Circulating sex steroids during pregnancy and maternal risk of non-epithelial ovarian cancer.

BACKGROUND: Sex steroid hormones have been proposed to play a role in the development of non-epithelial ovarian cancers (NEOC) but so far no direct epidemiological data are available.METHODS: A case-control study was nested within the Finnish Maternity Cohort, the world's largest bio-repository of serum specimens from pregnant women. Study subjects were selected among women who donated a blood sample during a singleton pregnancy that led to the birth of their last child preceding diagnosis of NEOC. Case subjects were 41 women with sex-cord stromal tumors (SCST) and 21 with germ cell tumors (GCT). Three controls, matching the index case for age, parity at the index pregnancy, and date at blood donation were selected (n=171). Odds ratios (OR) and 95% confidence intervals (CI) associated with concentrations of testosterone, androstenedione, 17-OH-progesterone, progesterone, estradiol and sex hormone binding globulin (SHBG) were estimated through conditional logistic regression.RESULTS: For SCST, doubling of testosterone, androstenedione and 17-OH-progesterone concentrations were associated with about 2-fold higher risk of SCST [ORs and 95% CI of 2.16 (1.25-3.74), 2.16 (1.20-3.87), and 2.62 (1.27-5.38), respectively]. These associations remained largely unchanged after excluding women within 2, 4 or 6 years lag-time between blood donation and cancer diagnosis. Sex steroid hormones concentrations were not related to maternal risk of GCT.CONCLUSIONS: This is the first prospective study providing initial evidence that elevated androgens play a role in the pathogenesis of SCST. Impact: Our study may note a particular need for larger confirmatory investigations on sex steroids and NEOC.

Comparison of naphthalene bioavailability determined by whole-cell biosensing and availability determined by extraction with Tenax

A rapid biological method for the determination of the bioavailability of naphthalene was developed and its value as an alternative to extraction-based chemical approaches demonstrated. Genetically engineered whole-cell biosensors are used to determine bioavailable naphthalene and their responses compared with results from Tenax extraction and chemical analysis. Results show a 1:1 correlation between biosensor results and chemical analyses for naphthalene-contaminated model materials and sediments, but the biosensor assay is much faster. This work demonstrates that biosensor technology can perform as well as standard chemical methods, though with some advantages including the inherent biological relevance of the response, rapid response time, and potential for field deployment. A survey of results from this work and the literature shows that bioavailability under non-equilibrium conditions nonetheless correlates well with K(oc) or K(d). A rationale is provided wherein chemical resistance is speculated to be operative.

Gériatrie [Geriatry]

This review discuss several studies published in 2007 that will modify current therapeutic attitudes. New evidence confirm that antipsychotics increase mortality in demented elderly persons with behavioral symptoms. Unfortunately, donepezil was no more effective than placebo to treat agitation in these patients. Aspirine, nonsteroidal anti-inflammatories, as well as supplementation with folate, vitamines B6 and B12 did not prove beneficial to prevent cognitive decline. Hormonal substitution with DHEA, testosterone, and growth hormone is ineffective as anti-aging medicine, while calcium and vitamin d'effectiveness was confirmed in fracture prevention. Finally, several studies report prognostic information that will prove important to improve preparation plan for future heat wave.

Premenopausal serum androgens and breast cancer risk: a nested case-control study.

