Biomedical subjects

R Santti

Publications and source records attributed to R Santti.

At least 19 recordsLinked to original sources

PubMed2001

Possible action of the proximal rhabdosphincter muscle in micturition of the adult male rat.

Micturition requires high bladder pressure and simultaneous opening of the urethra. In adult male rat, a rhabdosphincter (RB) is known to be electrically active when the bladder pressure is high. This indicates a closure rather than an opening of the urethra, which is inconsistent with the requirements of optimal urodynamics. In order to solve this problem, we simultaneously recorded electromyogram (EMG) of the proximal RB, bladder pressure, and flow rate. Micturition was evoked by an increased volume of saline in the bladder. A computer-based recording device was used with minimal filtering. The EMG was recorded with a monopolar flexible suction electrode. The suction electrode records action potentials resembling those obtained with a microelectrode technique. During the early high-frequency intraluminal pressure oscillation period (IPHFO), the increase of pressure initially associated with a decrease of potential of the RB. When the first flow peak appeared, the relationship of the bladder pressure and RB single EMG activities changed. The increasing pressure coincided with the positive potential wave (depolarisation). It was interrupted by a transient negative polarity period called transient repolarisation (TRP) coinciding with a flow rate peak, thus indicating an opening of the RB lumen. After the TRP, the depolarisation continued. Additional experiments employing different methods are needed for positive identification of the TRP mechanism.

Animals↗

PubMed2001

No evidence for the in vivo activity of aromatase-inhibiting flavonoids.

Measurements of the aromatase-inhibiting and antioxidative capacities of flavonoids in vitro showed that slight changes in flavonoid structure may result in marked changes in biological activity. Several flavonoids such as 7-hydroxyflavone and chrysin (5,7-dihydroxyflavone) were shown to inhibit the formation of 3H-17beta-estradiol from 3H-androstenedione (IC(50)<1.0 microM) in human choriocarcinoma JEG-3 cells and in human embryonic kidney cells HEK 293 transfected with human aromatase gene (Arom+HEK 293). Flavone and quercetin (3,3',4',5,7-pentahydroxyflavone) showed no inhibition (IC(50)>100 microM). None of the requirements for optimal antioxidative capacity (2,3-double bond with 4'-hydroxy group, 3-hydroxyl group, 5,7-dihydroxy structure and the orthodihydroxy structure in the B-ring) is relevant for the maximum inhibition of aromatase by flavonoids. After oral administration to immature rats at a dose of 50 mg/kg body weight, which considerably exceeds amounts found in daily human diets, neither aromatase-inhibiting nonestrogenic flavonoids, such as chrysin, nor estrogenic flavonoids, such as naringenin and apigenin, induced uterine growth or reduced estrogen- or androgen-induced uterine growth. The inability of flavonoids to inhibit aromatase and, consequently, uterine growth in short-term tests may be due to their relatively poor absorption and/or bioavailability.

Androstenedione↗

PubMed2001

Uptake and metabolism of hydroxymatairesinol in relation to its anticarcinogenicity in DMBA-induced rat mammary carcinoma model.

The chemopreventive effects of hydroxymatairesinol (HMR), a lignan extracted from Norway spruce (Picea abies), on the development of mammary carcinoma induced by 7,12-dimethylbenz[a]anthracene (DMBA) was studied in rats. HMR administered via diet in an average daily dose of 4.7 mg/kg body wt starting before DMBA induction reduced tumor volume and tumor growth, but no significant reduction in tumor multiplicity (number of tumors/rat) was observed. The predominant histological type in the control group was type B (well-differentiated adenocarcinoma, 78%). The proportion of type B tumors decreased to 35% in the HMR group, while the type A (poorly differentiated) and type C (atrophic) tumor proportions increased. Anticarcinogenic effects of dietary HMR (4.7 mg/kg) were also evident when the administration started after DMBA induction and was seen as growth inhibition of established tumors. Dietary HMR supplementation significantly increased serum and urinary enterolactone and HMR concentrations but had no significant effect on the uterine weight, suggesting that HMR or its major metabolite enterolactone did not have an antiestrogenic effect. Further studies are warranted to further clarify and verify HMR action and the associated mechanisms in mammary tumorigenesis.

