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Sample records for exposure alters follicle-stimulating

  1. Fluoride Exposure, Follicle Stimulating Hormone Receptor Gene Polymorphism and Hypothalamus-pituitary-ovarian Axis Hormones in Chinese Women.

    PubMed

    Zhao, Ming Xu; Zhou, Guo Yu; Zhu, Jing Yuan; Gong, Biao; Hou, Jia Xiang; Zhou, Tong; Duan, Li Ju; Ding, Zhong; Cui, Liu Xin; Ba, Yue

    2015-09-01

    The effects of fluoride exposure on the functions of reproductive and endocrine systems have attracted widespread attention in academic circle nowadays. However, it is unclear whether the gene-environment interaction may modify the secretion and activity of hypothalamus-pituitary- ovarian (HPO) axis hormones. Thus, the aim of this study was to explore the influence of fluoride exposure and follicle stimulating hormone receptor (FSHR) gene polymorphism on reproductive hormones in Chinese women. A cross sectional study was conducted in seven villages of Henan Province, China during 2010-2011. A total of 679 women aged 18-48 years were recruited through cluster sampling and divided into three groups, i.e. endemic fluorosis group (EFG), defluoridation project group (DFPG), and control group (CG) based on the local fluoride concentration in drinking water. The serum levels of gonadotropin releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were determined respectively and the FSHR polymorphism was detected by real time PCR assay. The results provided the preliminary evidence indicating the gene-environment interaction on HPO axis hormones in women. PMID:26464260

  2. 21 CFR 522.1002 - Follicle stimulating hormone.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Follicle stimulating hormone. 522.1002 Section 522....1002 Follicle stimulating hormone. (a)(1) Specifications. Each package contains 2 vials. One vial... hormone. The other vial contains 10 milliliters of aqueous diluent. (2) Sponsor. See No. 052923 in §...

  3. 21 CFR 522.1002 - Follicle stimulating hormone.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Follicle stimulating hormone. 522.1002 Section 522....1002 Follicle stimulating hormone. (a)(1) Specifications. Each package contains 2 vials. One vial... hormone. The other vial contains 10 milliliters of aqueous diluent. (2) Sponsor. See No. 052923 in §...

  4. 21 CFR 522.1002 - Follicle stimulating hormone.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Follicle stimulating hormone. 522.1002 Section 522....1002 Follicle stimulating hormone. (a)(1) Specifications. Each package contains 2 vials. One vial... hormone. The other vial contains 10 milliliters of aqueous diluent. (2) Sponsor. See No. 052923 in §...

  5. 21 CFR 522.1002 - Follicle stimulating hormone.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Follicle stimulating hormone. 522.1002 Section 522....1002 Follicle stimulating hormone. (a)(1) Specifications. Each package contains 2 vials. One vial... hormone. The other vial contains 10 milliliters of aqueous diluent. (2) Sponsor. See No. 052923 in §...

  6. 21 CFR 522.1002 - Follicle stimulating hormone.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Follicle stimulating hormone. 522.1002 Section 522....1002 Follicle stimulating hormone. (a)(1) Specifications. Each package contains 2 vials. One vial... hormone. The other vial contains 10 milliliters of aqueous diluent. (2) Sponsor. See 059521 in §...

  7. Follicle-stimulating hormone levels in male workers exposed to urban chemical, physical, and psychosocial stressors.

    PubMed

    Tomei, G; Tomao, E; Ciarrocca, M; Rosati, M V; Caciari, T; Gamberale, D; Palermo, P; De Sio, S; Tria, M; Panfili, A; Tomei, F

    2009-07-01

    The aim of this study is to evaluate whether occupational exposure to urban stressors could cause alterations in the follicle-stimulating hormone (FSH) levels in traffic policemen compared to a control group. After excluding the subjects with main confounding factors, traffic policemen and male controls were matched by age, working life, body mass index (BMI), drinking habit, cigarette smoking history, and daily consumption of Italian coffee, 166 traffic policemen and 166 controls were included into the study. FSH levels were significantly higher in traffic policemen compared to male controls (P < 0.05). The distribution of FSH values in traffic policemen and controls was significant (P < 0.05). Our results suggest that occupational exposure to low doses of chemical and psychosocial stressors may alter plasma levels of FSH in traffic policemen more than in the control group. If the results obtained are confirmed by further research, the plasma levels of FSH may be used as early biological markers, valuable for the group, used in occupational set even before the appearance of disorders of male fertility. PMID:19671632

  8. 21 CFR 862.1300 - Follicle-stimulating hormone test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Follicle-stimulating hormone test system. 862.1300... Systems § 862.1300 Follicle-stimulating hormone test system. (a) Identification. A follicle-stimulating hormone test system is a device intended to measure follicle-stimulating hormone (FSH) in plasma,...

  9. Intra-cervical application of Misoprostol at estrus alters the content of cervical hyaluronan and the mRNA expression of follicle stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR) and cyclooxygenase-2 in the ewe.

    PubMed

    Leethongdee, S; Kershaw-Young, C M; Scaramuzzi, R J; Khalid, M

    2010-06-01

    The complex anatomy the of ovine cervix limits the success of transcervical artificial insemination in sheep, but Misoprostol (a PGE(1) analogue) relaxes the cervix and facilitates transcervical artificial insemination. However, the mechanism by which Misoprostol causes cervical relaxation is not known. This study examined if intra-cervical Misoprostol altered the hyaluronan content and the mRNA expression of COX-2, LHR, or FSHR in the cervix of the estrus ewe. Estrus was synchronized in cyclic ewes with progestagen pessaries and 48 h after sponge removal ewes were treated intra-cervically with 0 (controls), 200, or 400 microg Misoprostol. Hyaluronan content was determined by ELISA and mRNA expression of LHR, FSHR, and COX-2 was analyzed by in situ hybridization using digoxigenin-11-uridine-5'-triphosphate labeled riboprobes. The hyaluronan content of the cervix was significantly higher in sheep that received 200 (P<0.05) or 400 (P<0.05) microg Misoprostol compared to controls. Moreover, it was significantly (P<0.05) higher in the vaginal region compared to mid and uterine regions. Misoprostol increased (P<0.05) the mRNA expression of LHR and COX-2 but not FSHR. The expression for all three genes was highest in the vaginal region and lowest in uterine region. The luminal epithelium and circular smooth muscle layers had higher (P<0.05) expression for LHR, FSHR, and COX-2 mRNAs, and the sub-epithelial stroma had the lowest (P<0.05). We propose that the intra-cervical application of Misoprostol induces the mRNA expression of LHR, FSHR, and COX-2 through a positive feedback loop. The data suggest that softening of the cervix by Misoprostol is caused by an increase in the hyaluronan content of the cervix. PMID:20171717

  10. 76 FR 2807 - New Animal Drugs; Change of Sponsor; Follicle Stimulating Hormone

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-18

    ...; Follicle Stimulating Hormone AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The... sponsor for a new animal drug application (NADA) for follicle stimulating hormone from Ausa International... hormone) to Therio, Inc., 8801 Anderson Ave., Manhattan, KS 66503. Accordingly, the Agency is amending...

  11. Effects of external radiation therapy for cancer of the prostate on the serum concentrations of testosterone, follicle-stimulating hormone, luteinizing hormone and prolactin

    SciTech Connect

    Tomic, R.; Bergman, B.; Damber, J.E.; Littbrand, B.; Loefroth, P.O.

