Uncovering physical activity trade-offs in transportation policy: A spatial agent-based model of Bogotá, Colombia.

BACKGROUND: Transportation policies can impact health outcomes while simultaneously promoting social equity and environmental sustainability. We developed an agent-based model (ABM) to simulate the impacts of fare subsidies and congestion taxes on commuter decision-making and travel patterns. We report effects on mode share, travel time and transport-related physical activity (PA), including the variability of effects by socioeconomic strata (SES), and the trade-offs that may need to be considered in the implementation of these policies in a context with high levels of necessity-based physical activity. METHODS: The ABM design was informed by local stakeholder engagement. The demographic and spatial characteristics of the in-silico city, and its residents, were informed by local surveys and empirical studies. We used ridership and travel time data from the 2019 Bogotá Household Travel Survey to calibrate and validate the model by SES. We then explored the impacts of fare subsidy and congestion tax policy scenarios. RESULTS: Our model reproduced commuting patterns observed in Bogotá, including substantial necessity-based walking for transportation. At the city-level, congestion taxes fractionally reduced car use, including among mid-to-high SES groups but not among low SES commuters. Neither travel times nor physical activity levels were impacted at the city level or by SES. Comparatively, fare subsidies promoted city-level public transportation (PT) ridership, particularly under a 'free-fare' scenario, largely through reductions in walking trips. 'Free fare' policies also led to a large reduction in very long walking times and an overall reduction in the commuting-based attainment of physical activity guidelines. Differential effects were observed by SES, with free fares promoting PT ridership primarily among low-and-middle SES groups. These shifts to PT reduced median walking times among all SES groups, particularly low-SES groups. Moreover, the proportion of low-to-mid SES commuters meeting weekly physical activity recommendations decreased under the 'freefare' policy, with no change observed among high-SES groups. CONCLUSIONS: Transport policies can differentially impact SES-level disparities in necessity-based walking and travel times. Understanding these impacts is critical in shaping transportation policies that balance the dual aims of reducing SES-level disparities in travel time (and time poverty) and the promotion of choice-based physical activity.

Genetic Ancestry-specific Molecular and Survival Differences in Admixed Patients With Breast Cancer.

OBJECTIVE: We aim to determine whether incremental changes in genetic ancestry percentages influence molecular and clinical outcome characteristics of breast cancer in an admixed population. BACKGROUND: Patients with breast cancer are predominantly characterized as "Black" or "White" based on self-identified race/ethnicity or arbitrary genetic ancestry cutoffs. This limits scientific discovery in populations that are admixed or of mixed race/ethnicity as they cannot be classified based on historical race/ethnicity boxes or genetic ancestry cutoffs. METHODS: We used The Cancer Genome Atlas cohort and focused on genetically admixed patients that had less than 90% European, African, Asian, or Native American ancestry. RESULTS: Genetically admixed patients with breast cancer exhibited improved 10-year overall survival relative to those with >90% European ancestry. Within the luminal A subtype, patients with lower African ancestry had longer 10-year overall survival compared to those with higher African ancestry. The correlation of genetic ancestry with gene expression and DNA methylation in the admixed cohort revealed novel ancestry-specific intrinsic PAM50 subtype patterns. In luminal A tumors, genetic ancestry was correlated with both the expression and methylation of signaling genes, while in basal-like tumors, genetic ancestry was correlated with stemness genes. In addition, we took a machine-learning approach to estimate genetic ancestry from gene expression or DNA methylation and were able to accurately calculate ancestry values from a reduced set of 10 genes or 50 methylation sites that were specific for each molecular subtype. CONCLUSIONS: Our results suggest that incremental changes in genetic ancestry percentages result in ancestry-specific molecular differences even between well-established PAM50 subtypes which may influence disparities in breast cancer survival outcomes. Accounting for incremental changes in ancestry will be important in future research, prognostication, and risk stratification, particularly in ancestrally diverse populations.

PRAME induces genomic instability in uveal melanoma.

PRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells. This effect is mediated at least in part by ubiquitination of SMC1A and altered cohesin function. PRAME expression renders cells susceptible to inhibition of PARP1/2, suggesting increased dependence on alternative base excision repair pathways. These findings reveal a distinct oncogenic function of PRAME that can be targeted therapeutically in cancer.

PRAME induces genomic instability in uveal melanoma.

PRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells. This effect is mediated at least in part by ubiquitination of SMC1A and altered cohesin function. PRAME expression renders cells susceptible to inhibition of PARP1/2, suggesting increased dependence on alternative base excision repair pathways. These findings reveal a distinct oncogenic function of PRAME than can be targeted therapeutically in cancer.

Impact of Tumor Necrosis Factor Receptor 1 (TNFR1) Polymorphism on Dry Eye Disease.

The goal of the study was to examine whether a genetic polymorphism in tumor necrosis factor receptor 1 (TNFR1) gene impacted the dry eye disease (DED) phenotype and response to anti-inflammatory therapy. The prospective study included 328 individuals with various dry eye (DE) symptoms and signs recruited from the Miami Veterans Hospital eye clinic between October 2013 and October 2017. The population underwent genetic profiling for a polymorphism within the TNFR1 gene (rs1800693 [TT, TC, CC]). The study examined the genotype distribution and relationships between the genotype, phenotype, and response to anti-inflammatory therapy. The mean age of the population was 61.7 ± 9.8 years. Here, 92% self-identified as male, 44% as White, and 21% as Hispanic; 13% (n = 42) of individuals had a CC genotype. DED symptoms and signs were similar across the three genotype groups. Thirty individuals (four with CC) were subsequently treated with an anti-inflammatory agent. There was a non-significant trend for individuals with CC genotype to have a partial or complete symptomatic response to treatment compared with the other two groups (100% for CC vs. 40% for TT and 36.4% for TC, p = 0.22). In conclusion, the presence of homozygosity of minor allele C (CC genotype) in a single nucleotide polymorphism (SNP) within TNFR1 was noted in a minority of individuals with various aspects of DED, but did not impact the DED phenotype. Our findings suggest that the current phenotyping strategies for DED are insufficient to identify underlying disease contributors, including potential genetic contributors.

Actualización sobre el síndrome de Eagle y sus complicaciones neurocardiológicas: casos clínicos / An update on Eagle´s syndrome and its neuro-cardiological complications: clinical cases

El síndrome de Eagle o síndrome estilohioideo o sín-drome de la arteria carótida es un trastorno que se origina por la mineralización y elongación del pro-ceso estiloides. Factores traumáticos agudos y cró-nicos, así como otras teorías, han sido propuestos para explicar la etiología y patogenia de esta altera-ción. El conjunto de síntomas puede incluir: dolor fa-ríngeo, odinofagia, disfagia, cefalea, con irradiación a oreja y zona cervical. Si bien existen varias clasifi-caciones, de manera universal se acepta que existen principalmente dos formas de presentación de esta patología: el tipo I o clásico, generalmente asociado a un trauma faríngeo y acompañado de dolor en la zona faríngea y cervical, y el tipo II o carotídeo, que sue-le presentar molestia cervical, cefalea y alteración de la presión arterial, con riesgo de daño de la ac-tividad cardíaca. La identificación de este síndrome suele ser confusa dada la similitud de los síntomas con otras afecciones. El diagnóstico debe realizarse en base a los síntomas y a los estudios por imágenes específicos. El tratamiento puede ser conservador y actuar simplemente sobre los síntomas, o bien, qui-rúrgico. El objetivo del presente trabajo es realizar una revisión actualizada de la literatura sobre el sín-drome de Eagle y presentar tres casos clínicos con distintas manifestaciones (AU)

Eagle's syndrome or styloid syndrome or stylo-carotid artery syndrome is a disease caused by mineralization and elongation of the styloid process. Acute and chronic traumatic factors, along with other hypothesis, have been proposed to explain the aetiology and pathogenesis of this condition. Symptoms can include: pharynx pain, odynophagia, dysphagia, headache, with radiating pain to the ear and neck. Despite there are several classifications, it is universally accepted that this pathology can present in two forms: the type I or classic, generally associated to tonsillar trauma and characterized by pharyngeal and neck pain, and the type II or carotid artery type, which frequently presents with neck pain, headache, blood pressure variation, with risk of damage to cardiac function. Identifying of Eagle's syndrome is often confusing because some symptoms are shared with other pathologies. Diagnosis must be made on the basis of symptoms and imaging studies. Treatment can be conservative, acting only on symptoms, or surgical. The aim of this paper is to provide an updated review of the literature on Eagle syndrome and to present three clinical cases with different manifestations (AU)

Demographic and economic trends in vertebral fracture surgeries throughout the United States.