4-Butyrolactone↗

PubMed2001

Altered structure and function of reproductive organs in transgenic male mice overexpressing human aromatase.

Aromatization of androgens is a key step in estrogen production, and it regulates the delicate balance between estrogens and androgens in the gonads and sex steroid target tissues. In the present study, we generated transgenic mice (AROM(+)) bearing the human ubiquitin C promoter/human P450 aromatase fusion gene. AROM(+) male mice are characterized by an imbalance in sex hormone metabolism, resulting in elevated serum E(2) concentrations, combined with significantly reduced testosterone and FSH levels, and elevated levels of PRL and corticosterone. AROM(+) males present a multitude of severe structural and functional alterations in the reproductive organs, such as cryptorchidism associated with Leydig cell hyperplasia, dysmorphic seminiferous tubules, and disrupted spermatogenesis. The males also have small or rudimentary accessory sex glands with abnormal morphology; a prominent prostatic utricle with squamous epithelial metaplasia, and edema in the ejaculatory ducts and vas deferens. In addition, the abdominal muscle wall is thin, and the adrenal glands are enlarged, with cortical hyperplasia. Some of the abnormalities, such as undescended testes and undeveloped prostate, resemble those observed in animals exposed perinatally to high levels of exogenous estrogen, indicating that the elevated aromatase activity results in excessive estrogen exposure during early phases of development. Some of the disorders in the reproductive organs, furthermore, can be explained by the fact that AROM(+) males are hypoandrogenic, and have elevated levels of serum PRL and corticosterone. Thus, the AROM(+) mouse model provides a novel tool to investigate the consequences of a prolonged increase in conversion of androgens to estrogens which results in complex hormonal disturbances altering the structure and function of various male reproductive organs.

Abdominal Muscles↗

PubMed2001

Nontraumatic urethral dyssynergia in neonatally estrogenized male rats.

PURPOSE: Bladder outlet obstruction develops in estrogen treated males. Because of the lack of electromyography recordings, earlier studies have not clarified the failure mechanisms of voiding. We simultaneously recorded electromyography activity of the proximal rhabdosphincter in neonatally estrogenized rats with transvesical cystometry and urethral flow, followed by morphometric analysis of the urethral structure. MATERIALS AND METHODS: Rats treated neonatally with 10 microg. diethylstilbestrol daily on days 1 to 5 after birth were used in urodynamics and morphological studies at ages 5 to 6.5 months. Using anesthesia the bladder, anterior surface of the proximal rhabdosphincter and distal urethra were exposed to record simultaneously the high frequency oscillations of intraluminal bladder pressure, and the rates of intermittent flow from the distal urethra and electromyography activity of the proximal rhabdosphincter with a suction electrode. RESULTS: Neonatally estrogenized rats had higher mean maximal bladder pressure plus or minus standard deviation (42.1 +/- 6.4 versus 37.7 +/- 4.9 mm. Hg, p = 0.01), decreased mean flow (2.3 +/- 0.1 versus 4.1 +/- 1.6 ml. per minute, p < 0.0001) and mean increment of proximal rhabdosphincter electromyography depolarization amplitude (3.0 +/- 0.78 versus 2.6 +/- 0.87 mV., p = 0.02) compared with controls, while mean transient repolarization was absent or highly decreased (-0.3 +/- 0.61 versus 0.3 +/- 0.9 mV., p = 0.04). Morphologically the proximal rhabdosphincter was atrophied with increased connective tissue. CONCLUSIONS: Alterations in the structure and electromyography activity of the urethral musculature imply that neonatal exposure to diethylstilbestrol predisposes male rats to urethral atrophy and dyssynergia, evident as altered electromyography activity of the proximal rhabdosphincter.

Animals↗

PubMed2001

Co-localization of androgen receptor with estrogen receptor beta in the lower urinary tract of the male rat.

PURPOSE: Androgens and estrogens influence voiding. In this study their target sites in the lower urinary tract of the male rat were identified. MATERIALS AND METHODS: Cryosections of the bladder body, bladder neck, prostatic urethra, mid proximal urethra and prostatic autonomic ganglia of adult male rats were immunostained with specific estrogen receptor alpha, estrogen receptor beta (ERbeta) or androgen receptor (AR) antibodies. The sections were then examined under conventional, fluorescence or confocal fluorescence microscopy. RESULTS: Co-expression of AR and ERbeta in the urothelium, bladder smooth muscle cells, proximal urethra striated muscle cells and neurons in the autonomic ganglia of the prostatic plexus suggests that estrogen and androgen have direct effects in the lower urinary tract. CONCLUSIONS: The local interaction of AR and ERbeta in the hormonal control of voiding is an intriguing possibility.