    1983-08-01

    Testosterone, luteinizing hormone, follicle-stimulating hormone and prolactin were analyzed in serum from 31 patients with carcinoma of the prostate treated primarily with megavoltage radiation therapy. The total tumor dose varied between 58 and 71 gray (mean 63.5 gray). Absorbed doses to the testes were measured at approximately 1 to more than 10 gray. We investigated retrospectively 17 patients 3 to 60 months (mean 20 months) after therapy and found significantly lower serum testosterone concentrations and significantly higher luteinizing and follicle-stimulating hormone concentrations than in age-matched controls. Of the patients, 14 were followed before and after radiation treatment. Testosterone concentrations were reduced significantly 1 week as well as 3 months after treatment but pre-treatment values were found on analysis 6 and 12 months after treatment. The values for luteinizing and follicle-stimulating hormones were significantly higher 3, 6 and 12 months after radiation treatment compared to pre-treatment values. The follicle-stimulating hormone value already increased after 1 week. The greatest observed testosterone alteration occurred 1 week after treatment in patients who received more than 10 gray over the gonads. The use of lead shields protecting the testes reduced the dose absorbed to the gonads by approximately 50 percent.

  12. Prediagnostic circulating follicle stimulating hormone concentrations and ovarian cancer risk.

    PubMed

    McSorley, Meghan A; Alberg, Anthony J; Allen, Diane S; Allen, Naomi E; Brinton, Louise A; Dorgan, Joanne F; Kaaks, Rudolf; Rinaldi, Sabina; Helzlsouer, Kathy J

    2009-08-01

    Gonadotropins have been indicted in ovarian carcinogenesis but direct evidence has been limited and inconsistent. The aim of this study was to determine the association between prediagnostic levels of follicle stimulating hormone (FSH) and subsequent development of invasive epithelial ovarian cancer. A nested case-control study was conducted using cases and controls drawn from three cohorts: CLUE I and CLUE II of Washington County, MD, and the Island of Guernsey Study, United Kingdom. In total, 67 incident invasive epithelial ovarian cancer cases were each matched to 1 to 2 controls on age, menopausal status, time since last menstrual period, current hormone use and other relevant factors. FSH concentrations were classified into ranked thirds of low, medium or high based on the distribution among controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH concentrations. Results of the analysis showed that ovarian cancer risk decreased with higher FSH concentrations (p-trend = 0.005). Compared with the lowest third of FSH concentrations, the OR among those in the middle and highest thirds were 0.45 [95% Confidence Interval (CI): 0.20-1.00] and 0.26 (95% CI: 0.10-0.70), respectively. Associations persisted after excluding cases diagnosed within 5 years of follow-up. In conclusion, a reduction in subsequent risk of invasive epithelial ovarian cancer was observed among women with higher circulating FSH concentrations. These findings contradict the hypothesized role of FSH as a risk factor in ovarian carcinogenesis. PMID:19444906

  13. Sex-specific regulation of follicle-stimulating hormone secretion by synaptotagmin 9

    PubMed Central

    Roper, Lindsey K.; Briguglio, Joseph S.; Evans, Chantell S.; Jackson, Meyer B.; Chapman, Edwin R.

    2015-01-01

    The anterior pituitary releases six different hormones that control virtually all aspects of vertebrate physiology, yet the molecular mechanisms underlying their Ca2+-triggered release remain unknown. A subset of the synaptotagmin (syt) family of proteins serve as Ca2+ sensors for exocytosis in neurons and neuroendocrine cells, and are thus likely to regulate pituitary hormone secretion. Here we show that numerous syt isoforms are highly expressed in the pituitary gland in a lobe, and sex-specific manner. We further investigated a Ca2+-activated isoform, syt-9, and found that it is expressed in a subpopulation of anterior pituitary cells, the gonadotropes. Follicle-stimulating hormone (FSH) and syt-9 are highly co-localized in female, but not male, mice. Loss of syt-9 results in diminished basal and stimulated FSH secretion only in females, resulting in alterations in the oestrus cycle. This work uncovers a new function for syt-9 and reveals a novel sex difference in reproductive hormone secretion. PMID:26482442

  14. 21 CFR 862.1300 - Follicle-stimulating hormone test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Follicle-stimulating hormone test system. 862.1300 Section 862.1300 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  15. 21 CFR 862.1300 - Follicle-stimulating hormone test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Follicle-stimulating hormone test system. 862.1300 Section 862.1300 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  16. 21 CFR 862.1300 - Follicle-stimulating hormone test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Follicle-stimulating hormone test system. 862.1300 Section 862.1300 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  17. 21 CFR 862.1300 - Follicle-stimulating hormone test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Follicle-stimulating hormone test system. 862.1300 Section 862.1300 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  18. Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires β-catenin

    PubMed Central

    Parakh, Tehnaz N.; Hernandez, Jennifer A.; Grammer, Jean C.; Weck, Jennifer; Hunzicker-Dunn, Mary; Zeleznik, Anthony J.; Nilson, John H.

    2006-01-01

    Estrogens profoundly influence the physiology and pathology of reproductive and other tissues. Consequently, emphasis has been placed on delineating the mechanisms underlying regulation of estrogen levels. Circulating levels of estradiol in women are controlled by follicle-stimulating hormone (FSH), which regulates transcription of the aromatase gene (CYP19A1) in ovarian granulosa cells. Previous studies have focused on two downstream effectors of the FSH signal, cAMP and the orphan nuclear receptor steroidogenic factor-1 (NR5A1). In this report, we present evidence for β-catenin (CTNNB1) as an essential transcriptional regulator of CYP19A1. FSH induction of select steroidogenic enzyme mRNAs, including Cyp19a1, is enhanced by β-catenin. Additionally, β-catenin is present in transcription complexes assembled on the endogenous gonad-specific CYP19A1 promoter, as evidenced by chromatin immunoprecipitation assays. Transient expression and RNAi studies demonstrate that FSH- and cAMP-dependent regulation of this promoter is sensitive to alterations in the level of β-catenin. The stimulatory effect of β-catenin is mediated through functional interactions with steroidogenic factor-1 that involve four acidic residues within its ligand-binding domain, mutation of which attenuates FSH/cAMP-induced Cyp19a1 mRNA accumulation. Together, these data demonstrate that β-catenin is essential for FSH/cAMP-regulated gene expression in the ovary, identifying a central and previously unappreciated role for β-catenin in estrogen biosynthesis, and a potential broader role in other aspects of follicular maturation. PMID:16895991

  19. Proteomic and functional profiles of a follicle-stimulating hormone positive human nonfunctional pituitary adenoma.

    PubMed

    Wang, Xiaowei; Guo, Tianyao; Peng, Fang; Long, Ying; Mu, Yun; Yang, Haiyan; Ye, Ningrong; Li, Xuejun; Zhan, Xianquan