ABSTRACT: INTRODUCTION: Prospective epidemiologic studies have consistently shown that levels of circulating androgens in postmenopausal women are positively associated with breast cancer risk. However, data in premenopausal women are limited. METHODS: A case-control study nested within the New York University Women's Health Study was conducted. A total of 356 cases (276 invasive and 80 in situ) and 683 individually-matched controls were included. Matching variables included age and date, phase, and day of menstrual cycle at blood donation. Testosterone, androstenedione, dehydroandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) were measured using direct immunoassays. Free testosterone was calculated. RESULTS: Premenopausal serum testosterone and free testosterone concentrations were positively associated with breast cancer risk. In models adjusted for known risk factors of breast cancer, the odds ratios for increasing quintiles of testosterone were 1.0 (reference), 1.5 (95% confidence interval (CI), 0.9 to 2.3), 1.2 (95% CI, 0.7 to 1.9), 1.4 (95% CI, 0.9 to 2.3) and 1.8 (95% CI, 1.1 to 2.9; Ptrend = 0.04), and for free testosterone were 1.0 (reference), 1.2 (95% CI, 0.7 to 1.8), 1.5 (95% CI, 0.9 to 2.3), 1.5 (95% CI, 0.9 to 2.3), and 1.8 (95% CI, 1.1 to 2.8, Ptrend = 0.01). A marginally significant positive association was observed with androstenedione (P = 0.07), but no association with DHEAS or SHBG. Results were consistent in analyses stratified by tumor type (invasive, in situ), estrogen receptor status, age at blood donation, and menopausal status at diagnosis. Intra-class correlation coefficients for samples collected from 0.8 to 5.3 years apart (median 2 years) in 138 cases and 268 controls were greater than 0.7 for all biomarkers except for androstenedione (0.57 in controls). CONCLUSIONS: Premenopausal concentrations of testosterone and free testosterone are associated with breast cancer risk. Testosterone and free testosterone measurements are also highly reliable (that is, a single measurement is reflective of a woman's average level over time). Results from other prospective studies are consistent with our results. The impact of including testosterone or free testosterone in breast cancer risk prediction models for women between the ages of 40 and 50 years should be assessed. Improving risk prediction models for this age group could help decision making regarding both screening and chemoprevention of breast cancer.

Comment on reversal of hypogonadotropic hypogonadism in a Chinese cohort.

The reversal of congenital hypogonadotropic hypogonadism (CHH) is a relatively recent phenomenon that has gained increasing attention over the past 10 years. Yet to date, only one prospective study has been conducted estimating that 10% (95% confidence interval [CI]: 2%-18%) of cases undergo reversal. [1] Other retrospective studies have reported rates in the range of 5%-8% [2],[3] and a recent study showed 44/308 (14%, 95% CI: 11%-19%) CHH patients underwent reversal. [4] Moreover, a time-to-event analysis in this large cohort revealed a lifetime reversal incidence of 22%. The article by Mao and colleagues presented in this issue is a meaningful contribution to our understanding of reversal as it examines the largest retrospective cohort to date. [5] Interestingly, they report the rate of reversal as 5% (95% CI: 3%-8%) in this Chinese cohort. It is difficult to reconcile the discrepancies in rates of reversibility and direct comparisons are hampered by the variable definitions employed. Using a novel definition for reversal (i.e, either endogenous testosterone (T) >270 ng dl−1 , serum T gradually increasing above 150 ng dl−1 with increased testicular volume, or normal spontaneous sperm production/normal erectile function/ejaculation), Mao and colleagues posit that testicular size and triptorelin-stimulated LH levels are reliable predictive factors for reversal. However, these cannot be considered as hard and fast rules for predicting reversal as the groups intersect - akin to the overlap observed between CHH patients and those with delayed puberty. Indeed, the fact that approximately half (44%, 95% CI: 25%-66%) of the reversal patients in the study by Mao et al.[5] were diagnosed between 17 and 19 years of age, underscores the challenge in differentiating CHH from extreme normal variants of puberty. This study further lends credence the recently reported observations that reversals may relapse. [4],[6] The notion that reversal may not be lasting highlights the vulnerability of the reproductive axis among CHH patients. While the mechanism(s) for relapse are unclear, it seems plausible that environmental, metabolic or psychiatric stressors could contribute. The factors that Mao and colleagues identify as significantly different in cases of reversal, were not informative for identifying those cases that relapsed back to a hypogonadal state. Notably, reversal has been reported in probands harboring mutations in genes underlying CHH. [1],[3],[4],[6] Unfortunately, comprehensive genetic screening on the Chinese cohort is not available. The reversal phenomenon is fascinating for its glimpse into the plasticity of the neuroendocrine control of reproduction. Future directions will almost certainly include investigation of specific genetic signatures and novel biomarkers for predicting reversal (and relapse). Yet CHH is a rare condition and to fully elucidate the biology of reversible CHH, it will be important to harmonize definitions of what constitutes a reversal, carefully phenotype patients and chart the natural history of their CHH. In this way, this unique human disease model may offer further insights into the control of human reproduction and provide opportunities to translate discoveries into enhanced approaches to improve the care and quality of life for these patients.