Animals↗

PubMed2000

Differential expression of estrogen receptors alpha and beta in adult rat accessory sex glands and lower urinary tract.

Estrogens induce pronounced structural and functional changes in male accessory sex glands and the lower urinary tract in both sexes, but the exact mechanisms of estrogen action are not fully understood. This study was undertaken to localise the tissue cell types that express estrogen receptor in adult rats, and to determine the receptor subtype (ERalpha and ERbeta) in order to identify sites that may respond directly to estrogens. In the male accessory sex glands (seminal vesicles, prostatic lobes and ampullary glands), ERbeta mRNA and protein were strongly expressed in the epithelium but not in the stroma, while ERalpha mRNA was present only in the fibromuscular tissue surrounding the prostatic collecting ducts in the posterior periurethral region and in ampullary gland stroma. In the epithelium of the urinary bladder and urethra of both sexes, high level of ERbeta mRNA and protein, but no ERalpha mRNA, was detected. The connective tissue in urinary bladder of both males and females, as well as that in prostatic urethra in males expressed ERalpha mRNA. The neural cells in the autonomic ganglia of the prostatic plexus were strongly positive for ERbeta mRNA, but were completely devoid of ERalpha. We conclude that ERbeta is the predominant ER subtype in the epithelium of adult male rat accessory sex glands and the lower urinary tract of both males and females, as well as in the prostatic neural plexus regulating the function of the lower urinary tract in males, while ERalpha is present only in the stromal compartment of distinct sites. These results indicate that in these tissues in intact adults there are multiple targets for direct estrogen action. Furthermore, the differential or complementary expression of the two ER subtypes suggests that they may have specific functions, and may explain the complex structural and functional changes induced by estrogens.

Animals↗

PubMed2000

Differential expression of estrogen receptors alpha and beta in adult rat accessory sex glands and lower urinary tract.

Estrogens induce pronounced structural and functional changes in male accessory sex glands and the lower urinary tract in both sexes, but the exact mechanisms of estrogen action are not fully understood. This study was undertaken to localise the tissue cell types that express estrogen receptor in adult rats, and to determine the receptor subtype (ER alpha and ER beta) in order to identify sites that may respond directly to estrogens. In the male accessory sex glands (seminal vesicles, prostatic lobes and ampullary glands), ER beta mRNA and protein were strongly expressed in the epithelium but not in the stroma, while ER alpha mRNA was present only in the fibromuscular tissue surrounding the prostatic collecting ducts in the posterior periurethral region and in ampullary gland stroma. In the epithelium of the urinary bladder and urethra of both sexes, high level of ER beta mRNA and protein, but no ER alpha mRNA, was detected. The connective tissue in urinary bladder of both males and females, as well as that in prostatic urethra in males expressed ER alpha mRNA. The neural cells in the autonomic ganglia of the prostatic plexus were strongly positive for ER beta mRNA, but were completely devoid of ER alpha. We conclude that ER beta is the predominant ER subtype in the epithelium of adult male rat accessory sex glands and the lower urinary tract of both males and females, as well as in the prostatic neural plexus regulating the function of the lower urinary tract in males, while ER alpha is present only in the stromal compartment of distinct sites. These results indicate that in these tissues in intact adults there are multiple targets for direct estrogen action. Furthermore, the differential or complementary expression of the two ER subtypes suggests that they may have specific functions, and may explain the complex structural and functional changes induced by estrogens.

Adolescent↗

PubMed2000

Hydroxymatairesinol, a novel enterolactone precursor with antitumor properties from coniferous tree (Picea abies).