    2015-06-01

    Nonfunctional pituitary adenoma (NFPA) is highly heterogeneous with different hormone-expressed subtypes in NFPA tissues including follicle-stimulating hormone (FSH) positive, luteinizing hormone-positive, FSH/luteinizing hormone-positive, and negative types. To analyze in-depth the variations in the proteomes among different NFPA subtypes for our long-term goal to clarify molecular mechanisms of NFPA and to detect tumor biomarker for personalized medicine practice, a reference map of proteome of a human FSH-expressed NFPA tissue was described here. 2DE and PDQuest image analysis were used to array each protein. MALDI-TOF PMF and human Swiss-Prot databases with MASCOT search were used to identify each protein. A good 2DE pattern with high level of between-gel reproducibility was attained with an average positional deviation 1.98 ± 0.75 mm in the IEF direction and 1.62 ± 0.68 mm in the SDS-PAGE direction. Approximately 1200 protein spots were 2DE-detected and 192 redundant proteins that were contained in 141 protein spots were PMF-identified, representing 107 nonredundant proteins. Those proteins were located in cytoplasm, nucleus, plasma membrane, extracellular space, and so on, and those functioned in transmembrane receptor, ion channel, transcription/translation regulator, transporter, enzyme, phosphatase, kinase, and so on. Several important pathway networks were characterized from those identified proteins with DAVID and Ingenuity Pathway Analysis systems, including gluconeogenesis and glycolysis, mitochondrial dysfunction, oxidative stress, cell-cycle alteration, MAPKsignaling system, immune response, TP53-signaling, VEGF-signaling, and inflammation signaling pathways. Those resulting data contribute to a functional profile of the proteome of a human FSH-positive NFPA tissue, and will serve as a reference for the heterogeneity analysis of NFPA proteomes. PMID:25809007

  20. Properties of follicle-stimulating-hormone receptor in cell membranes of bovine testis.

    PubMed Central

    Cheng, K W

    1975-01-01

    A simple method for preparing plasma membranes from bovine testes is described. Bovine testicular receptor has a high affinity and specificity for 125I-labelled human FSH (follicle-stimulating hormone). The specific binding of 125I-labelled human FSH to the plasma membranes is a saturable process with respect to the amounts of receptor protein and FSH added. The association and dissociation of 125I-labelled human FSH are time- and temperature-dependent, and the binding of labelled human FSH to bovine testicular receptor is strong and not readily reversible. Scatchard [Ann. N.Y. Acad. Sci. (1949) 51, 660-672] analysis indicates a dissociation constant, Kd, of 9.8 X10(-11)M, and 5.9 X 10(-14)mol of binding sites/mg of membrane protein. The testicular membrane receptor is heat-labile. Preheating at 40 degrees C for 15 min destroyed 30% of the binding activity. Specific binding is pH-dependent, with an optimum between pH 7.0 and 7.5. Brief exposure to extremes of pH caused irreversible damage to the receptors. The ionic strength of the incubation medium markedly affects the association of 125I-labelled human FSH with its testicular receptor. Various cations at concentrations of 0.1M inhibit almost completely the binding of 125I-labelled human FSH. Nuclectides and steroid hormones at concentrations of 1mM and 5mu/ml respectively have no effect on the binding of FSH to its receptor. Incubation of membranes with and chymotrypsin resulted in an almost complete loss of binding activity, suggesting that protein moieties are essential for the binding of 125I-labelled human FSH. Binding of 125I-labelled human FSH to bovine testicular receptor does not result in destruction or degradation of the hormone. PMID:242318

  1. Pharmacologic profiling of corifollitropin alfa, the first developed sustained follicle stimulant.

    PubMed

    Verbost, Pieter; Sloot, Willem N; Rose, Ursula M; de Leeuw, Renato; Hanssen, Rob G J M; Verheijden, Gijs F M

    2011-01-25

    Corifollitropin alfa (Elonva®, MSD, previously N.V. Organon or Schering-Plough Oss, The Netherlands) is a newly developed sustained follicle stimulant composed of the α subunit of human follicle-stimulating hormone (FSH) and a hybrid β subunit formed by fusion of the human chorionic gonadotropin β subunit carboxy terminal peptide with the β subunit of human FSH. Binding characteristics of corifollitropin alfa at the rat FSH receptor and transactivation properties at the rat FSH receptor, human luteinizing hormone (LH) receptor, and human thyroid-stimulating hormone receptor (TSH receptor) were assessed in vitro. Bioactivity of corifollitropin alfa in rats was also assessed. Serum corifollitropin alfa levels in rats and dogs were used to derive the main pharmacokinetic parameters of corifollitropin alfa. Binding and transactivation profile of corifollitropin alfa to rat FSH receptor was specific and comparable to that of recombinant human FSH, with no intrinsic TSH receptor or LH receptor activation. From pharmacokinetic studies, circulating half-life of corifollitropin alfa was calculated to be 17.3h in rats and 46.9h in dogs, 1.5- to 2-fold longer than recombinant FSH. Corifollitropin alfa demonstrated a 2- to 4-fold increase in bioactivity (ovarian weight, serum estradiol and progesterone, ovulated ova) over recombinant FSH across all in vivo parameters assessed. These data demonstrate that corifollitropin alfa is a specific ligand with high affinity for FSH receptor, lacking intrinsic activity for LH receptor and TSH receptor. By virtue of its increased in vivo half-life, corifollitropin alfa can be a valuable alternative to FSH by acting as a sustained follicle stimulant. PMID:21115001

  2. A rapid solid-phase radioimmunoassay for human plasma follicle-stimulating hormone.

    PubMed

    Lovesey, A C

    1980-01-01

    The measurement of plasma levels of human follicle-stimulating hormone (FSH) has proved to be of value for the study of the hypothalamic-hypophyseal-gonadal axis, greatly facilitating the diagnosis and mangement of problems relating to the menopause and infertility. In the present work a solid-phase radioimmunoassay for human FSH has been developed. This system is characterised by high precision, is economical, and is considerably faster to operate than conventional double antibody systems used in the hospital assay service. Reference values for plasma FSH in various endocrine states are recorded and discussed. PMID:6769381

  3. Comparative glycomics of the glycoprotein follicle stimulating hormone: glycopeptide analysis of isolates from two mammalian species.

    PubMed

    Dalpathado, Dilusha S; Irungu, Janet; Go, Eden P; Butnev, Vladimir Y; Norton, Katie; Bousfield, George R; Desaire, Heather

    2006-07-18

    Follicle stimulating hormone (FSH) is one of the important hormones that regulate gonadal functions. This hormone is glycosylated, and the glycans greatly influence the biological properties. In the present study the negatively charged glycopeptides of equine and human pituitary follicle stimulating hormone (eFSH and hFSH) have been characterized in a glycosylation site-specific manner using FT-ICR-MS and Edman sequencing. The characteristic pattern of glycan distribution at each glycosylation site has been deduced and compared between horse and human FSH preparations. The data suggest that site-specific differences exist between glycoforms of human and equine FSH. For instance, except for one site in the beta subunit (Asn7) of hFSH all other sites in both species have sulfated glycoforms. Also, glycoforms at Asn52 of hFSH are all complex type, whereas in eFSH, both complex and hybrid structures exist at this site. There is also a higher percentage of sulfated glycans in the latter site compared to the former. This is the first study that characterizes the glycans from this hormone in a glycosylation site-specific manner, and these data can be used to begin correlative studies between glycosylation structure and hormone function. PMID:16834341