Background: Vertebral fractures, frequently resulting from high-impact trauma to the spine, are an increasingly relevant public health concern. Little is known about the long-term economic and demographic trends affecting patients undergoing surgery for such fractures. This study examines national economic and demographic trends in vertebral fracture surgery in the United States to improve value-based care and health care utilization. Methods: The National Inpatient Sample (NIS) was queried for patients who underwent surgical treatment of a vertebral fracture (ICD-9-CM-3.53) (excluding kyphoplasty and vertebroplasty) between 1993 and 2015. Demographic data included patient age, sex, income, insurance type, hospital size, and location. Economic data including aggregate charge, aggregate cost, hospital cost, and hospital charge were analyzed. Results: The number of vertebral fracture surgeries, excluding kyphoplasty and vertebroplasty, increased 461% from 3,331 in 1993 to 18,675 in 2014, while inpatient mortality increased from 1.9% to 2.5%.The mean age of patients undergoing vertebral fracture surgeries increased from 42 in 1993 to 53 in 2015. The aggregate cost of surgery increased from $189,164,625 in 2001 to $1,060,866,580 in 2014, a 461% increase. Conclusions: The significant increase in vertebral fracture surgeries between 1993 and 2014 may reflect an increased rate of fractures, more surgeons electing to treat fractures surgically, or a combination of both. The increasing rate of vertebral fracture surgery, coupled with increasing hospital costs and mortality, signifies that the treatment of vertebral fractures remains a challenging issue in healthcare. Further research is necessary to determine the underlying cause of both the increase in surgeries and the increasing mortality rate.

Translational Epidemiology: An Integrative Approach to Determine the Interplay Between Genetic Ancestry and Neighborhood Socioeconomic Status on Triple Negative Breast Cancer.

OBJECTIVE: To investigate the impact of global and local genetic ancestry and neighborhood socioeconomic status (nSES), on breast cancer (BC) subtype, and gene expression. BACKGROUND: Higher rates of aggressive BC subtypes [triple negative breast cancer (TNBC)] and worse overall BC survival are seen in black women [Hispanic Black (HB) and non-Hispanic Black (NHB)] and women from low nSES. However, the complex relationship between genetic ancestry, nSES, and BC subtype etiology remains unknown. METHODS: Genomic analysis was performed on the peripheral blood from a cohort of 308 stage I to IV non-Hispanic White (NHW), Hispanic White (HW), HB, and NHB women with BC. Patient and tumor characteristics were collected. Global and local ancestral estimates were calculated. Multinomial logistic regression was performed to determine associations between age, stage, genetic ancestry, and nSES on rates of TNBC compared to estrogen receptor (ER+)/epidermal growth factor receptor 2 (HER2-), ER+/HER2+, and ER-/HER2+ disease. RESULTS: Among 308 women, we identified a significant association between increasing West African (WA) ancestry and odds of TNBC [odds ratio (OR): 1.06, 95% confidence interval (95% CI): 1.001-1.126, P =0.046] as well as an inverse relationship between higher nSES and TNBC (OR: 0.343, 95% CI: 0.151-0.781, P =0.011). WA ancestry remained significantly associated with TNBC when adjusting for patient age and tumor stage, but not when adjusting for nSES (OR: 1.049, 95% CI: -0.987-1.116, P =0.120). Local ancestry analysis, however, still revealed nSES-independent enriched WA ancestral segment centered at χ 2 =42004914 ( p =3.70×10 -5 ) in patients with TNBC. CONCLUSIONS: In this translational epidemiologic study of genetic ancestry and nSES on BC subtype, we discovered associations between increasing WA ancestry, low nSES, and higher rates of TNBC compared to other BC subtypes. Moreover, on admixture mapping, specific chromosomal segments were associated with WA ancestry and TNBC, independent of nSES. However, on multinomial logistic regression adjusting for WA ancestry, women from low nSES were more likely to have TNBC, independent of genetic ancestry. These findings highlight the complex nature of TNBC and the importance of studying potential gene-environment interactions as drivers of TNBC.

Female Prostate Development: Morphological Analysis of the Budding Dynamic.

