Development Of Female Reproductive Organs Research Articles

TT-10 may elevate YAP and repair mouse uterine damage resulting from the inhibition effect of ibuprofen on COX2-PGE2 and YAP

Ibuprofen (IBU) is an emerging environmental contaminant that, in high doses, can damage reproductive organs in humans and other mammals. Recently, its effects on the uterus have been investigated. It is known that the COX2-PGE2 pathway and Yes-associated protein (YAP) are involved in female reproductive organ development and form a COX2-PGE2-EP2-Gas-β-catenin-YAP-COX2 positive feedback loop, in addition, TT-10, a pharmacological product, has been found to increase YAP. In this study, IBU was orally administrated to female mice for 7 d at doses of 0, 50, 100, and 200 mg/kg·bw/day (control, low, medium, and high doses, respectively). In addition, 0, 50, 100, and 200 μmol/L IBU was added in vitro to cultured uterine cells for 7 d at control, low, medium, and high doses, respectively; then, 0, 5, 10, and 20 μmol/L TT-10 were given to the in vitro uterine culture containing 100 μmol/L IBU to observe the effect of YAP activation. The results showed that medium and high doses of IBU inhibited the COX2-PGE2 pathway, decreasing YAP and increasing pYAP, leading to reduced circPVT1, elevated miR-149, and increased apoptosis, ultimately damaging the uterus. Conversely, 10 μmol/L TT-10 maximally enhanced YAP, which regulated COX2-PGE2 pathway activation, increased circPVT1, and decreased miR-149, and promoted cell proliferation, preventing uterine damage. This suggests that IBU may cause uterine damage by inhibiting the COX2-PGE2 pathway and YAP, and that appropriate doses of TT-10 may repair this damage by elevating YAP and stimulating COX2 via the feedback loop.

Mutation of DEFECTIVE EMBRYO SAC1 results in a low seed-setting rate in rice by regulating embryo sac development.

The seed-setting rate has a significant effect on grain yield in rice (Oryza sativa L.). Embryo sac development is essential for seed setting; however, the molecular mechanism underlying this process remains unclear. Here, we isolated defective embryo sac1 (des1), a rice mutant with a low seed-setting rate. Cytological examination showed degenerated embryo sacs and reduced fertilization capacity in des1. Map-based cloning revealed a nonsense mutation in OsDES1, a gene that encodes a putative nuclear envelope membrane protein (NEMP)-domain-containing protein that is preferentially expressed in pistils. The OsDES1 mutation disrupts the normal formation of functional megaspores, which ultimately results in a degenerated embryo sac in des1. Reciprocal crosses showed that fertilization is abnormal and that the female reproductive organ is defective in des1. OsDES1 interacts with LONELY GUY (LOG), a cytokinin-activating enzyme that acts in the final step of cytokinin synthesis; mutation of LOG led to defective female reproductive organ development. These results demonstrate that OsDES1 functions in determining the rice seed-setting rate by regulating embryo sac development and fertilization. Our study sheds light on the function of NEMP-type proteins in rice reproductive development.

Early Diagnosis of 60, XX/XY Chimerism in Cattle using RT-PCR

Background: Freemartinism is a special kind of cell chimerism occuring in female calf born co-twin with male calf. It is one of the most common forms of intersexuality found in cattle, arises as a consequence of vascular anastamosis between fetuses of different genders. Freemartinism causes alterations in the development of female reproductive organs and sterility. However, there were reports of fertile heterosexual twins also. Hence, the present study aimed at early diagnosis of 60, XX/XY chimerism in heterosexual pregnancies to prevent the unnecessary economic losses and preserve valuable genetic material. Methods: Chromosomal profile of female and male calves were analyzed through short term lymphocyte culture technique. The gene expression levels of ZFX and SRY genes were determined through SYBR green real-time PCR. Result: Both female and male co-twins were found to possess 60, XX/60, XY chimerism, yielding the PCR products of both the male (SRY) and female (ZFX) specific genes. A real-time PCR revealed higher levels of ZFX gene expression in female (81.66 per cent) and male (88.35 per cent) calves than SRY gene. Combination of karyotyping and real-time PCR gave a confirmative diagnosis of freemartinism, suggesting the early diagnosis soon after birth.