  4. Role of follicle-stimulating hormone on biliary cyst growth in autosomal dominant polycystic kidney disease

    PubMed Central

    Onori, Paolo; Mancinelli, Romina; Franchitto, Antonio; Carpino, Guido; Renzi, Anastasia; Brozzetti, Stefania; Venter, Julie; Francis, Heather; Glaser, Shannon; Jefferson, Douglas M.; Alpini, Gianfranco; Gaudio, Eugenio

    2014-01-01

    Background Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the progressive development of renal and hepatic cysts. Follicle-stimulating hormone (FSH) has been demonstrated to be a trophic factor for biliary cells in normal rats and experimental cholestasis induced by bile duct ligation (BDL). Aims To assess the effect of FSH on cholangiocyte proliferation during ADPKD using both in vivo and in vitro models. Methods Evaluation of FSH receptor (FSHR), FSH, phospho-extracellular-regulated kinase (pERK) and c-myc expression in liver fragments from normal patients and patients with ADPKD. In vitro, we studied proliferating cell nuclear antigen (PCNA) and cAMP levels in a human immortalized, non-malignant cholangiocyte cell line (H69) and in an immortalized cell line obtained from the epithelium lining the hepatic cysts from the patients with ADPKD (LCDE) with or without transient silencing of the FSH gene. Results Follicle-stimulating hormone is linked to the active proliferation of the cystic wall and to the localization of p-ERK and c-myc. This hormone sustains the biliary growth by activation of the cAMP/ERK signalling pathway. Conclusion These results showed that FSH has an important function in cystic growth acting on the cAMP pathway, demonstrating that it provides a target for medical therapy of hepatic cysts during ADPKD. PMID:23617956

  5. Data on the characterization of follicle-stimulating hormone monoclonal antibodies and localization in Japanese eel pituitary.

    PubMed

    Kim, Dae-Jung; Park, Chae-Won; Byambaragchaa, Munkhzaya; Kim, Shin-Kwon; Lee, Bae-Ik; Hwang, Hyung-Kyu; Myeong, Jeong-In; Hong, Sun-Mee; Kang, Myung-Hwa; Min, Kwan-Sik

    2016-09-01

    Monoclonal antibodies were generated against recombinant follicle-stimulating hormone (rec-FSH) from Japanese eel Anguilla japonica; rec-FSH was produced in Escherichia coli and purified using Ni-NTA Sepharose column chromatography. In support of our recent publication, "Production and characterization of monoclonal antibodies against recombinant tethered follicle-stimulating hormone from Japanese eel Anguilla japonica" [1], it was important to characterize the specificity of eel follicle-stimulating hormone antibodies. Here, the production and ELISA system of these monoclonal antibodies are presented. The affinity-purified monoclonal antibodies specifically detected eel rec-FSH in ELISA and on western blots of rec-FSH produced from CHO cells. Immunohistochemical analysis revealed that FSH staining was specifically localized in the eel pituitary. PMID:27331121

  6. Follicle-Stimulating Hormone: A Review of Form and Function in the Treatment of Infertility.

    PubMed

    Smitz, Johan; Wolfenson, Claudio; Chappel, Scott; Ruman, Jane

    2016-06-01

    The use of gonadotropin therapy, including follicle-stimulating hormone (FSH), represents an indispensable part of fertility treatment. There are a number of FSH preparations commercially available or in development, including both urinary-derived products (urinary-derived FSH [uFSH]) and FSH produced through recombinant techniques (recombinant FSH [rFSH]). Differences in the glycosylation patterns of FSH give rise to a number of naturally occurring isoforms that may differ functionally. The relative concentrations of these isoforms vary over the course of the menstrual cycle and the lifetime, indicating that these differences in glycosylation may have physiologic relevance. Although both uFSH and rFSH contain human FSH, there are differences in the glycosylation patterns, which may give rise to differences in biologic activity between products. Current FSH products have been shown to have high purity and to exhibit consistent, favorable efficacy and safety profiles for the treatment of infertility, regardless of urinary or recombinant origin. PMID:26446000

  7. Role of the Extracellular and Intracellular Loops of Follicle-Stimulating Hormone Receptor in Its Function

    PubMed Central

    Banerjee, Antara A.; Mahale, Smita D.

    2015-01-01

    Follicle-stimulating hormone receptor (FSHR) is a leucine-rich repeat containing class A G-protein coupled receptor belonging to the subfamily of glycoprotein hormone receptors (GPHRs), which includes luteinizing hormone/choriogonadotropin receptor (LH/CGR) and thyroid-stimulating hormone receptor. Its cognate ligand, follicle-stimulating hormone binds to, and activates FSHR expressed on the surface of granulosa cells of the ovary, in females, and Sertoli cells of the testis, in males, to bring about folliculogenesis and spermatogenesis, respectively. FSHR contains a large extracellular domain (ECD) consisting of leucine-rich repeats at the N-terminal end and a hinge region at the C-terminus that connects the ECD to the membrane spanning transmembrane domain (TMD). The TMD consists of seven α-helices that are connected to each other by means of three extracellular loops (ELs) and three intracellular loops (ILs) and ends in a short-cytoplasmic tail. It is well established that the ECD is the primary hormone binding domain, whereas the TMD is the signal transducing domain. However, several studies on the ELs and ILs employing site directed mutagenesis, generation of chimeric receptors and in vitro characterization of naturally occurring mutations have proven their indispensable role in FSHR function. Their role in every phase of the life cycle of the receptor like post translational modifications, cell surface trafficking, hormone binding, activation of downstream signaling, receptor phosphorylation, hormone–receptor internalization, and recycling of hormone–receptor complex have been documented. Mutations in the loops causing dysregulation of these processes lead to pathophysiological conditions. In other GPHRs as well, the loops have been convincingly shown to contribute to various aspects of receptor function. This review article attempts to summarize the extensive contributions of FSHR loops and C-terminal tail to its function. PMID:26236283

  8. Association of follicle stimulating hormone receptor promoter with ovarian response in IVF-ET patients

    PubMed Central

    Dan, Wang; Jing, Gao; Liangbin, Xia; Ting, Zhang; Ying, Zeng

    2015-01-01

    Background: Poor ovarian response phenomenon has been observed in some of the in vitro fertilization-embryo transfer patients. Some investigations found that follicle stimulating hormone receptor (FSHR) gene plays a role in the process, but no direct evidence shows the correlation between genotypes of FSHR and ovarian response. Objective: Exploring the molecular mechanism behind the mutation of FSHR promoter association with ovarian granulosa cells and poor ovarian response. Materials and Methods: This cross sectional study was performed using 158 women undergoing the controlled short program ovarian stimulation for IVF treatment. The 263 bp DNA fragments before the follicle stimulating hormone (FSH) receptor 5' initiation site were sequenced in the patients under IVF cycle, 70 of which had poor ovarian response and 88 showed normal ovarian responses. Results: With a mutation rate of 40%, 63 in 158 cases showed a 29th site G→A point mutation; among the mutated cases, the mutation rate of the poor ovarian responders was significantly higher than the normal group (60% versus 23.9%; χ2=21.450, p<0.001). Besides, the variability was also obvious in antral follicle count, and ovum pick-ups. The estradiol peak values and the number of mature eggs between the two groups had significant difference. However, there was no obvious variability (t=0.457, p=0.324) in the basic FSH values between the two groups (normal group, 7.2±2.3 U/L; mutation group, 7.1±2.0 U/L). Conclusion: The activity of FSHR promoter is significantly affected by the 29th site G→A mutation that will weaken promoter activity and result in poor response to FSH. PMID:26730247

  9. Effects of inorganic and organic manganese supplementation on gonadotropin-releasing hormone-I and follicle-stimulating hormone expression and reproductive performance of broiler breeder hens.

