developmental abnormalities even at low-dose exposures. DDT and BPA derivatives have structural similarities in their chemical features. In this short review, unclear points on the molecular mechanisms of adverse effects of DDT found on alligators are summarized from data in the literature, and recent experimental and molecular research on BPA derivatives is investigated to introduce novel perspectives on BPA derivatives. Especially, a recently developed BPA derivative, bisphenol C (BPC), is structurally similar to a DDT derivative called dichlorodiphenyldichloroethylene (DDE).

Harnessing a Different Dependency: How to Identify and Target Androgen Receptor-Positive Versus Quadruple-Negative Breast Cancer.

The androgen receptor (AR) is a promising therapeutic target for a subset of triple-negative breast cancers (TNBCs) in which AR is expressed. However, the mechanistic action of AR and the degree to which primary and metastatic tumors depend on AR, both before and after conventional treatment, remain to be defined. We discuss preclinical and clinical data for AR+ TNBC, the difficulties in monitoring AR protein levels, new methods for determining AR status, the influence of AR on "stemness" in the context of TNBC, the role of combined inhibition of sex steroid production and AR, and the role of AR in regulation of the immune system. Although the exact role of AR in subsets of TNBC is still being characterized, new therapies that target AR and the production of androgens may provide additional options for patients with TNBC for whom chemotherapy is currently the sole treatment option.