KETERKAITAN CARA KERJA KONTRASEPSI HORMONAL DENGAN RISIKO TERJADINYA KANKER PAYUDARA

ABSTRACT
 Introduction: Breast cancer has attacked 42.1 per 100,000 female residents in Indonesia with an average mortality rate of 17 per 100,000. One of the risk factors is the usage of hormonal contraceptives which is the main contraceptive option used in Indonesia. There are a number of differences regarding the risk factors for the use of hormonal contraceptives against breast cancer, so this review was created to examine the relationship between how hormonal contraception works and its risk for breast cancer.
 Discussion: Breast cancer is a deadly disease common in women, both in developing and developed countries. One of the risk factors considered is the usage of hormonal contraceptives. Most contraceptives consist of estrogen and progesterone. Estrogen and progesterone are important hormones for the development of female reproductive organs and the physiological function of the body including breast. Most studies show an increased risk of breast cancer and some show no association so this issue still causes controversy. The link between hormonal contraceptives and breast cancer should be studied in more detail taking into account other risk factors, breast cancer pathophysiology, and the length of time they are studied. 
 Conclusion: Estrogen and progesterone found in hormonal contraceptives have several important functions for the body, one of which is the development of physiological functions of several organs in the body including breast. On the other hand, low doses of hormonal contraceptives have minimal effects on breast cancer and there are still many risk factors other than hormonal contraceptives that should be studied.

The neglected other half - role of the pistil in plant heat stress responses.

Heat stress coinciding with reproductive stage leads to a significant loss in reproductive organs viability, resulting in lower seed-set and crop productivity. Successful fertilization and seed formation are determined by the viability of male and female reproductive organs. The impact of heat stress on the male reproductive organ (pollen) is studied more often compared to the female reproductive organ (pistil). This is attributed to easier accessibility of the pollen coupled with the notion that the pistil's role in fertilization and seed-set under heat stress is negligible. However, depending on species and developmental stages, recent studies reveal varying degrees of sensitivity of the pistil to heat stress. Remarkably, in some cases, the vulnerability of the pistil is even greater than the pollen. This article summarizes the current knowledge of the impact of heat stress on three critical stages of pistil for successful seed-set, that is, female reproductive organ development (gametogenesis), pollen-pistil interactions including pollen capture on stigma and pollen tube growth in style, as well as fertilization and early embryogenesis. Further, future research directions are suggested to unravel molecular basis of heat stress tolerance in pistil, which is critical for sustaining crop yields under predicted warming scenarios.

A suggested bisphenol A metabolite (MBP) interfered with reproductive organ development in the chicken embryo while a human-relevant mixture of phthalate monoesters had no such effects

ABSTRACTBisphenol A (BPA) and phthalate diesters are ubiquitous environmental contaminants. While these compounds have been reported as reproductive toxicants, their effects may partially be attributed to metabolites. The aim of this study was to examine reproductive organ development in chicken embryos exposed to the BPA metabolite, 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP; 100 µg/g egg) or a human-relevant mixture of 4 phthalate monoesters (85 µg/g egg). The mixture was designed within the EU project EDC-MixRisk based upon a negative association with anogenital distance in boys at 21 months of age in a Swedish pregnancy cohort. Chicken embryos were exposed in ovo from an initial stage of gonad differentiation (embryonic day 4) and dissected two days prior to anticipated hatching (embryonic day 19). No discernible effects were noted on reproductive organs in embryos exposed to the mixture. MBP-treated males exhibited retention of Müllerian ducts and feminization of the left testicle, while MBP-administered females displayed a diminished the left ovary. In the left testicle of MBP-treated males, mRNA expression of female-associated genes was upregulated while the testicular marker gene SOX9 was downregulated, corroborating a feminizing effect by MBP. Our results demonstrate that MBP, but not the phthalate monoester mixture, disrupts both male and female reproductive organ development in an avian embryo model.

Genetics of human female infertility†.