The presence of the prostate in female mammals has long been known. However, pieces of information related to its development are still lacking. The aim of this study was to explore the budding dynamic during the initial prostate development in female gerbils. Pregnant females were timed, the fetuses were euthanized, and the urogenital sinus was dissected out between the embryonic days 20 and 24 (E20-E24 groups). Newborn pups (1-day-old; P1 group) underwent the same procedures. The female prostate development was based on epithelial buds which arose far from the paraurethral mesenchyme (PAM). The epithelial buds reached the PAM at prenatal day 24, crossing a small gap in the smooth muscle layer between the periurethral mesenchyme (PEM) and the PAM. Steroid nuclear receptors such as the androgen receptor and estrogen receptor alpha were localized in the PEM through the urethral wall, although some epithelial labeling was also present in the urogenital sinus epithelium (UGE). P63-positive cells were found only in the UGE, becoming restricted to the basal compartment after the 23rd prenatal day. The results showed that the gerbil female prostate exhibits a distinct budding pattern as compared to the male prostate development.

Multiregional genetic evolution of metastatic uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and leads to deadly metastases for which there is no approved treatment. Genetic events driving early tumor development are well-described, but those occurring later during metastatic progression remain poorly understood. We performed multiregional genomic sequencing on 22 tumors collected from two patients with widely metastatic UM who underwent rapid autopsy. We observed multiple seeding events from the primary tumors, metastasis-to-metastasis seeding, polyclonal seeding, and late driver variants in ATM, KRAS, and other genes previously unreported in UM. These findings reveal previously unrecognized temporal and anatomic complexity in the genetic evolution of metastatic uveal melanoma, and they highlight the distinction between early and late phases of UM genetic evolution with implications for novel therapeutic approaches.

Uphyloplot2: visualizing phylogenetic trees from single-cell RNA-seq data.

BACKGROUND: Recent advances in single cell sequencing technologies allow for greater resolution in assessing tumor clonality using chromosome copy number variations (CNVs). While single cell DNA sequencing technologies are ideal to identify tumor sub-clones, they remain expensive and in contrast to single cell RNA-seq (scRNA-seq) methods are more limited in the data they generate. However, CNV data can be inferred from scRNA-seq and bulk RNA-seq, for which several tools have been developed, including inferCNV, CaSpER, and HoneyBADGER. Inferences regarding tumor clonality from CNV data (and other sources) are frequently visualized using phylogenetic plots, which previously required time-consuming and error-prone, manual analysis. RESULTS: Here, we present Uphyloplot2, a python script that generates phylogenetic plots directly from inferred RNA-seq data, or any Newick formatted dendrogram file. The tool is publicly available at https://github.com/harbourlab/UPhyloplot2/ . CONCLUSIONS: Uphyloplot2 is an easy-to-use tool to generate phylogenetic plots to depict tumor clonality from scRNA-seq data and other sources.

Life expectancy and mortality in 363 cities of Latin America.

The concept of a so-called urban advantage in health ignores the possibility of heterogeneity in health outcomes across cities. Using a harmonized dataset from the SALURBAL project, we describe variability and predictors of life expectancy and proportionate mortality in 363 cities across nine Latin American countries. Life expectancy differed substantially across cities within the same country. Cause-specific mortality also varied across cities, with some causes of death (unintentional and violent injuries and deaths) showing large variation within countries, whereas other causes of death (communicable, maternal, neonatal and nutritional, cancer, cardiovascular disease and other noncommunicable diseases) varied substantially between countries. In multivariable mixed models, higher levels of education, water access and sanitation and less overcrowding were associated with longer life expectancy, a relatively lower proportion of communicable, maternal, neonatal and nutritional deaths and a higher proportion of deaths from cancer, cardiovascular disease and other noncommunicable diseases. These results highlight considerable heterogeneity in life expectancy and causes of death across cities of Latin America, revealing modifiable factors that could be amenable to urban policies aimed toward improving urban health in Latin America and more generally in other urban environments.

Dual Screen for Efficacy and Toxicity Identifies HDAC Inhibitor with Distinctive Activity Spectrum for BAP1-Mutant Uveal Melanoma.