Effect of sex and prior exposure to a cafeteria diet on the distribution of sex hormones between plasma and blood cells

It is generally assumed that steroid hormones are carried in the blood free and/or bound to plasma proteins. We investigated whether blood cells were also able to bind/carry sex-related hormones: estrone, estradiol, DHEA and testosterone. Wistar male and female rats were fed a cafeteria diet for 30 days, which induced overweight. The rats were fed the standard rat diet for 15 additional days to minimize the immediate effects of excess ingested energy. Controls were always kept on standard diet. After the rats were killed, their blood was used for 1) measuring plasma hormone levels, 2) determining the binding of labeled hormones to washed red blood cells (RBC), 3) incubating whole blood with labeled hormones and determining the distribution of label between plasma and packed cells, discounting the trapped plasma volume, 4) determining free plasma hormone using labeled hormones, both through membrane ultrafiltration and dextrancharcoal removal. The results were computed individually for each rat. Cells retained up to 32% estrone, and down to 10% of testosterone, with marked differences due to sex and diet (the latter only for estrogens, not for DHEA and testosterone). Sex and diet also affected the concentrations of all hormones, with no significant diet effects for estradiol and DHEA, but with considerable interaction between both factors. Binding to RBC was non-specific for all hormones. Estrogen distribution in plasma compartments was affected by sex and diet. In conclusion: a) there is a large non-specific RBC-carried compartment for estrone, estradiol, DHEA and testosterone deeply affected by sex; b) Prior exposure to a cafeteria (hyperlipidic) diet induced hormone distribution changes, affected by sex, which hint at sex-related structural differences in RBC membranes; c) We postulate that the RBC compartment may contribute to maintain free (i.e., fully active) sex hormone levels in a way similar to plasma proteins non-specific binding.