About 10% of women of reproductive age are unable to conceive or carry a pregnancy to term. Female factors alone account for at least 35% of all infertility cases and comprise a wide range of causes affecting ovarian development, maturation of oocytes, and fertilization competence, as well as the potential of a fertilized egg for preimplantation development, implantation, and fetal growth. Genetic abnormalities leading to infertility in females comprise large chromosome abnormalities, submicroscopic chromosome deletion and duplications, and DNA sequence variations in the genes that control numerous biological processes implicated in oogenesis, maintenance of ovarian reserve, hormonal signaling, and anatomical and functional development of female reproductive organs. Despite the great number of genes implicated in reproductive physiology by the study of animal models, only a subset of these genes is associated with human infertility. In this review, we mainly focus on genetic alterations identified in humans and summarize recent knowledge on the molecular pathways of oocyte development and maturation, the crucial role of maternal-effect factors during embryogenesis, and genetic conditions associated with ovarian dysgenesis, primary ovarian insufficiency, early embryonic lethality, and infertility.

Low temperature-induced aberrations in male and female reproductive organ development cause flower abortion in chickpea.

Chickpea (Cicer arietinum L.) is susceptible to low temperature (LT) at reproductive stage. LT causes flower abortion and delays pod set in chickpea until terminal drought becomes an issue, thereby decreasing yield potential. In chickpea, flower and anther/pollen development as well as LT-induced abnormalities on anther and pollen development are described inadequately. In the present manuscript, we report flower development stages, anther development stages, and aberrations in male gamete formation in chickpea under LT. Flower length was linearly correlated to flower and anther stages and can be used to predict these stages in chickpea. LT affected male gamete development in a flower/anther age-dependent manner where outcome ranged from no pollen formation to pollen sterility or no anther dehiscence to delayed dehiscence. In anthers, LT inhibited microsporogenesis, microgametogenesis, tapetum degeneration, breakage of septum and stomium, and induced pollen sterility. Whereas disruption of male function was the prime cause of abortion in flowers below vacuolated pollen stage, flower abortion was due to a combination of male and female reproductive functions in flowers with mature pollen. The study will help in elucidating mechanisms governing flower development, anther and pollen development, and tolerance/susceptibility to LT.

Cytokinin response factors integrate auxin and cytokinin pathways for female reproductive organ development.

The developmental programme of the pistil is under the control of both auxin and cytokinin. Crosstalk between these factors converges on regulation of the auxin carrier PIN-FORMED 1 (PIN1). Here, we show that in the triple transcription factor mutant cytokinin response factor 2 (crf2) crf3 crf6 both pistil length and ovule number were reduced. PIN1 expression was also lower in the triple mutant and the phenotypes could not be rescued by exogenous cytokinin application. pin1 complementation studies using genomic PIN1 constructs showed that the pistil phenotypes were only rescued when the PCRE1 domain, to which CRFs bind, was present. Without this domain, pin mutants resemble the crf2 crf3 crf6 triple mutant, indicating the pivotal role of CRFs in auxin-cytokinin crosstalk.

Abstract B1-23: Early growth response (EGR1) is a critical regulator of cellular metabolism and predicts increased responsiveness to antiestrogens in breast cancer