Drug screens leading to successful targeted therapies in cancer have been mainly based on cell viability assays identifying inhibitors of dominantly acting oncogenes. In contrast, there has been little success in discovering targeted therapies that reverse the effects of inactivating mutations in tumor-suppressor genes. BAP1 is one such tumor suppressor that is frequently inactivated in a variety of cancers, including uveal melanoma, renal cell carcinoma, and mesothelioma. Because BAP1 is an epigenetic transcriptional regulator of developmental genes, we designed a two-phase drug screen involving a cell-based rescue screen of transcriptional repression caused by BAP1 loss, followed by an in vivo screen of lead compounds for rescue of a BAP1-deficient phenotype with minimal toxicity in Xenopus embryos. The first screen identified 9 compounds, 8 of which were HDAC inhibitors. The second screen eliminated all except one compound due to inefficacy or toxicity. The resulting lead compound, quisinostat, has a distinctive activity spectrum, including high potency against HDAC4, which was recently shown to be a key target of BAP1. Quisinostat was further validated in a mouse model and found to prevent the growth of BAP1-mutant uveal melanomas. This innovative strategy demonstrates the potential for identifying therapeutic compounds that target tumor-suppressor mutations in cancer. IMPLICATIONS: Few drugs have been identified that target mutations in tumor suppressors. Using a novel 2-step screening approach, strategy, we identified quisinostat as a candidate for therapy in BAP1-mutant uveal melanoma. HDAC4 is implicated as a key target in uveal melanoma and perhaps other BAP1-mutant cancers.

Impact of Genetic Ancestry on Prognostic Biomarkers in Uveal Melanoma.

Uveal melanoma (UM) is the most common cancer of the eye and leads to metastatic death in up to half of patients. Genomic prognostic biomarkers play an important role in clinical management in UM. However, research has been conducted almost exclusively in patients of European descent, such that the association between genetic admixture and prognostic biomarkers is unknown. In this study, we compiled 1381 control genomes from West African, European, East Asian, and Native American individuals, assembled a bioinformatic pipeline for assessing global and local ancestry, and performed an initial pilot study of 141 UM patients from our international referral center that manages many admixed individuals. Global and local estimates were associated with genomic prognostic determinants. Expression quantitative trait loci (eQTL) analysis was performed on variants found in segments. Globally, after correction for multiple testing, no prognostic variable was significantly enriched in a given ancestral group. However, there was a trend suggesting an increased proportion of European ancestry associated with expression of the PRAME oncogene (q = 0.06). Locally enriched European haplotypes were associated with the poor prognosis class 2 gene expression profile and with genes involved in immune regulation (q = 4.7 × 10-11). These findings reveal potential influences of genetic ancestry on prognostic variables, implicate immune genes in prognostic differences based on ancestry, and provide a basis for future studies of admixed patients with UM using rigorous genetic ancestry methodology.

Single-cell analysis reveals new evolutionary complexity in uveal melanoma.

Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. Here, we interrogate the tumor microenvironment at single-cell resolution using scRNA-seq of 59,915 tumor and non-neoplastic cells from 8 primary and 3 metastatic samples. Tumor cells reveal novel subclonal genomic complexity and transcriptional states. Tumor-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including CD8+ T cells predominantly expressing the checkpoint marker LAG3, rather than PD1 or CTLA4. V(D)J analysis shows clonally expanded T cells, indicating that they are capable of mounting an immune response. An indolent liver metastasis from a class 1B UM is infiltrated with clonally expanded plasma cells, indicative of antibody-mediated immunity. This complex ecosystem of tumor and immune cells provides new insights into UM biology, and LAG3 is identified as a potential candidate for immune checkpoint blockade in patients with high risk UM.

BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers.

The BAP1 tumor suppressor is mutated in many human cancers such as uveal melanoma, leading to poor patient outcome. It remains unclear how BAP1 functions in normal biology or how its loss promotes cancer progression. Here, we show that Bap1 is critical for commitment to ectoderm, mesoderm, and neural crest lineages during Xenopus laevis development. Bap1 loss causes transcriptional silencing and failure of H3K27ac to accumulate at promoters of key genes regulating pluripotency-to-commitment transition, similar to findings in uveal melanoma. The Bap1-deficient phenotype can be rescued with human BAP1, by pharmacologic inhibition of histone deacetylase (HDAC) activity or by specific knockdown of Hdac4. Similarly, BAP1-deficient uveal melanoma cells are preferentially vulnerable to HDAC4 depletion. These findings show that Bap1 regulates lineage commitment through H3K27ac-mediated transcriptional activation, at least in part, by modulation of Hdac4, and they provide insights into how BAP1 loss promotes cancer progression.

The Association between Neighborhood Environments and Physical Activity from Pregnancy to Postpartum: a Prospective Cohort Study.