    PubMed

    Xie, Jingjing; Tian, Chuanhuan; Zhu, Yongwen; Zhang, Liyang; Lu, Lin; Luo, Xugang

    2014-04-01

    Manganese is an essential microelement. Manganese deficiency affects reproduction performance and reproductive hormones in layers. However, little is known about its effects and the possible mechanism in regulating reproduction in broiler breeder hens. In the current study, broiler breeder hens at peak production were fed with diets supplemented with 0, 120, or 240 mg of Mn/kg as MnSO4 or Mn proteinate for 13 wk. Manganese supplementation did not alter egg laying rate, egg weight, fertility, hatchability, or hatchling weight over a 13-wk trial period. However, 240 mg of Mn/kg supplementation significantly increased serum Mn (P < 0.05). Manganese supplements increased the eggshell breaking strength (P < 0.05) without affecting the eggshell thickness. There was no difference in serum cholesterol and estradiol. Expression of follicle-stimulating hormone) and gonadotropin-releasing hormone-I (GnRH-I) genes was significantly elevated by 240 mg of Mn/kg (P < 0.05). Furthermore, inorganic Mn supplementation doubled GnRH-I expression compared with supplementation with the organic form (P < 0.05), although serum Mn was comparable between these 2 supplements. No obvious difference was shown in gene expression of luteinizing hormone, prolactin, GnRH-I receptor, inducible NO synthase, and dopamine receptor D1 in the pituitary as well as tyrosine hydroxylase and inducible NO synthase in the hypothalamus. This suggests that dietary Mn supplementation could improve eggshell quality in the long term. The central mechanism of nontoxic high doses of Mn suggested the transcriptional activation of GnRH-I and follicle-stimulating hormone genes. The central effect of inorganic Mn activating GnRH-I genes compared with the reduced effect by organic Mn could possibly be due to a decreased capacity of the latter passing through the blood-brain barrier. PMID:24706974

  10. Profiling follicle stimulating hormone-induced gene expression changes in normal and malignant human ovarian surface epithelial cells.

    PubMed

    Ho, Shuk-Mei; Lau, Kin-Mang; Mok, Samuel Chi-Ho; Syed, Viqar

    2003-07-01

    Epidemiological data have implicated the pituitary gonadotropin follicle stimulating hormone (FSH) as both a risk factor for and a protective agent against epithelial ovarian cancer. Yet, little is known about how this hormone could play such opposing roles in ovarian carcinogenesis. Complementary DNA microarrays containing 2400 named genes were used to examine FSH-induced gene expression changes in ovarian cancer (OC) and immortalized normal human ovarian surface epithelial (HOSE) cell lines. Two-way t-statistics analyses of array data identified two distinct sets of FSH-regulated genes in HOSE and in established OC cell lines established from patients (OVCA cell lines). Among the HOSE cell lines, FSH increased expression of 57% of the 312 genes and downregulated 43%. In contrast, FSH diminished expression of 92% of the 177 genes in the OVCA cell lines. All but 18 of the genes affected by FSH in HOSE cell lines were different from those altered in OVCA cell lines. Among the 18 overlapping genes, nine genes exhibited the same direction of change following FSH challenge, while the other nine showed discordance in response between HOSE and OVCA cell lines. The FSH-induced differential expression of seven out of nine genes was confirmed by real-time RT-PCR. Gene-specific antisense oligonuleotides (ODNs) were used to inhibit the expression of genes encoding GTPase activating protein (rap1GAP), neogenin, and restin in HOSE and OVCA cells. Antisense ODNs to neogenin and restin, but not an antisense ODN to rap1GAP, were effective in inhibiting OVCA cell growth, diminishing proliferating cell nuclear antigen expression, and increasing caspase 3 activities. Furthermore, the ODN to rap1GAP was further shown to be ineffective in altering migration properties of OVCA cell lines. HOSE cell proliferation was not affected by treatment with any of the antisense ODNs. In summary, gene profiling data reveal for the first time that FSH may exert different biological actions on OVCA

  11. Characterization of human follicle-stimulating hormone binding to human granulosa cells by an immunoenzymological method.

    PubMed

    Perrotin, F; Royere, D; Roussie, M; Combarnous, Y; Lansac, J; Müh, J P

    1992-04-01

    An original, nonradiometric method has been developed for studying the binding parameters of native follicle-stimulating hormone (FSH) to its specific receptors in human ovarian granulosa cells. After binding and washing of the cells, hFSH was desorbed from its receptors and quantitatively measured by a specific enzyme immunoassay (EIA) in which nonspecific binding was estimated in the presence of an excess of equine chorionic gonadotropin (eCG/PMSG), which binds to human FSH receptors but does not interfere in the hFSH EIA. This method makes use of native nonmodified hFSH molecules (in contrast to radiometric methods) and permits direct estimation of the binding parameters (Kd and total number of sites). The Kd of hFSH for its human granulosa receptors measured by this technique (4.8 +/- 0.3 x 10(-10) M) is close to that determined by other methods. However, we found a total number of specific FSH receptors per granulosa cell (1 to 6 x 10(4) higher than that reported by others by Scatchard analysis of competition dose-response curves in radioreceptor assays. The method is also sensitive enough to measure the in vivo occupancy of receptors by endogenous hFSH, which was found to be less than 6% in women undergoing hormonal treatment for in vitro fertilization. PMID:1621987

  12. Discordances between follicle stimulating hormone (FSH) and anti-Müllerian hormone (AMH) in female infertility

    PubMed Central

    2010-01-01

    Background Follicle stimulating hormone (FSH) and anti-Müllerian hormone (AMH) represent the two most frequently utilized laboratory tests in determining ovarian reserve (OR). This study determined the clinical significance of their concordance and discordance in female infertility patients. Methods We investigated 366 consecutive infertility patients (350 reached IVF), excluding women with polycystic ovarian syndrome (PCOS). They were considered to have normal FSH and AMH if values fell within age-specific (as-) 95% confidence intervals (CI), and to suffer from diminished ovarian reserve (DOR) if FSH exceeded and/or AMH fell below those. The two hormones, thus, could be concordant (Group I), both normal (IA) or abnormal (IB), show normal AMH/abnormal FSH (Group II) or normal FSH/abnormal AMH (Group III). Oocyte yields, stratified for age categories, were then studied in each group as reflection of OR. Results Oocyte yields significantly decreased from groups IA to II to III and IB. Predictive values of as-FSH/AMH patterns changed, however, at different ages. Except at very young and very old ages, normal as-AMH better predicted higher oocytes yields than normal as-FSH, though above age 42 years normal as-FSH predicts good oocyte yields even with abnormally low AMH. Under age 42 discrepancies between as- FSH and as-AMH remain similarly predictive of oocyte yields at all ages. Discussion Concordances and discordances between as-FSH and as-AMH improve OR assessments and predictability of oocyte yields in IVF. PMID:20565808

