Expression and function of G-protein-coupled receptorsin the male reproductive tract

This review focuses on the expression and function of muscarinic acetylcholine receptors (mAChRs), α1-adrenoceptors and relaxin receptors in the male reproductive tract. The localization and differential expression of mAChR and α1-adrenoceptor subtypes in specific compartments of the efferent ductules, epididymis, vas deferens, seminal vesicle and prostate of various species indicate a role for these receptors in the modulation of luminal fluid composition and smooth muscle contraction, including effects on male fertility. Furthermore, the activation of mAChRs induces transactivation of the epidermal growth factor receptor (EGFR) and the Sertoli cell proliferation. The relaxin receptors are present in the testis, RXFP1 in elongated spermatids and Sertoli cells from rat, and RXFP2 in Leydig and germ cells from rat and human, suggesting a role for these receptors in the spermatogenic process. The localization of both receptors in the apical portion of epithelial cells and smooth muscle layers of the vas deferens suggests an involvement of these receptors in the contraction and regulation of secretion.Esta revisão enfatiza a expressão e a função dos receptores muscarínicos, adrenoceptores α1 e receptores para relaxina no sistema reprodutor masculino. A expressão dos receptores muscarínicos e adrenoceptores α1 em compartimentos específicos de dúctulos eferentes, epidídimo, ductos deferentes, vesícula seminal e próstata de várias espécies indica o envolvimento destes receptores na modulação da composição do fluido luminal e na contração do músculo liso, incluindo efeitos na fertilidade masculina. Além disso, a ativação dos receptores muscarínicos leva à transativação do receptor para o fator crescimento epidermal e proliferação das células de Sertoli. Os receptores para relaxina estão presentes no testículo, RXFP1 nas espermátides alongadas e células de Sertoli de rato e RXFP2 nas células de Leydig e germinativas de ratos e humano, sugerindo o envolvimento destes receptores no processo espermatogênico. A localização de ambos os receptores na porção apical das células epiteliais e no músculo liso dos ductos deferentes de rato sugere um papel na contração e na regulação da secreção.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de FarmacologiaUNIFESP, EPM, Depto. de FarmacologiaSciEL

Effects of morphine and methadone on the immune system. Results of a 6-week study in the Riv:TOX rat

Drugsverslaafden hebben door hun levensstijl een grotere kans op virusziekten zoals Hepatitis-B en AIDS. Drugs, zoals heroine en methadon, zouden hierbij een bevorderende invloed kunnen hebben door de weerstand voor infecties te verminderen. In dit rapport worden de resultaten samengevat van een studie naar de invloed van morfine en methadon op het afweersysteem bij de rat. Het onderzoek is opgezet volgens het "two tier" model zoals gebruikelijk in de immuuntoxicologie. In tier I worden de dieren nog niet gecompromitteerd door immunisaties of infectieprocedures. Ratten die gedurende zes weken werden behandeld met morfine en methadon vertoonden vanaf de laagst geteste dosering een toename in het gewicht van de mesenteriale lymfklieren, terwijl histopathologisch een toename van de celrijkdom van de mergstrengen werd gezien. Dit wijst op een effect op de humorale immuniteit. Op de overige onderzochte organen, lever, nieren, testes, hypofyse, milt, thymus en popliteale lymfklieren werden geen effecten waargenomen die aan stimulatie van een opiaatreceptor toegeschreven konden worden. Deze resultaten geven aan dat verder onderzoek in de Tier II fase, gebruikmakend van gerichte immuunfunctietests is geindiceerd.HI

Accumulation and toxicity of cadmium in pigs

Zeugen en beren kregen vanaf speenleeftijd gedurende 5 maanden een rantsoen waaraan 0, 5, 10, 40 of 160 mg Cd/kg was toegevoegd, met als doel de overdracht van Cd uit het voer te kwantificeren en de toxiciteit te onderzoeken. Niertoxiciteit was het kritische effect, histopathologische lesies werden waargenomen vanaf een concentratie van ca. 80 mg/kg in de nier na 5 maanden. Uit de waargenomen relatie tussen totaal ingenomen hoeveelheid Cd en het gehalte in lever en nier kon een grenswaarde worden afgeleid, opdat wordt voldaan aan de ontwerpnormen te weten 0,3-0,4 mg Cd/kg voer.VHIRIV

Subacuut toxiciteits onderzoek met ratten gevoed met een dieet met ergotamine-tartraat. 1 Algemeen gedeelte