Contribution of estrogen and GluN2B subunit to the HtraKO mouse phenotype

Htr1a is one of the most widespread serotonin receptor across the brain, strongly expressed in CAI region of hippocampus. Our laboratory studies the phenotypic alteration in 5HTla- deficient mice (Htr1aK0), characterized an abnormal anxious-like behavior. Our aim is to evaluate the regulation of this cognitive process by understanding the circuitry involved. This phenotype sets up early during development and has durable effect in adulthood. Our laboratory showed that adult Htr1aK0 male mice displaying exuberant dendritic growth of oblique dendrites in a specific layer of a CAI pyramidal neurons, the stratum radiatum. Application of drugs in organotypic cultures and by in vivo injections revealed that GluN2B, a subunit of NMDA receptor highly expressed during development, is responsible for this dendritic exuberance. Immunohistochemistry highlighted in particular a synaptic enrichment of GluN2B in stratum radiatum of Htr1aK0 CAI pyramidal neurons at puberty. Finally, original analysis of Htr1aK0 mouse behavior showed a different response to anxiety between male and female. Htr1a activation down-regulates the CaMKII activity in the CAI pyramidal neurons. CaMKII directly favors the membrane conductance and stability of GluN2B at the synapse. In the context of the Htr1aK0 mouse, GluN2B is the final common pathway of our phenotype. This subunit is well known to regulate the threshold of LTD/LTP and the dendritogenesis during development. In my thesis, I establish a link between the gender differences in the morphology and the physiology in the Htr1aK0 mice during development to understand how these characteristics shape the circuit with prominent cognitive impacts in adulthood. My study highlighted that during development, Htr1aK0 male mice show a constant increase of the dendritic growth of oblique dendrites from early ages until adulthood associated with an increased physiological impact of altered GluN2A/GluN2B ratio. Whereas during puberty, synaptic contribution of GluN2B to NMDA response is higher in Htr1aK0 compared to WT male mice, this ratio comes back to normal values towards adulthood. However, this recovery of the ratio of GluN2A/GluN2B located at the synaptic level is concomitant with the lateral diffusion of excess GluN2B subunits, leading to extrasynaptic enrichment. The main impact was a lowering of the LTP threshold characterized by strong increased potentiation of synaptic strength after 5 Hz low frequency stimulation. Moreover, the extrasynaptic GluN2B overexpression leads to a shift of the maturation phase switch explaining the exuberant morphology. However, Htr1aK0 females characterized during the 3 first weeks of development by an increase of the dendritic growth of oblique dendrites showed starting at puberty that the dendrite arborization returns progressively to WT values. The physiological impact of GluN2B was investigated and directly linked to this morphology, since Htr1aK0 female mice does not show alteration of the synaptic strength during development. These observations show a compensation occurring in Htr1aK0 female, responsible for a rescue of the phenotype morphologically, physiologically and to be tested behaviorally. We highlighted then the biological processes underlying this compensation. During development, sexual hormones such as testosterone and estrogen are responsible to induce sexual differentiation of specific brain regions. I demonstrated that estrogen, but not testosterone, was able to reduce both in vitro and in vivo the dendritic arborization early during development, through activation of GPER-1, a G-coupled protein estrogen receptor, which phenocopy the activation of Htr1a by reducing GluN2B conductance and stability. I then identified a pathway, parallel to Htr1a, able to regulate GluN2B and responsible for the morphological and physiological phenotype in Htr1aK0 female mice. The specific rise of estrogen occurring at puberty in female is responsible for the compensation observed and induces a late rescue of the Htr1aK0 phenotype by activation GPER-1. -- Htr1a est un des récepteurs à la sérotonine les plus répandus dans le cerveau, fortement exprimé dans la région CAI de l'hippocampe. Notre laboratoire étudie les altérations phénotypiques de souris déficientes pour ce récepteur (Htr1aK0), caractérisées