Abstract Breast cancer is the most commonly diagnosed cancer in women and about 1 million new cases per year are diagnosed worldwide. About 70% of all breast cancers are estrogen receptor alpha positive (ER+). Antiestrogens (e.g., Tamoxifen or Faslodex) or aromatase inhibitors (e.g., Letrozole) are often used to treat ER+ breast cancers. However, resistance to these therapies (endocrine resistance) is prevalent in the clinic and the underlying mechanisms remain unclear. We have recently shown that the oncogene MYC is overexpressed in ER+ breast cancer and up-regulates glucose and glutamine uptake in endocrine resistant breast cancer cells, which suggests that the metabolomic profile of endocrine resistant breast cancer cells may contain features that are distinct from sensitive cells. In this study, to identify the biochemical pathways that are differentially regulated in endocrine resistance in breast cancer cells, we have analyzed gene expression data and untargeted metabolite profiles of ER+ MCF7-derived breast cancer cells that are antiestrogen sensitive (LCC1) or antiestrogen resistant (LCC9) under basal conditions. Glycolysis and glutamine-dependent pathways were increased in endocrine resistant cells. Integration of the transcriptomics and metabolomics data predicted an essential role for a gene-metabolite network associated with early growth response (EGR1) and glutamine metabolism in endocrine resistant cells. EGR1 is an immediate-early gene induced by E2, growth factors, or stress signals, and has been reported to exhibit both tumor suppressor and promoter activities, based on cellular context. While EGR1 mediated signaling is important for the normal development of female reproductive organs, its precise role in breast cancer remains unknown. EGR1 gene expression and protein levels were significantly higher in LCC1 cells compared with LCC9 cells. Kaplan-Meier survival curves with gene expression data obtained from ER+ human breast tumors treated with endocrine therapy show that higher EGR1 expression is associated with a more favorable prognosis: GSE17705 [HR=0.38 (0.21-0.69); p=0.00083], GSE6532 (ER+ samples on GPL96 platform) [HR=0.55 (0.34-0.9); p=0.017]. In GSE20181, pre-treatment vs 90 days post-treatment comparisons show significantly increased levels of EGR1 expression (p<0.0001) only in the responder group. Interestingly, in both LCC1 and LCC9 cells, EGR1 overexpression increased ER protein levels and cell proliferation while EGR1 knockdown decreased ER protein levels and cell proliferation. Therefore, to understand the precise role of down-regulated EGR1 in regulating cellular metabolism and survival in endocrine resistance, we compared metabolite profiles in LCC9 cells following knockdown or overexpression of EGR1. Several major biochemical pathways such as glycolysis, lipid metabolism, glutathione, and polyamine metabolism were shown to be regulated by EGR1 in LCC9 cells. Collectively, these findings indicate that down-regulated EGR1 is an important regulator of the aberrant cellular metabolic pathways specific to endocrine resistance. Furthermore, high levels of EGR1 may serve as a favorable prognostic marker in endocrine treatment strategies in breast cancer. Citation Format: Ayesha N. Shajahan-Haq, Lu Jin, Amrita K. Cheema, Simina M. Boca, Yuriy Gusev, Krithika Bhuvaneshwar, Diane M. Demas, Habtom Ressom, Ryan Michalek, Xi Chen, Jianhua Xuan, Subha Madhavan, Robert Clarke. Early growth response (EGR1) is a critical regulator of cellular metabolism and predicts increased responsiveness to antiestrogens in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-23.

Sex steroid hormone levels and reproductive development of eight-year-old children following in utero and environmental exposure to phthalates.

In utero exposure to phthalates may adversely affect reproductive development in children due to the anti-androgenic properties of the pthalates. Accordingly, we aimed to determine the effects of in utero and environmental phthalate exposure on the reproductive development of eight-year-old children. We recruited 180 children in central Taiwan during November 2001 and followed them until August 2009 when all children became eight years old. Birth outcomes were collected. Bone age, hormone concentrations, and reproductive developmental stages were determined. Phthalate metabolite levels, including mono-2-ethylhexyl phthalate [MEHP], mono-n-butyl phthalate [MnBP], and mono-benzyl phthalate [MBzP], were assessed. No significant gender differences were found in in utero phthalate exposure. Maternal urinary levels of phthalate metabolites did not correlate significantly with birth outcomes, physical characteristics, and reproductive hormones of the eight-year-old children. Regarding the urinary phthalate metabolite levels of the eight-year-old children, MEHP correlated significantly with serum progesterone levels. MEHP levels in girls correlated significantly with serum progesterone levels. MnBP correlated significantly with serum FSH in all children. In girls, MnBP correlated with serum FSH, and MBzP correlated with serum progesterone and FSH levels. Urinary phthalate metabolite levels did not correlate with female developmental stages or the development of female reproductive organs. Phthalate metabolites did not correlate with the physical characteristics and reproductive hormones in boys. Therefore, environmental exposure to phthalates, as determined by urinary phthalate metabolite levels of eight-year-old children, may affect reproductive hormone levels in children, indicating that further studies on the environmental health effects of phthalates are warranted.