The potential for the extraction of the plant lignan hydroxymatairesinol (HMR) in large scale from Norway spruce (Picea abies) has given us the opportunity to study the metabolism and biological actions of HMR in animals. HMR, the most abundant single component of spruce lignans, was metabolized to enterolactone (ENL) as the major metabolite in rats after oral administration. The amounts of urinary ENL increased with the dose of HMR (from 3 to 50 mg/kg), and only minor amounts of unmetabolized HMR isomers and other lignans were found in urine. HMR (15 mg/kg body wt po) given for 51 days decreased the number of growing tumors and increased the proportion of regressing and stabilized tumors in the rat dimethylbenz[a]anthracene-induced mammary tumor model. HMR (50 mg/kg body wt) did not exert estrogenic or antiestrogenic activity in the uterine growth test in immature rats. HMR also showed no antiandrogenic responses in the growth of accessory sex glands in adult male rats. Neither ENL nor enterodiol showed estrogenic or antiestrogenic activity via a classical alpha- or beta-type estrogen receptor-mediated pathway in vitro at < 1.0 microM. HMR was an effective antioxidant in vitro.

4-Butyrolactone↗

PubMed2000

Distribution of collagen XII and XIV in the bladder wall of the male rat with outlet obstruction.

PURPOSE: Our previous studies indicate that neonatal estrogenization with diethylstilbestrol (neoDES) of male mice and rats causes partial outlet obstruction. In the present study, type XII and XIV collagens were localized in the bladder to study their role in the development of obstruction. MATERIALS AND METHODS: The bladder sections immunostained with smooth muscle specific a-actin antibody were double labeled either with collagen type XII or type XIV antibodies. The specimens were then analyzed with conventional and confocal fluorescence microscope. RESULTS: Type XII and XIV collagens were not evenly distributed in the bladder. Further, in neonatally estrogenized rats collagen XIV appeared inside smooth muscle fascicles. CONCLUSIONS: Non-overlapping distributions of collagen XII and XIV suggest their different roles in the urinary bladder. Penetration of collagen XIV inside smooth muscle fascicles may have a role in the development of DES-induced partial outlet obstruction.

Animals↗

PubMed1999

Expression of the vitellogenin gene in the liver of juvenile whitefish (Coregonus lavaretus L. s.l.) exposed to effluents from pulp and paper mills.

Juvenile whitefish (Coregonus lavaretus L. s.l.) were exposed by caging in the field to diluted effluents from three operating pulp, paper, and paperboard mills in Southern Lake Saimaa, Finland. The expression of the vitellogenin gene, used as a biomarker of estrogenic contamination of effluents, was measured using a Northern blotting method. Increased mRNA levels, the most specific and reliable evidence for estrogen receptor-mediated actions in vivo, were found in fish caged in the vicinity of one of three mills studied. This mill was found to discharge wood-derived compounds, such as sterols and resin acids, into Lake Saimaa in amounts considerably exceeding those from the other two mills. The increased vitellogenin gene expression suggests that the effluent is a source of estrogenic contaminants.

Animals↗

PubMed1998

Dietary phytoestrogens and their role in hormonally dependent disease.

Epidemiological studies suggest that diets rich in phytoestrogens (plant estrogens), particularly soy and unrefined grain products, may be associated with low risk of breast and prostate cancer. It has also been proposed that dietary phytoestrogens could play a role in the prevention of other estrogen-related conditions, namely cardiovascular disease, menopausal symptoms and post-menopausal osteoporosis. However, there is no direct evidence for the beneficial effects of phytoestrogens in humans. All information is based on consumption of phytoestrogen-rich diets, and the causal relationship and the mechanisms of phytoestrogen action in humans still remain to be demonstrated. In addition, the possible adverse effects of phytoestrogens have not been evaluated. It is plausible that phytoestrogens, as any exogenous hormonally active agent, might also cause adverse effects in the endocrine system, i.e. act as endocrine disrupters.

Animals↗

PubMed1998

Genistein exerts estrogen-like effects in male mouse reproductive tract.

The aim of this study was to evaluate the estrogenicity of genistein in the neonatal and adult male mouse reproductive tract. In intact adults, genistein (2.5 mg s.c./kg of body weight/day for 9 days) reduced testicular and serum testosterone concentrations, pituitary LH-content and prostate weight. In castrated adults, genistein (0.025-2.5 mg s.c./kg of body weight) increased expression of c-fos gene in prostatic urethra. In adult, neonatally estrogenized mice showing an increased estrogen sensitivity, a 10-day treatment with genistein (2.5 mg s.c./kg of body weight) induced development of squamous epithelial metaplasia in prostatic collecting ducts. Neonatally, only a very high dose of genistein (1 mg/pup per day; i.e. approximately 500 mg/kg of body weight) induced persistent structural changes, similar to those seen in mice treated neonatally with diethylstilbestrol, in the urethroprostatic complex. These results suggest that in adult males, genistein induces the typical estrogenic effects in doses comparable to those present in soy-based diets, while in neonatal animals, considerably higher doses are required to show estrogen-like activity.