In this study reduced food intake, food efficiency and growth were noticed at dose levels of 100 mg EAT/kg diet and higher. Slight changes in the red blood parameters were seen in the 100 and 500 mg EAT/kg diet dose groups. Urea concentration was increased in the females of the highest dose group. The urinalyses showed an increased urine production of male of the 100 and 500 mg/kg diet. Endocrinological analyses revealed decreased T4 (500 mg/kg diet) and TSH (100 and 500 mg EAT/kg diet, only in males). Macroscopical examination revealed gaseous distension of the duodenum, pale thyroids, red tail tips and enlarged iliacal lymph nodes. In the females of 20, 100 and 500 mg EAT/kg diet relative heart, brain and liver weights were higher than the control. The relative ovaries weights were increased at the 100 and 500 mg EAT/kg diet levels. In males (100 and 500 mg EAT/kg diet) relative heart and liver weights were elevated. A slight increase in regenerative and degenerative changes in the kidneys, strong activation of the iliacal lymph nodes was seen in the highest dose group. In the tail of the animal of the 500 mg EAT/kg diet group degenerative changes in the longitudinal skeletal muscle, sometimes accompanied by slight fibrosis was observed.HIG

Impaired Nipple Development and Parturition in LGR7 Knockout Mice

LGR7 is a G-protein coupled receptor with structural homology to the gonadotrophin and thyrotrophin receptors. Recently, LGR7 was deorphanized, and it was shown that relaxin is the ligand for LGR7. To further study the function of this receptor, mice deficient for LGR7 were generated by replacing part of the transmembrane-encoding region with a LacZ reporter cassette. Here we show that LGR7 is expressed in various tissues, including the uterus, heart, brain, and testis. Fertility studies using female LGR7(−/−) mice showed normal fertility and litter size. However, some females were incapable of delivering their pups, and several pups were found dead. Moreover, all offspring died within 24 to 48 h after delivery because female LGR7(−/−) mice were unable to feed their offspring due to impaired nipple development. In some male LGR7(−/−) mice, spermatogenesis was impaired, leading to azoospermia and a reduction in fertility. Interestingly, these phenomena were absent in mutant mice at older ages or in later generations. Taken together, results from LGR7 knockout mice indicate an essential role for the LGR7 receptor in nipple development during pregnancy. Moreover, a defect in parturition was observed, suggesting a role for LGR7 in the process of cervical ripening

[Subchronische toxiciteit van propylgallaat.]

A subchronic toxicity experiment with propyl gallate in SPF-derived Wistar RIVM:TOX rats was performed. Groups of 10 female and 10 male rats were fed a semisynthetic diet containing 0, 490, 1910 and 7455 mg propyl gallate /kg feed. Body weight gain was recorded weekly and food-intake twice weekly. Other parameters comprised haematology, biochemical determinations in urine, serum and liver and complete histopathological examinations. Adverse effects of propyl gallate observed in the high dose group were effects on the haemopoeitic system reflected in the haematological parameters and the morphological changes in the spleen. The other effects observed comprised decreased incidence of the nephrocalcinosis in female rats, the increased activity of EROD in the high dose group and increased activity of the conjugating enzymes; glucorynyl-transferase and glutathion-s-transferase, in the mid and high dose group of propyl gallate. The effects on the nephrocalcinosis and on the conjugating enzymes may be considered as not adverse. The no observed adverse effect level (NOAEL) is 1910 mg propyl gallate /kg feed corresponding with 135 mg propyl gallate /kg body weight.HIG

Mice deficient for soluble adenylyl cyclase are infertile because of a severe sperm-motility defect

To acquire the ability to fertilize, spermatozoa undergo complex, but at present poorly understood, activation processes. The intracellular rise of cAMP produced by the bicarbonate-dependent soluble adenylyl cyclase (sAC) has been suggested to play a central role in initiating the cascade of the events that culminates in spermatozoa maturation. Here, we show that targeted disruption of the sAC gene does not affect spermatogenesis but dramatically impairs sperm motility, leading to male sterility. sAC mutant spermatozoa are characterized by a total loss of forward motility and are unable to fertilize oocytes in vitro. Interestingly, motility in sAC mutant spermatozoa can be restored on cAMP loading, indicating that the motility defect observed is not caused by a structural defect. We, therefore, conclude that sAC plays an essential and nonredundant role in the activation of the signaling cascade controlling motility and, therefore, in fertility. The crucial role of sAC in fertility and the absence of any other obvious pathological abnormalities in sAC-deficient mice may provide a rationale for developing inhibitors that can be applied as a human male contraceptive