  13. Discrepancies between Antimullerian Hormone and Follicle Stimulating Hormone in Assisted Reproduction

    PubMed Central

    Cahill, David; Gordon, Uma

    2013-01-01

    Data from 107 women undergoing their first IVF/ICSI were analyzed. Relationships between antimullerian hormone (AMH) and follicle stimulating hormone (FSH) were analyzed after dividing patients into four groups according to AMH/FSH levels. Concordance was noted in 57% of women (both AMH/FSH either normal or abnormal) while 43%of women had discordant values (AMH/FSH one hormone normal and the other abnormal). Group 1 (AMH and FSH in normal range) and group 2 (normal AMH and high FSH) were younger compared to group 3 (low AMH and normal FSH) and group 4 (both AMH/FSH abnormal). Group 1 showing the best oocyte yield was compared to the remaining three groups. Groups 3 and 4 required higher dose of gonadotrophins for controlled ovarian hyperstimulation showing their low ovarian reserve. There was no difference in cycle cancellation, clinical pregnancy, and live birth/ongoing pregnancy rate in all groups. These tests are useful to predict ovarian response but whether AMH is a substantially better predictor is not yet established. PMID:24454387

  14. Development of Follicle-Stimulating Hormone Receptor Binding Probes to Image Ovarian Xenografts

    PubMed Central

    Lee, Chung-Wein; Guo, Lili; Matei, Daniela; Stantz, Keith

    2015-01-01

    The Follicle-Stimulating Hormone Receptor (FSHR) is used as an imaging biomarker for the detection of ovarian cancer (OC). FSHR is highly expressed on ovarian tumors and involved with cancer development and metastatic signaling pathways. A decapeptide specific to the FSHR extracellular domain is synthesized and conjugated to fluorescent dyes to image OC cells in vitro and tumors xenograft model in vivo. The in vitro binding curve and the average number of FSHR per cell are obtained for OVCAR-3 cells by a high resolution flow cytometer. For the decapeptide, the measured EC50 was 160 μM and the average number of receptors per cell was 1.7 × 107. The decapeptide molecular imaging probe reached a maximum tumor to muscle ratio five hours after intravenous injection and a dose-dependent plateau after 24–48 hours. These results indicate the potential application of a small molecular weight imaging probe specific to ovarian cancer through binding to FSHR. Based on these results, multimeric constructs are being developed to optimize binding to ovarian cells and tumors. PMID:26779384

  15. Follicle stimulating hormone increases spermatogonial stem cell colonization during in vitro co-culture.

    PubMed

    Narenji Sani, Reza; Tajik, Parviz; Yousefi, Mohammad Hassan; Movahedin, Mansoureh; Qasemi-Panahi, Babak; Shafiei, Shiva; Ahmadi Hamedani, Mahmood

    2013-01-01

    The complex process of spermatogenesis is regulated by various factors. Studies on spermatogonial stem cells (SCCs) have provided very important tool to improve herd genetic and different field. 0.2 to 0.3 percent of total cells of seminiferous tubules is consist of spermatogonial stem cells. To investigate and biomanipulation of these cells, proliferation and viability rate of cells should be increased in vitro, at first. Follicle stimulating hormone (FSH) has been suggested to play a determinant role in the survival of germ cells in addition to increasing spermatogonial proliferation. In this study, the in vitro effects of FSH on spermatogonial cell colony formation were investigated. Sertoli and spermatogonial cells were isolated from 3-5 months old calves. The identity of the Sertoli cells and spermatogonial stem cells were confirmed through immunocytochemistry and colony morphology, respectively. Co-cultured Sertoli and spermatogonial cells were treated with FSH in different dose of 10, 20 and 40 IU mL(-1) FSH, before colony assay. Results indicated that, FSH increased in vitro colonization of spermatogonial cells in comparison with control group. In conclusion, using FSH provided proper bovine spermatogonial stem cell culture medium for in vitro study of these cells. PMID:25593684

  16. Follicle stimulating hormone increases spermatogonial stem cell colonization during in vitro co-culture

    PubMed Central

    Narenji Sani, Reza; Tajik, Parviz; Yousefi, Mohammad Hassan; Movahedin, Mansoureh; Qasemi-Panahi, Babak; Shafiei, Shiva; Ahmadi Hamedani, Mahmood

    2013-01-01

    The complex process of spermatogenesis is regulated by various factors. Studies on spermatogonial stem cells (SCCs) have provided very important tool to improve herd genetic and different field. 0.2 to 0.3 percent of total cells of seminiferous tubules is consist of spermatogonial stem cells. To investigate and biomanipulation of these cells, proliferation and viability rate of cells should be increased in vitro, at first. Follicle stimulating hormone (FSH) has been suggested to play a determinant role in the survival of germ cells in addition to increasing spermatogonial proliferation. In this study, the in vitro effects of FSH on spermatogonial cell colony formation were investigated. Sertoli and spermatogonial cells were isolated from 3-5 months old calves. The identity of the Sertoli cells and spermatogonial stem cells were confirmed through immunocytochemistry and colony morphology, respectively. Co-cultured Sertoli and spermatogonial cells were treated with FSH in different dose of 10, 20 and 40 IU mL-1 FSH, before colony assay. Results indicated that, FSH increased in vitro colonization of spermatogonial cells in comparison with control group. In conclusion, using FSH provided proper bovine spermatogonial stem cell culture medium for in vitro study of these cells. PMID:25593684

  17. Corifollitropin alfa, a long-acting follicle-stimulating hormone agonist for the treatment of infertility.

    PubMed

    Loutradis, Dimitris; Drakakis, Petros; Vlismas, Antonis; Antsaklis, Aristidis

    2009-04-01

    Corifollitropin alfa is being developed by Schering-Plough Corp as an injectable, long-acting follicle-stimulating hormone (FSH) agonist for the treatment of infertility. A single dose of corifollitropin alfa could initiate and sustain multifollicular growth in patients undergoing controlled ovarian stimulation, such as during in vitro fertilization or intracytoplasmic sperm injection. The agent comprises an alpha-subunit, which is identical to that of FSH, and a beta-subunit, which is produced by the fusion of the C-terminal peptide from the beta-subunit of chorionic gonadotropin to the beta-subunit of FSH. Corifollitropin alfa has a longer half-life compared with FSH and thus requires less frequent dosing. The drug was well tolerated and does not appear to be associated with any serious adverse events or the formation of antibodies. The initial results from a large, phase III, double-blind clinical trial indicated that the ongoing pregnancy rate achieved with corifollitropin alfa treatment was high and similar to the rate established with daily treatment of recombinant FSH. The number of oocytes retrieved following the administration of corifollitropin alfa was slightly higher compared with the number observed with daily recombinant FSH treatment. Thus, corifollitropin alfa has the potential to serve as a viable fertility agent and to gain a place in the infertility market. PMID:19337959

  18. Different follicle stimulating hormone/luteinizing hormone ratios for ovarian stimulation.

    PubMed

    Duijkers, I J; Vemer, H M; Hollanders, J M; Willemsen, W N; Bastiaans, L A; Hamilton, C J; Thomas, C M; Borm, G F