Aging↗

PubMed1998

Biomarker responses in whitefish (Coregonus lavaretus L. s.l.) experimentally exposed in a large lake receiving effluents from pulp and paper industry.

Physiological and biochemical biomarker responses were studied in juvenile whitefish (Coregonus lavaretus L. s.l.) exposed experimentally to effluent from the forest industry. The large study area (609 km2), Southern Lake Saimaa, in Southeast Finland, receives 330,000 m3 d-1 of biologically and 55,000 m3 d-1 of chemically treated effluents, discharged from two integrated elementary chlorine free (ECF) bleached kraft pulp and paper mills, from one ECF pulp mill, and from one mill producing unbleached pulp and cardboard. The assessment of exposure to effluent discharged from the mills was based on lake water chlorophenolics (CPs) and resin acids (RAs) measured in samples collected from the 22 experimental sites along the area. Despite the low levels of effluent constituents in the lake, they were still accumulated in detectable levels in fish bile, indicating an exposure to the bioactive compounds of effluents. In comparison to the reference area, a two- to four-fold increase in ethoxyresorufin O-deethylase (EROD) activity was observed in whitefish exposed in the vicinity (1-6 km) of all the mills. However, cytochrome P450 1A1 (CYP1A1) gene expression was increased in only one of the receiving areas, indicating higher sensitivity of the EROD activity in the present study. There were no statistically significant correlations between EROD activity and the ambient water concentrations of the CPs, the RAs, or effluent dilution expressed by water sodium concentration. Neither bile chlorophenolics nor bile resin acids showed a significant correlation with EROD. No significant changes in circulating reproductive steroids, 17beta-estradiol and testosterone, in juvenile whitefish were observed. The vitellogenin gene was expressed in the vicinity of the pulp mill discharging the most wood-derived compounds, i.e. resin acids and wood-sterols, including beta-sitosterol. No differences were observed in plasma immunoglobulin M, glucose, or lactate concentrations between the effluent sources.

Animals↗

PubMed1998

Inhibition of 17beta-hydroxysteroid oxidoreductase by flavonoids in breast and prostate cancer cells.

Several flavonoids and isoflavonoids were found to inhibit 17beta-oxidoreduction of estrogens by the purified 17beta-HSOR type 1, or in cell lines expressing 17beta-HSOR type 1 enzyme (T-47D breast cancer cells) or type 2 (PC-3 prostate cancer cells). The structural demands for the inhibition of estrone (E1) reduction and estradiol (E2) oxidation catalyzed by 17beta-HSOR types 1 and 2, respectively, were not identical. Flavones, flavanones, and isoflavones hydroxylated at both the double ring (positions 5 and 7) and ring B (position 4') were the most potent inhibitors of E1 reduction in T-47D cells, and by the purified type 1 enzyme whereas flavones hydroxylated at positions 3, 5, and 7 of rings A and C, with or without a hydroxyl group in ring B, were capable of inhibiting E2 oxidation in PC-3 cells. Change to flavanone structure, or hydroxylation at position 3 of ring C of flavones, or methylation of the hydroxyl group at position 4' of ring B of flavones and isoflavones reduced or abolished their inhibitory activity on E1 reduction in T-47D cells. On the contrary, hydroxyl group at position 3 of flavones (flavonol structure) markedly increased the inhibition of E2 oxidation in PC-3 cells. Thus, changes in the number and location of hydroxyl groups may discriminate inhibition of E1 reduction and E2 oxidation. Some of the differences may be due to differences in pharmacokinetics of these compounds in T-47D and PC-3 cells. Inhibition of 17beta-HSORs could lead to an alteration in the availability of the highly active endogenous estrogen, but the effects of these compounds in vivo cannot be predicted on the basis of these results alone. Some of these compounds (isoflavones) are estrogenic per se, and they may replace endogenous estrogens, whereas flavones are only very weakly estrogenic or nonestrogenic. Regarding prevention or treatment of estrogen-related diseases, apigenin, coumestrol, and genistein raise special interest.