Androgen Receptor (AR) Physiological Roles in Male and Female Reproductive Systems: Lessons Learned from AR-Knockout Mice Lacking AR in Selective Cells1

Androgens/androgen receptor (AR) signaling is involved primarily in the development of male-specific phenotypes during embryogenesis, spermatogenesis, sexual behavior, and fertility during adult life. However, this signaling has also been shown to play an important role in development of female reproductive organs and their functions, such as ovarian folliculogenesis, embryonic implantation, and uterine and breast development. The establishment of the testicular feminization (Tfm) mouse model exploiting the X-linked Tfm mutation in mice has been a good in vivo tool for studying the human complete androgen insensitivity syndrome, but this mouse may not be the perfect in vivo model. Mouse models with various cell-specific AR knockout (ARKO) might allow us to study AR roles in individual types of cells in these male and female reproductive systems, although discrepancies are found in results between labs, probably due to using various Cre mice and/or knocking out AR in different AR domains. Nevertheless, no doubt exists that the continuous development of these ARKO mouse models and careful studies will provide information useful for understanding AR roles in reproductive systems of humans and may help us to develop more effective and more specific therapeutic approaches for reproductive system-related diseases.

Endometriosis as systemic genetic problem

Current data contributing to the origin and development of endometriosis (E) — sever common disease of reproductive age women are reviewed. Numerous theories and hypothesis as well as basic pathological mechanisms underlying E are briefly outlined. Whole gene-net and particular groups of candidate genes involved in E are presented. The later include genes of detoxification system, sex hormones and their receptors, cytokines gene, onco- suppressors the genes contributing to embryonic development of female reproductive organs and cell proliferation Major molecular genetic data imply epigenetic impact in the origin of disease which results from progressive disregulation of endometrium genome functions provoked by unfavorable combinations of candidate genes of some signaling pathways and defects in their expression due to abnormal methylation pattern. Histone modifications and the faults of miRNA content. In line with systemic genetic concept initial stages of E could be provoked by different genetic, epigenetic and even external factors which outcome is the same pathophysiological and pathomorphological damages clinically classified as E. Two feasible molecular genetic routs of E. are suggested. Both are relying on unscheduled expression of early embryonic genes such as WNT4, HOX10, HOX11, GALT provoking the changes in genetic program of endometriotic cells (metaplasia) and their subsequent progression as the lesions of ectopic endometrium

Ovarian regulation of neuromedin U and its local actions in the ovary, mediated through neuromedin U receptor 2

Neuromedin U (NMU) was originally identified as an anorexigenic peptide that modulates appetite as well as energy homeostasis through the brain-gut axis. Although growing evidence has linked NMU activity with the development of female reproductive organs, no direct expression of and function for NMU in these organs has been pinpointed. Using a superovulated rat model, we found that NMU is directly expressed in the ovary, where its transcript level is tightly regulated by gonadotropins. Ovarian microdissection and immunohistochemical staining showed clearly that NMU is expressed mainly in theca/interstitial cells and to a moderate extent in granulosa cells. Primary cell studies together with reporter assays indicated the Nmu mRNA level in these cells is strongly induced via cAMP signaling, whereas this increase in expression can be reversed by the degradation message residing within its 3'-untranslated region, which recruits cis-acting mRNA degradation mechanisms, such as the gonadotropin-induced zinc finger RNA-binding protein Zfp36l1. This study also demonstrated that NMUR2, but not NMUR1, is the dominant NMU receptor in the ovary, where its expression is restricted to theca/interstitial cells. Treatment with NMU led to induction of the early response c-Fos gene, phosphorylation of extracellular signal-regulated kinase 1/2, and promotion of progesterone production in both developing and mature theca/interstitial cells. Taken as a whole, this study demonstrates that NMU and NMU receptor 2 compose a novel autocrine system in theca/interstitial cells in which the intensity of signaling is tightly controlled by gonadotropins.