    1993-09-01

    The aim of the present study was to investigate whether reducing the amount of luteinizing hormone (LH) in gonadotrophic preparations impairs follicular growth in in-vitro fertilization (IVF) cycles during suppression of endogenous LH levels. A selected group of 20 IVF patients was randomly divided into two groups. One group was treated with Org 31338 [follicle stimulating hormone (FSH)/LH 3:1], the other group with Metrodin (purified FSH), both during pituitary down-regulation with buserelin. A fixed daily dose of 150 IU FSH i.m. was given. Serum concentrations of FSH, LH, oestradiol and progesterone were determined frequently and serial ultrasound examinations were performed. Multiple follicular growth with concomitant rise of oestradiol levels was observed in all cycles. The duration of the stimulation phase was shorter in the group treated with Org 31338 than in the group treated with Metrodin. The number of follicles and oocytes and the fertilization rate was larger and the mean embryo quality was higher in the Org 31338 group, but the differences did not reach statistical significance. No significant differences were found in hormonal values. In women with normal endocrine profiles, lowering of the LH activity in gonadotrophic preparations during gonadotrophin-releasing hormone agonist treatment results in adequate ovarian stimulation. However, a preparation with some LH needed a shorter stimulation than a purified FSH preparation. Whether the other beneficial effects of Org 31338 also occur in a larger population needs further investigation. PMID:8253923

  19. Cadmium, follicle-stimulating hormone, and effects on bone in women age 42-60 years, NHANES III

    SciTech Connect

    Gallagher, Carolyn M.; Moonga, Baljit S.; Kovach, John S.

    2010-01-15

    Background: Increased body burden of environmental cadmium has been associated with greater risk of decreased bone mineral density (BMD) and osteoporosis in middle-aged and older women, and an inverse relationship has been reported between follicle-stimulating hormone (FSH) and BMD in middle-aged women; however, the relationships between cadmium and FSH are uncertain, and the associations of each with bone loss have not been analyzed in a single population. Objectives: The objective of this study was to evaluate the associations between creatinine-adjusted urinary cadmium (UCd) and FSH levels, and the associations between UCd and FSH with BMD and osteoporosis, in postmenopausal and perimenopausal women aged 42-60 years. Methods: Data were obtained from the Third National Health Examination and Nutrition Survey, 1988-1994 (NHANES III). Outcomes evaluated were serum FSH levels, femoral bone mineral density measured by dual energy X-ray absorptiometry, and osteoporosis indicated by femoral BMD cutoffs based on the international standard. Urinary cadmium levels were analyzed for association with these outcomes, and FSH levels analyzed for association with bone effects, using multiple regression. Subset analysis was conducted by a dichotomous measure of body mass index (BMI) to proxy higher and lower adipose-synthesized estrogen effects. Results: UCd was associated with increased serum FSH in perimenopausal women with high BMI (n=642; {beta}=0.45; p{<=}0.05; R{sup 2}=0.35) and low BMI (n=408; {beta}=0.61; p{<=}0.01; R{sup 2}=0.34). Among perimenopausal women with high BMI, BMD was inversely related to UCd ({beta}=-0.04; p{<=}0.05) and FSH ({beta}=-0.03; p{<=}0.05). In postmenopausal women with low BMI, an incremental increase in FSH was associated with 2.78 greater odds for osteoporosis (109 with and 706 without) (OR=2.78; 95% CI=1.43, 5.42; p{<=}0.01). Conclusion: Long-term cadmium exposure at environmental levels is associated with increased serum FSH, and both FSH

  20. Targeting of follicle stimulating hormone peptide-conjugated dendrimers to ovarian cancer cells

    NASA Astrophysics Data System (ADS)

    Modi, Dimple A.; Sunoqrot, Suhair; Bugno, Jason; Lantvit, Daniel D.; Hong, Seungpyo; Burdette, Joanna E.

    2014-02-01

    Ovarian cancer is the most lethal gynecological malignancy. Current treatment modalities include a combination of surgery and chemotherapy, which often lead to loss of fertility in premenopausal women and a myriad of systemic side effects. To address these issues, we have designed poly(amidoamine) (PAMAM) dendrimers to selectively target the follicle stimulating hormone receptor (FSHR), which is overexpressed by tumorigenic ovarian cancer cells but not by immature primordial follicles and other non-tumorigenic cells. Fluorescein-labeled generation 5 (G5) PAMAM dendrimers were conjugated with the binding peptide domain of FSH (FSH33) that has a high affinity to FSHR. The targeted dendrimers exhibited high receptor selectivity to FSHR-expressing OVCAR-3 cells, resulting in significant uptake and downregulation of an anti-apoptotic protein survivin, while showing minimal interactions with SKOV-3 cells that do not express FSHR. The selectivity of the FSH33-targeted dendrimers was further validated in 3D organ cultures of normal mouse ovaries. Immunostaining of the conjugates revealed their selective binding and uptake by ovarian surface epithelium (OSE) cells that express FSHR, while sparing the immature primordial follicles. In addition, an in vivo study monitoring tissue accumulation following a single intraperitoneal (i.p.) injection of the conjugates showed significantly higher accumulation of FSH33-targeted dendrimers in the ovary and oviduct compared to the non-targeted conjugates. These proof-of-concept findings highlight the potential of these FSH33-targeted dendrimers to serve as a delivery platform for anti-ovarian cancer drugs, while reducing their systemic side effects by preventing nonspecific uptake by the primordial follicles.Ovarian cancer is the most lethal gynecological malignancy. Current treatment modalities include a combination of surgery and chemotherapy, which often lead to loss of fertility in premenopausal women and a myriad of systemic side

  1. Molecular characterization and quantification of the follicle-stimulating hormone receptor in turbot (Scophthalmus maximus).

    PubMed

    Jia, Yudong; Sun, Ai; Meng, Zhen; Liu, Baoliang; Lei, Jilin

    2016-02-01

    Molecular cloning, characterization, and functional analysis of follicle-stimulating hormone receptor (FSHR) in female turbot (Scophthalmus maximus) were evaluated. Results showed that the full-length FSHR cDNA was 3824 bp long and contained a 2202 bp open reading frame that encoded a mature protein of 733 amino acids (aa) and a signal peptide of 18 aa. Multiple sequence analyses showed that turbot FSHR has high homology with the corresponding genes of other teleosts and significant homology with that of Hippoglossus hippoglossus. Turbot FSHR has the typical structural architecture of glycoprotein hormone receptors consisting of a large N-terminal extracellular domain, seven transmembrane domains and short C-terminal intracellular domain. FSHR mRNA was found to be abundant in the ovaries, but deficient in eyes, intestine, brain, muscle, gills, spleen, stomach, heart and kidney. Furthermore, FSHR mRNA was found to increase gradually from pre-vitellogenesis to migratory nucleus stages, with the highest values observed during the late vitellogenesis stage of the reproductive cycle. However, FSHR mRNA was found to decrease dramatically during the atresia stage. Meanwhile, functional analysis with HEK293T cells continual expressing FSHR demonstrated that FSHR was specifically stimulated by ovine FSH, but not ovine LH. These results indicate that turbot FSHR is mainly involved in the stimulation of vitellogenesis, regulation of oocyte maturation as well as promotion of ovarian development via specific ligand binding. These findings open doors to further investigation of physiological functions of FSHR, which will be valuable for fish reproduction and broodstock management. PMID:26358315

  2. Insulin Receptor Substrate 1, the Hub Linking Follicle-stimulating Hormone to Phosphatidylinositol 3-Kinase Activation.