par un comportement avec des traits anxieux. Notre objectif est d'évaluer la régulation de ces processus cognitifs en comprenant les connexions nerveuses impliquées. Ce phénotype se met en place tôt au cours du développement et présente un effet durable à l'âge adulte. Notre laboratoire a montré que les souris Htr1aK0 mâles adultes se caractérisent par une croissance exubérante des dendrites obliques dans une couche spécifique des neurones pyramidaux du CAI, le stratum radiatum. L'application de drogues sur cultures organotypiques et par injections in vivo ont révélé que GluN2B, une sous-unité du récepteur NMDA fortement exprimée au cours du développement, est responsable de cette exubérance dendritique. Des expériences d'immunohistochimie ont notamment mis en évidence un enrichissement synaptique de GluN2B durant la puberté dans le stratum radiatum des neurones de la région CAI des souris Htr1aK0. Finalement, l'analyse originale du comportement des souris Htr1aK0 a montré une différence de réponse à l'anxiété entre mâles et femelles. L'activation de Htr1a diminue l'activité de la CaMKII dans les neurones pyramidaux du CAI. La CaMKII favorise directement la conductance et la stabilité de la sous-unité GluN2B à la synapse. Dans le contexte de la souris Htr1aK0, GluN2B est le « médiateur » de notre phénotype. Cette sous-unité est particulièrement connue pour réguler le seuil de LTD-LTP ainsi que la dendritogénèse durant le développement. Dans ma thèse, j'ai établi le lien entre les différences dépendant du genre dans la morphologie et physiologie des souris Htr1aK0 au cours du développement pour comprendre comment ces caractéristiques modulent le circuit accompagnés d'impacts cognitifs visibles à l'âge adulte. Mon étude a mis en évidence que durant le développement, les souris mâles Htr1aK0 montrent une constante augmentation de la croissance des dendrites obliques entre les premières semaines et l'âge adulte associée à une augmentation de l'impact physiologique du ratio GluN2A/GluN2B altéré. Alors que durant la puberté, la contribution synaptique de GluN2B à la réponse NMDA est plus haute chez la souris mâle Htr1aK0 que le WT, ce ratio revient à des valeurs normales à l'âge adulte. Cependant, cette récupération de l'expression du récepteur au niveau synaptique est concomitante avec la diffusion des sous-unités GluN2B excédantes, amenant alors à un enrichissement extrasynaptique. Le principal impact est une diminution du seuil de la LTP caractérisée par une forte potentiation de la plasticité après une stimulation basse fréquence à 5 Hz. De plus, la surexpression des GluN2B extrasynaptiques conduit à un décalage de la bascule à la phase de maturation, expliquant la morphologie dendritique exubérante. Cependant, les femelles Htr1aK0 initialement caractérisées pendant les 3 premières semaines du développement par une augmentation de la croissance des dendrites obliques montrent à partir de la puberté que cette arborisation dendritique retourne à des valeurs WT. L'impact physiologique de GLuN2B a été investigué et mis en lien avec cette morphologie, étant donné que les femelles Htr1aK0 ne montrent pas d'altération de la plasticité durant le développement. Ces observations montrent une compensation se produisant chez la femelle Htr1aK0, responsable d'une récupération du phénotype morphologique, physiologique et peut-être comportemental. Nous avons souligné les processus biologiques sous-jacent à cette compensation. Au cours du développement, les hormones sexuelles telles que la testostérone et l'estrogène sont responsables de la différentiation sexuelle de régions du cerveau spécifiques. J'ai démontré que l'estrogène, mais pas la testostérone, était capable de réduire in vitro et in vivo l'arborisation dendritique tôt dans le développement au travers de l'activation du récepteur GPER-1, un récepteur aux estrogènes couplés à un protéine G, qui phénocopie l'activation de Htr1a en réduisant la conductance et la stabilité de GluN2B à la membrane. J'ai identifié une voie de signalisation parallèle à celle de Htr1a, capable de réguler GluN2B et responsable du phénotype morphologique et physiologique de la souris femelle Htr1aK0. La montée spécifique d'estrogène se déroulant à la puberté chez la femelle est responsable de cette compensation et implique une récupération tardive du phénotype Htr1aK0 par l'activation de GPER-1.