Developmental toxicity of pharmaceuticals in lower vertebrates

The release of human pharmaceuticals in the aquatic environment has become an issue of societal concern. More than 160 Active Pharmaceutical Ingredients (APIs) have been detected in surface waters, although generally at low concentrations (ng-ug/l). Most available ecotoxicological information on these pharmaceuticals originates from acute testing using algae, Daphnia and fish; results from long-term exposures are still very scarce, particularly in vertebrates. There is, however, emerging evidence to suggest that several human and veterinary pharmaceuticals may pose a serious threat to aquatic wildlife. Still, there are only two examples where exposure to pharmaceuticals has been indisputably linked to adverse effects in wild vertebrates, i.e. the feminizing effects of the synthetic estrogen ethinylestradiol (EE2) in fish and the decline in vulture populations caused by the non-steroidal anti-inflammatory drug diclofenac in India and Pakistan. We are currently studying effects of steroidal hormone APIs on sex organ development following exposure during early life-stages in birds (egg injection), frogs and fish (exposure via ambient water). The results show that the developing Mullerian duct (absent in fish) is a highly sensitive target for endocrine disruption and developmental toxicity in amphibians and birds. In birds, both diethylstilbestrol (DES) and EE2, injected into the embryonated egg, cause a disrupted differentiation and malformations in different parts of the oviduct, including the shell gland. Egg injection of EE2 also resulted in eggshell thinning in the next generation of eggs, and a dramatically altered pattern of expression of the enzyme carbonic anhydrase in the shell gland. Eggshell thinning is probably the most serious ecotoxic effect that has afflicted avian wildlife. Based on these and other data, we propose that eggshell thinning could represent a developmental effect in the Mullerian duct rather than a direct effect of pollutants in the oviduct of the adult egg-laying bird. The Mullerian duct also proved to be a sensitive target of toxicity in frogs. Exposure of tadpoles to EE2 resulted in a skewed sex ratio with almost complete feminization at an ecologically relevant concentration. A partial or complete lack of oviducts was observed in these frogs, resulting in ovulation directly into the abdominal cavity. Also the gestogenic pharmaceutical levonorgestrel (LNG), used in contraceptives and other hormone therapies, has recently been demonstrated to give rise to oviductal agenesis following developmental exposure. Unlike the impact in EE2-exposed frogs, the adult ovaries of the LNG-exposed frogs also displayed an increased fraction of immature oocytes, arrested in early meiotic prophase. We conclude that both EE2 and LNG are potent developmental toxicants at environmentally relevant exposures in frogs, giving rise to dysfunctional female sex organs with subsequent sterility. In conclusion, exposure to pharmaceutical steroids during early life stages can permanently impair female reproductive organ development and fertility in lower vertebrates.

Tnt1retrotransposon tagging ofSTFinMedicago truncatulareveals tight coordination of metabolic, hormonal and developmental signals during leaf morphogenesis

Tnt1 (transposable element if Nicotiana tabaccum cell type 1) is one of the very few active LTR retrotransposons used for gene tagging in plants. In the model legume Medicago truncatula, Tnt1 has been effectively used as a gene knock-out tool to generate several very useful mutants. stenofolia (stf) is such a mutant identified by Tnt1 insertion in a WUSCHEL-like homeobox transcription factor. STF is required for blade outgrowth, leaf vascular patterning and female reproductive organ development in barrel medic and woodland tobacco. Using transcript profiling and metabolite analysis, we uncovered that mutant leaves are compromised in steady-state levels of multiple phytohormones, sugar metabolites and derivatives including flavonoids and polyamines. In the lam1 mutant (caused by deletion of the STF ortholog in Nicotiana sylvestris), while glucose, fructose, mannose, galactose, myo-inositol and aromatic aminoacids are dramatically reduced, sucrose is comparable to wild-type levels, and glutamine, proline, putrescine, nicotine and sorbitol are highly increased. We demonstrated that both stf and lam1 mutants accumulate reduced levels of free auxin and ABA in their leaves, and ectopic expression of STF in tobacco leads to auxin and cytokinin overproduction phenotypes including formation of tumors on the roots and crown. These data suggest that STF mediated integration of metabolic and hormonal signals are required for lateral organ morphogenesis and elaboration.