17-Hydroxysteroid Dehydrogenases↗

PubMed1996

Wood-derived estrogens: studies in vitro with breast cancer cell lines and in vivo in trout.

The wood-derived compound, beta-sitosterol (purity > 90%), was shown to be estrogenic in fish. It induced the expression of the vitellogenin gene in the liver of juvenile and methyltestosterone-treated rainbow trout. Structural similarities to beta-sitosterol notwithstanding, cholesterol, citrostadienol, beta-sitostanol, and 5-androstene-3 beta,17 beta-diol, an estrogenic member of the androstenic steroid group, were inactive. An abietic acid mixture (37% abietic acid, 6% dehydroabietic acid, and a remainder of unknown compounds) showed slight hormonal activity in feed, but it was completely inactive when given intraperitoneally in implants. The estrogenic component of the abietic acid preparation was not identified. In addition, to beta-sitosterol and abietic acid, several other wood-derived compounds including betulin, isorhapontigenin, isorhapontin, and pinosylvin were estrogenic in breast cancer cells (MCF-7 or T-47D). However, betulin and pinosylvin, available in sufficient amounts for in vivo testing, did not induce the expression of the vitellogenin gene. Differences in the primary sequences of human and fish estrogen receptors (hormone as well as DNA-binding regions) or uptake and metabolism of the compounds may explain the discrepancy between the two estrogen bioassays. Wood-derived compounds such as beta-sitosterol, present in pulp and paper mill effluents, may account for the weak estrogenicity of debarking effluent seen at the vitellogenin expression bioassay.

Animals↗

PubMed1996

Animal models for the preneoplastic lesions of the prostate.

OBJECTIVES: Reliable and adequate animal models are required, not only for investigation of etiology, pathogenesis, and treatment of prostate cancer, but also for chemoprevention of prostatic carcinogenesis. METHODS: Animal models for the study of premalignant changes in the prostate are reviewed in the paper, with specific reference to the neonatally estrogenized mouse model. RESULTS: Neonatal treatment of newborn Han:NMRI mice with synthetic non-steroidal estrogen, diethylstilbestrol (DES; 2 micrograms/pup on days 1-3 after birth) promoted hyperplastic and dysplastic changes in the periurethral region of the prostate at the age of 9-18 months. Dietary soy partially inhibited the development of prostatic dysplasia in these neonatally estrogenized animals, which may be due to phytoestrogens contained in soy-rich food. CONCLUSION: Prostatic cancer and its possible precursors develop spontaneously, or can be induced by different chemical and hormonal manipulations in certain animal species and strains. Neonatal estrogenization of the mouse results in prostatic dysplasia, which can be partially prevented by dietary soy. There are morphological similarities between human prostatic intraepithelial neoplasia (PIN) and dysplastic changes in rodent prostates, but more data is needed before these dysplastic lesions can be considered equivalent to human PIN.

Animals↗

PubMed1996

Neonatal estrogenization of the male mouse results in urethral dysfunction.

PURPOSE: Analysis of voiding pattern, urodynamic measurements and immunohistochemical methods were performed in order to evaluate the effects of neonatal estrogenization on voiding functions of adult male mice. MATERIALS AND METHODS: Metabolic cages were used for recording the voiding volumes and frequencies. Bladder pressure and mean flow during voiding were measured in transvesical cystometry. Location of estrogen receptors and organization of smooth muscles in lower urinary track were demonstrated using immunohistochemical staining. RESULTS: Neonatally estrogenized (neoDES) male mice had lower voided urine volumes (the average voided urine volume and average of the three largest volumes) and higher voiding frequencies than control mice. In transvesical cystometry, the maximum bladder pressure during the high-frequency oscillation phase of voiding was significantly elevated. The average urinary flow rate was decreased. CONCLUSIONS: Urodynamically, these findings are consistent with the concept that neonatally estrogenized mice have infravesical obstruction. The predominance of estrogen receptors in the periurethral region and changes in urethral smooth muscle cells immunocytochemically stained with alpha-actin-antibody support the concept of urethral wall musculature as a target of estrogen action.

Age Factors↗