Ejaculate Characteristics Depend on Social Environment in the Horse (Equus caballus).

Sperm competition theory predicts semen characteristics to be affected by the social environment. We used the polygamous horse (Equus caballus) to experimentally study within-subject plasticity in response to different social environments. Stallions were sequentially exposed, over a period of 8 weeks each, to other stallions and then singly to mares, or vice versa (in adjacent boxes separated by grills). Ejaculates were collected to determine semen characteristics. Highest sperm numbers were found in stallions that were first exposed to other stallions and then to mares, while lowest sperm numbers were observed in stallions that had been exposed to mares but not yet to other stallions. One of three sperm velocity measures (curvilinear velocity) was consistently elevated in stallions that were first exposed to stallions and then to mares. Sperm number after exposure to mares and curvilinear sperm velocity after exposure to stallions were both positively correlated to average blood testosterone levels during the corresponding period of exposure. We conclude that ejaculate characteristics are plastic traits affected by the social environment in horses.

An Experimental Model of Prostatic Inflammation for Drug Discovery

There is increasing evidence to support a significant role for chronic non-bacterial, prostatic inflammation in the development of human voiding dysfunction and prostate cancer. Their increased prevalence with age suggests that the decrease of testosterone concentration and/or the ratio of testosterone-to-estradiol in serum may have a role in their development. The main objective of this study was to explore prostatic inflammation and its relationship with voiding dysfunction and prostate carcinogenesis by developing an experimental model. A novel selective estrogen receptor modulator (SERM), fispemifene, was tested for the prevention and treatment of prostatic inflammation in this model. Combined treatment of adult Noble rats with testosterone and estradiol for 3 to 6 weeks induced gradually developing prostatic inflammation in the dorsolateral prostatic lobes. Inflammatory cells, mainly T-lymphocytes, were first seen around capillaries. Thereafter, the lymphocytes migrated into the stroma and into periglandular space. When the treatment time was extended to 13 weeks, the number of inflamed acini increased. Urodynamical recordings indicated voiding dysfunction. When the animals had an above normal testosterone and estradiol concentrations but still had a decreased testosterone-to-estradiol ratio in serum, they developed obstructive voiding. Furthermore, they developed precancerous lesions and prostate cancers in the ducts of the dorsolateral prostatic lobes. Interestingly, inflammatory infiltrates were observed adjacent to precancerous lesions but not in the adjacency of adenocarcinomas suggesting that inflammation has a role in the early stages of prostate carcinogenesis. Fispemifene, a novel SERM tested in this experimental model, showed anti-inflammatory action by attenuating the number of inflamed acini in the dorsolateral prostate. Fispemifene exhibited also antiestrogenic properties by decreasing expression of estrogen-induced biomarkers in the acinar epithelium. These findings suggest that SERMs could be considered as a new therapeutic possibility in the prevention and in the treatment of chronic prostatic inflammation

Regulating Mechanisms of Gonadal and Pituitary Tumorigenesis in Mice Producing Human Chorionic Gonadotropin

Human chorionic gonadotropin (hCG) and luteinizing hormone (LH) are structurally and functionally similar glycoprotein hormones acting through the same luteinizing hormone chorionic gonadotropin receptor (LHCGR). The functions of LH in reproduction and hCG in pregnancy are well known. Recently, the expression of LHCGR has been found in many nongonadal tissues and cancers, and this has raised the question of whether LH/hCG could affect the function or tumorigenesis of these nongonadal tissues. We have also previously generated an hCG expressing mouse model presenting nongonadal phenotypes. Using this model it is possible to improve our understanding of nongonadal action of highly elevated LH/hCG. In the current study, we analyzed the effect of moderately and highly elevated hCG levels on male reproductive development and function. The main finding was the appearance of fetal Leydig cell (FLC) adenomas in prepubertal males. However, the development and differentiation of FLCs were not significantly affected. We also show that the function of hCG is different in FLCs and in adult Leydig cells (ALC), because in the latter cells hCG was not able to induce tumorigenesis. In FLCs, LHCGR is not desensitized or downregulated upon ligand binding. In this study, we found that the testicular expression of two G protein-coupled receptor kinases responsible for receptor desensitization or downregulation is increased in adult testis. Results suggest that the lack of LHCGR desensitization or downregulation in FLCs protect testosterone (Te) synthesis, but also predispose FLCs for LH/hCG induced adenomas. However, all the hCG induced nongonadal changes observed in male mice were possible to explain by the elevated Te level found in these males. Our findings indicate that the direct nongonadal effects of elevated LH/hCG in males are not pathophysiologically significant. In female mice, we showed that an elevated hCG level was able to induce gonadal tumorigenesis. hCG also induced the formation of pituitary adenomas (PA), but the mechanism was indirect. Furthermore, we found two new potential risk factors and a novel hormonally induced mechanism for PAs. Increased progesterone (P) levels in the presence of physiological estradiol (E2) levels induced the formation of PAs in female mice. E2 and P induced the expression and nuclear localization of a known cell-cycle regulator, cyclin D1. A calorie restricted diet was also able to prevent the formation of PAs, suggesting that obesity is able to promote the formation of PAs. Hormone replacement therapy after gonadectomy and hormone antagonist therapy showed that the nongonadal phenotypes observed in hCG expressing female mice were due to ovarian hyperstimulation. A slight adrenal phenotype was evident even after gonadectomy in hCG expressing females, but E2 and P replacement was able to induce a similar phenotype in WT females without elevated LH/hCG action. In conclusion, we showed that the direct effects of elevated hCG/LH action are limited only to the gonads of both sexes. The nongonadal phenotypes observed in hCG expressing mice were due to the indirect, gonadal hormone mediated effects of elevated hCG. Therefore, the gonads are the only physiologically significant direct targets of LHCGR signalling.