Estrogen Sensitivity of Target Genes and Expression of Nuclear Receptor Co-Regulators in Rat Prostate after Pre- and Postnatal Exposure to the Ultraviolet Filter 4-Methylbenzylidene Camphor

Background and objectivesIn previous studies, we found that the ultraviolet filter 4-methyl-benzylidene camphor (4-MBC) exhibits estrogenic activity, is a preferential estrogen receptor (ER)-β ligand, and interferes with development of female reproductive organs and brain of both sexes in rats. Here, we report effects on male development.Methods4-MBC (0.7, 7, 24, 47 mg/kg/day) was administered in chow to the parent generation before mating, during gestation and lactation, and to offspring until adulthood. mRNA was determined in prostate lobes by real-time reverse transcription–polymerase chain reaction and protein was determined by Western blot analysis.Results4-MBC delayed male puberty, decreased adult prostate weight, and slightly increased testis weight. Androgen receptor (AR), insulin-like growth factor-1 (IGF-1), ER-α, and ER-β expression in prostate were altered at mRNA and protein levels, with stronger effects in dorsolateral than ventral prostate. To assess sensitivity of target genes to estrogens, offspring were castrated on postnatal day 70, injected with 17β-estradiol (E2; 10 or 50 μg/kg, sc) or vehicle on postnatal day 84, and sacrificed 6 hr later. Acute repression of AR and IGF-1 mRNAs by E2, studied in ventral prostate, was reduced by 4-MBC exposure. This was accompanied by reduced co-repressor N-CoR (nuclear receptor co-repressor) protein in ventral and dorsolateral prostate, whereas steroid receptor coactivator-1 (SRC-1) protein levels were unaffected.ConclusionsOur data indicate that 4-MBC affects development of male reproductive functions and organs, with a lowest observed adverse effect level of 0.7 mg/kg. Nuclear receptor coregulators were revealed as targets for endocrine disruptors, as shown for N-CoR in prostate and SRC-1 in uterus. This may have widespread effects on gene regulation.

Effect of triflumuron on development of the female reproductive organs of <i>Tribolium castaneum</i> (Herbst)

Key words: Trifulmuron, Tribolium castaneum ; female reproductive organs Univ. j. zool. Rajshahi Univ. Vol.24, 2005. pp. 49-53

Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

Natriuretic peptides (NP) mediate their effects by activating membrane-bound guanylyl cyclase-coupled receptors A (NPR-A) or B (NPR-B). Whereas the pathophysiological role of NPR-A has been widely studied, only limited knowledge on the cardiovascular function of NPR-B is available. In vitro studies suggest antiproliferative and antihypertrophic actions of the NPR-B ligand C-type NP (CNP). Because of the lack of a specific pharmacological inhibitor, these effects could not clearly be attributed to impaired NPR-B signaling. Recently, gene deletion revealed a predominant role of NPR-B in endochondral ossification and development of female reproductive organs. However, morphological abnormalities and premature death of NPR-B-deficient mice preclude detailed cardiovascular phenotyping. In the present study, a dominant-negative mutant (NPR-BDeltaKC) was used to characterize CNP-dependent NPR-B signaling in vitro and in transgenic rats. Here we demonstrate that reduced CNP- but not atrial NP-dependent cGMP response attenuates antihypertrophic potency of CNP in vitro. In transgenic rats, NPR-BDeltaKC expression selectively reduced NPR-B but not NPR-A signaling. NPR-BDeltaKC transgenic rats display progressive, blood pressure-independent cardiac hypertrophy and elevated heart rate. The hypertrophic phenotype is further enhanced in chronic volume overload-induced congestive heart failure. Thus, this study provides evidence linking NPR-B signaling to the control of cardiac growth.

Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs

Guanylyl cyclase B is the receptor for a small peptide (C-type natriuretic peptide) produced locally in many different tissues. To unravel the functions of the receptor, we generated mice lacking guanylyl cyclase B through gene targeting. Expression of the receptor mRNA in tissues such as bone and female reproductive organs was evident, and significant phenotypes associated with each of these tissues were apparent in null mice. A dramatic impairment of endochondral ossification and an attenuation of longitudinal vertebra or limb-bone growth were seen in null animals. C-type natriuretic peptide-dependent increases of guanylyl cyclase B activity, but not basal enzyme activity, appeared to be required for the progression of endochondral ossification. Female mice were infertile, but male mice were not. This result was due to the failure of the female reproductive tract to develop. Thus, the guanylyl cyclase B receptor is critical for the development of both bone and female reproductive organs.