The objectives of this study were to determine if neighborhood measures were associated with physical activity cross-sectionally during late pregnancy (27-30 weeks' gestation), 3 months postpartum, and 12 months postpartum, and longitudinally with an increase in physical activity from late pregnancy to 12 months postpartum. Data are from the Pregnancy, Infection, and Nutrition (PIN3) and Postpartum Prospective Cohort Study. Dichotomized self-reported recreation and total physical activity hours/week were explored cross-sectionally at three time points, and as an increase over time. Four factors from a neighborhood environmental audit were examined: arterial or thoroughfare, walkable neighborhood, physical incivilities, and decoration. Secondary spatial data included population density, hilliness, intersection density, distance to nearest major road, distance to nearest park, distance to nearest physical activity facility, and distance to nearest bus stop. Multilevel mixed-effects logistic regression models were used to assess the association between environmental variables and physical activity measures. A number of environmental variables were associated with total and recreation physical activity at the three time points in cross-sectional models. For increase in recreation physical activity over time, a moderate distance to nearest major road was significantly associated with increased recreation physical activity from 3 to 12 months postpartum (tertile 2 OR 2.13, 95% CI 1.08, 4.22). Living the furthest distance from the nearest park was inversely associated with an increase in recreation physical activity from pregnancy to 3 months postpartum (tertile 3 OR 0.50, 95% CI 0.29, 0.85). The findings of this study indicate that several aspects of the neighborhood environment, such as walkability, access to transit, distance to recreation facilities, and road networks, are associated with physical activity during different stages of pregnancy and postpartum. Since physical activity may result in long-term health benefits for both the woman and child, environments that support this activity should be encouraged.

Intrauterine exposure to bisphenol A promotes different effects in both neonatal and adult prostate of male and female gerbils (Meriones unguiculatus).

Substances that mimic endogenous hormones may alter the cell signaling that govern prostate development and predispose it to developing lesions in adult and senile life. Bisphenol A is able to mimic estrogens, and studies have demonstrated that low levels of exposure to this compound have caused alterations during prostate development. The aim of this study was to describe the prostate development in both male and female neonatal gerbils in normal conditions and under exposure to BPA during intrauterine life, and also to analyze whether the effects of intrauterine exposure to BPA remain in adulthood. Morphological, stereological, three-dimensional reconstruction, and immunohistochemical methods were employed. The results demonstrated that in 1-day-old normal gerbils, the female paraurethral glands and the male ventral lobe are morphologically similar, although its tissue components-epithelial buds (EB), periurethral mesenchyme (PeM), paraurethral mesenchyme (PaM) or ventral mesenchymal pad (VMP), and smooth muscle (SM)-have presented different immunolabeling pattern for androgen receptor (AR), and for proliferating cell nuclear antigen (PCNA). Moreover, we observed a differential response of male and female prostate to intrauterine BPA exposure. In 1-day-old males, the intrauterine exposure to BPA caused a decrease of AR-positive cells in the PeM and SM, and a decrease of the proliferative status in the EB. In contrast, no morphological alterations were observed in ventral prostate of adult males. In 1-day-old females, BPA exposure promoted an increase of estrogen receptor alpha (ERα) positive cells in PeM and PaM, a decrease of AR-positive cells in EB and PeM, besides a reduction of cell proliferation in EB. Additionally, the adult female prostate of BPA-exposed animals presented an increase of AR- and PCNA-positive cells. These results suggest that the prostate of female gerbils were more susceptible to the intrauterine BPA effects, since they became more proliferative in adult life. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1740-1750, 2016.

Prepubertal exposure to bisphenol-A induces ERα upregulation and hyperplasia in adult gerbil female prostate.

Prostate physiology is highly dependent on oestrogenic and androgenic homeostasis. Interferences in this equilibrium, especially in early periods of life, may disrupt the prostate and increase the susceptibility to the development of diseases with ageing. Taking this into account, and considering the increase of environmental chemicals with endocrine-disrupting potential such as bisphenol-A (BPA), this study aimed to evaluate the prostates of adult female gerbils exposed to BPA and BPA plus testosterone from pubertal to adult periods. Morphological, stereological and chemical analyses revealed that long-term BPA exposure, even in environmental dosages, increases the proliferative status of the prostate, increases the number of ERα-positive stromal cells and elicits the development of prostatic hyperplasia in adult female gerbils. Moreover, we also observed that the association with testosterone did not increase the proliferative status of the gland, which shows that low levels of BPA are enough to cause an oestrogenic disruption of the prostate in young adults. This evidence suggests that this oestrogenic endocrine disruptor may increase the susceptibility to prostatic disorders with ageing.