Influência da mineralogia dos sedimentos das bacias hidrográficas dos rios Mogi-Guaçu e Pardo na composição química das águas de abastecimento público

This work studied bottom sediment from catchment area of 13 stations of water treatment of Mogi-Guaçu and Pardo river basins, through identification of mineralogical matrix and its correlation with potential bioavailable metal concentrations. The main clay minerals present were kaolinite and illite. The values of iron and manganese grades were derived from reddish-purple soil, which is rich of such elements. They had higher values on areas with weak vegetation cover compared with other areas linked with more vegetation density. Higher values of calcium at Campestrinho station (IG 69) were associated to occurrence by weathering of calcium feldspars markedly present on regional porphiritic acid rocks. The concentrations of phosphorous are characteristically high on areas near urbanized regions.

Avaliação do nível da vulnerabilidade do solo devido à presença de termelétrica a carvão (Figueira, PR- Brasil)

Rainwater samples were analyzed during a one-year period (June 1999 - June 2000) and presented concentration of pH = 4.9 (volume weight mean). The ions concentrations results showed a high sulfate concentration (35 µmol L-1), followed by the cations concentration of sodium, calcium and ammonium (35, 16 and 30 µmol L-1, respectively). Due to the great contribution of these cations in the sulfate neutralization action, the rainwater of this region had only a light acid characteristic. The soil characteristic was acid and the bioavailable concentration of the alkaline cations (Ca, Mg and K) presented high calcium concentrations (1001 ± 357 mg kg-1) compared with the other cations. The determination of soil sensitivity to acid rain was calculated by the ratio BC/Al3+ (BC = Ca2+ + Mg2+ + K+) and presented the average value of 5.1 ± 3.3. This preliminary evaluation of soil susceptibility by the ratio BC/Al3+ showed that the local soil and vegetation type (tropical Savannah) were sensitive to acid deposition. The long term of this impacting condition (acid rain, high sulfate deposition) could be harmful to the soil and vegetation quality.

Avaliação do teor de metais em sedimento do rio Betari no Parque Estadual Turístico do Alto Ribeira: PETAR, São Paulo, Brasil

The subsoil of the Vale do Ribeira was the focus of mining industries for the exploration of lead, mainly inside the park - PETAR. Despite the fact that the exploration has ended, the environmental effects of those activities are still present, due to great amounts of heavy metals that are leached. Concentrations of pseudo-total and bioavailable metals were determined in sediment samples of the Betari River, using atomic absorption spectrometry. The results demonstrated that the sediments are contaminated by Pb, Zn and Cu. The findings can contribute to an efficient and environmentally and economically adequate management of the park, for the conservation and the protection of the area.

Role of human hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) in steroid-dependent diseases in females –novel indications for HSD17B1 inhibitors. Phenotypic analysis of transgenic mice overexpressing human HSD17B1.

Hormone-dependent diseases, e.g. cancers, rank high in mortality in the modern world, and thus, there is an urgent need for new drugs to treat these diseases. Although the diseases are clearly hormone-dependent, changes in circulating hormone concentrations do not explain all the pathological processes observed in the diseased tissues. A more inclusive explanation is provided by intracrinology – a regulation of hormone concentrations at the target tissue level. This is mediated by the expression of a pattern of steroid-activating and -inactivating enzymes in steroid target tissues, thus enabling a concentration gradient between the blood circulation and the tissue. Hydroxysteroid (17beta) dehydrogenases (HSD17Bs) form a family of enzymes that catalyze the conversion between low active 17-ketosteroids and highly active 17beta-hydroxysteroids. HSD17B1 converts low active estrogen (E1) to highly active estradiol (E2) with high catalytic efficiency, and altered HSD17B1 expression has been associated with several hormone-dependent diseases, including breast cancer, endometriosis, endometrial hyperplasia and cancer, and ovarian epithelial cancer. Because of its putative role in E2 biosynthesis in ovaries and peripheral target tissues, HSD17B1 is considered to be a promising drug target for estrogen-dependent diseases. A few studies have indicated that the enzyme also has androgenic activity, but they have been ignored. In the present study, transgenic mice overexpressing human HSD17B1 (HSD17B1TG mice) were used to study the effects of the enzyme in vivo. Firstly, the substrate specificity of human HSD17B1 was determined in vivo. The results indicated that human HSD17B1 has significant androgenic activity in female mice in vivo, which resulted in increased fetal testosterone concentration and female disorder of sexual development appearing as masculinized phenotype (increased anogenital distance, lack of nipples, lack of vaginal opening, combination of vagina with urethra, enlarged Wolffian duct remnants in the mesovarium and enlarged female prostate). Fetal androgen exposure has been linked to polycystic ovary syndrome (PCOS) and metabolic syndrome during adulthood in experimental animals and humans, but the genes involved in PCOS are largely unknown. A putative mechanism to accumulate androgens during fetal life by HSD17B1 overexpression was shown in the present study. Furthermore, as a result of prenatal androgen exposure locally in the ovaries, HSD17B1TG females developed ovarian benign serous cystadenomas in adulthood. These benign lesions are precursors of low-grade ovarian serous tumors. Ovarian cancer ranks fifth in mortality of all female cancers in Finland, and most of the ovarian cancers arise from the surface epithelium. The formation of the lesions was prevented by prenatal antiandrogen treatment and by transplanting wild type (WT) ovaries prepubertally into HSD17B1TG females. The results obtained in our non-clinical TG mouse model, together with a literature analysis, suggest that HSD17B1 has a role in ovarian epithelial carcinogenesis, and especially in the development of serous tumors. The role of androgens in ovarian carcinogenesis is considered controversial, but the present study provides further evidence for the androgen hypothesis. Moreover, it directly links HSD17B1-induced prenatal androgen exposure to ovarian epithelial carcinogenesis in mice. As expected, significant estrogenic activity was also detected for human HSD17B1. HSD17B1TG mice had enhanced peripheral conversion of E1 to E2 in a variety of target tissues, including the uterus. Furthermore, this activity was significantly decreased by treatments with specific HSD17B1 inhibitors. As a result, several estrogen-dependent disorders were found in HSD17B1TG females. Here we report that HSD17B1TG mice invariably developed endometrial hyperplasia and failed to ovulate in adulthood. As in humans, endometrial hyperplasia in HSD17B1TG females was reversible upon ovulation induction, triggering a rise in circulating progesterone levels, and in response to exogenous progestins. Remarkably, treatment with a HSD17B1 inhibitor failed to restore ovulation, yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment. We also demonstrate that HSD17B1 is expressed in normal human endometrium, hyperplasia, and cancer. Collectively, our non-clinical data and literature analysis suggest that HSD17B1 inhibition could be one of several possible approaches to decrease endometrial estrogen production in endometrial hyperplasia and cancer. HSD17B1 expression has been found in bones of humans and rats. The non-clinical data in the present study suggest that human HSD17B1 is likely to have an important role in the regulation of bone formation, strength and length during reproductive years in female mice. Bone density in HSD17B1TG females was highly increased in femurs, but in lesser amounts also in tibias. Especially the tibia growth plate, but not other regions of bone, was susceptible to respond to HSD17B1 inhibition by increasing bone length, whereas the inhibitors did not affect bone density. Therefore, HSD17B1 inhibitors could be safer than aromatase inhibitors in regard to bone in the treatment of breast cancer and endometriosis. Furthermore, diseases related to improper growth, are a promising new indication for HSD17B1 inhibitors.

Determinação de fósforo biodisponível em rações de peixes utilizando extração assistida por ultra-som e espectrofotometria no visível

The aim of the present work was to develop and optimize a method for determination of bioavailable phosphorus in samples of feces and fish feed using ultrasound extraction and subsequent quantification by visible spectrophotometry. Using as extractor solution HNO3 0.50 mol L-1, the great conditions of extraction established were: sample mass - 100 mg, samples granulometry - < 60 µm, sonification time - five cycles of 40 s and ultrasound potency - 136 W. The proposed method was applied in studies of digestibility of this nutrient in different feeds used in diets of juvenile of Nile tilapia.