    PubMed

    Law, Nathan C; Hunzicker-Dunn, Mary E

    2016-02-26

    The ubiquitous phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many cellular functions. However, the mechanism by which G protein-coupled receptors (GPCRs) signal to activate PI3K is poorly understood. We have used ovarian granulosa cells as a model to investigate this pathway, based on evidence that the GPCR agonist follicle-stimulating hormone (FSH) promotes the protein kinase A (PKA)-dependent phosphorylation of insulin receptor substrate 1 (IRS1) on tyrosine residues that activate PI3K. We report that in the absence of FSH, granulosa cells secrete a subthreshold concentration of insulin-like growth factor-1 (IGF-1) that primes the IGF-1 receptor (IGF-1R) but fails to promote tyrosine phosphorylation of IRS1. FSH via PKA acts to sensitize IRS1 to the tyrosine kinase activity of the IGF-1R by activating protein phosphatase 1 (PP1) to promote dephosphorylation of inhibitory Ser/Thr residues on IRS1, including Ser(789). Knockdown of PP1β blocks the ability of FSH to activate PI3K in the presence of endogenous IGF-1. Activation of PI3K thus requires both PKA-mediated relief of IRS1 inhibition and IGF-1R-dependent tyrosine phosphorylation of IRS1. Treatment with FSH and increasing concentrations of exogenous IGF-1 triggers synergistic IRS1 tyrosine phosphorylation at PI3K-activating residues that persists downstream through protein kinase B (AKT) and FOXO1 (forkhead box protein O1) to drive synergistic expression of genes that underlies follicle maturation. Based on the ability of GPCR agonists to synergize with IGFs to enhance gene expression in other cell types, PP1 activation to relieve IRS1 inhibition may be a more general mechanism by which GPCRs act with the IGF-1R to activate PI3K/AKT. PMID:26702053

  3. Modulation of cultured porcine granulosa cell responsiveness to follicle stimulating hormone and epidermal growth factor

    SciTech Connect

    Buck, P.A.

    1986-01-01

    Ovarian follicular development is dependent upon the coordinated growth and differentiation of the granulosa cells which line the follicle. Follicle stimulating hormone (FSH) induces granulosa cell differentiation both in vivo and in vitro. Epidermal growth factor (EGF) stimulates granulosa cell proliferation in vitro. The interaction of these two effectors upon selected parameters of growth and differentiation was examined in monolayer cultures of porcine granulose cells. Analysis of the EGF receptor by /sup 125/I-EGF binding revealed that the receptor was of high affinity with an apparent dissociation constant of 4-6 x 10/sup -10/ M. The average number of receptors per cell varied with the state of differentiation both in vivo and in vitro; highly differentiated cells bound two-fold less /sup 125/I-EGF and this effect was at least partially induced by FSH in vitro. EGF receptor function was examined by assessing EGF effects on cell number and /sup 3/H-thymidine incorporation. EGF stimulated thymidine incorporation in both serum-free and serum-supplemented culture, but only in serum-supplemented conditions was cell number increased. EGF receptor function was inversely related to the state of differentiation and was attenuated by FSH. The FSH receptor was examined by /sup 125/I-FSH binding. EGF increased FSH receptor number, and lowered the affinity of the receptor. The function of these receptors was assessed by /sup 125/I-hCG binding and progesterone radioimmunoassay. If EGF was present continuously in the cultures. FSH receptor function was attenuated regardless of FSH receptor number. A preliminary effort to examine the mechanism of this interaction was performed by analyzing hormonally controlled protein synthesis with /sup 35/S-methionine labeling, SDS polyacrylamide gel electrophoresis and fluorography. FSH promoted the expression of a 27,000 dalton protein. This effect was attenuated by EGF.

  4. Follicle-Stimulating Hormone Increases the Risk of Postmenopausal Osteoporosis by Stimulating Osteoclast Differentiation

    PubMed Central

    Yu, Chunxiao; Zhang, Xu; Zhang, Haiqing; Guan, Qingbo; Zhao, Jiajun; Xu, Jin

    2015-01-01

    Objective The objectives of this study were to observe the changes in follicle-stimulating hormone (FSH) and bone mineral density (BMD) in postmenopausal women, to research the relationship between FSH and postmenopausal osteoporosis, and to observe the effects of FSH on osteoclast differentiation in RAW264.7 cells. Methods We analyzed 248 postmenopausal women with normal bone metabolism. A radioimmunoassay (RIA) was used to detect serum FSH, luteinizing hormone (LH), and estradiol (E2). Dual-energy X-ray absorptiometry was used to measure forearm BMD. Then, we analyzed the age-related changes in serum FSH, LH and E2. Additionally, FSH serum concentrations were compared between a group of postmenopausal women with osteoporosis and a control group. Osteoclasts were induced from RAW264.7 cells in vitro by receptor activator of nuclear factor kappa B ligand (RANKL), and these cells were treated with 0, 5, 10, and 20 ng/ml FSH. After the osteoclasts matured, tartrate-resistant acid phosphatase (TRAP) staining was used to identify osteoclasts, and the mRNA expression levels of genes involved in osteoclastic phenotypes and function, such as receptor activator of NF-κB (Rank), Trap, matrix metalloproteinase-9 (Mmp-9) and Cathepsin K, were detected in different groups using real-time PCR (polymerase chain reaction). Results 1. FSH serum concentrations in postmenopausal women with osteoporosis increased notably compared with the control group. 2. RANKL induced RAW264.7 cell differentiation into mature osteoclasts in vitro. 3. FSH increased mRNA expression of genes involved in osteoclastic phenotypes and function, such as Rank, Trap, Mmp-9 and Cathepsin K, in a dose-dependent manner. Conclusions The circulating concentration of FSH may play an important role in the acceleration of bone loss in postmenopausal women. FSH increases osteoclastogenesis in vitro. PMID:26241313

  5. Pre-diagnostic circulating follicle stimulating hormone (FSH) concentrations and ovarian cancer risk

    PubMed Central

    McSorley, MA; Alberg, AJ; Allen, DS; Allen, NE; Brinton, LA; Dorgan, JF; Kaaks, R; Rinaldi, S; Helzlsouer, KJ

    2009-01-01

    Gonadotropins have been indicted in ovarian carcinogenesis but direct evidence has been limited and inconsistent. The aim of this study was to determine the association between pre-diagnostic levels of follicle stimulating hormone (FSH) and subsequent development of invasive epithelial ovarian cancer. A nested case-control study was conducted using cases and controls drawn from three cohorts: CLUE I and CLUE II of Washington County, MD, and the Island of Guernsey Study, UK. In total, 67 incident invasive epithelial ovarian cancer cases were each matched to one to two controls on age, menopausal status, time since last menstrual period, current hormone use, and other relevant factors. FSH concentrations were classified into ranked thirds of low, medium, or high based on the distribution among controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH concentrations. Results of the analysis showed that ovarian cancer risk decreased with higher FSH concentrations (p-trend =0.005). Compared to the lowest third of FSH concentrations, the odds ratio among those in the middle and highest thirds were 0.45 (95% Confidence Interval (CI) 0.20– 1.00) and 0.26 (95% CI 0.10–0.70), respectively. Associations persisted after excluding cases diagnosed within five years of follow-up. In conclusion, a reduction in subsequent risk of invasive epithelial ovarian cancer was observed among women with higher circulating FSH concentrations. These findings contradict the hypothesized role of FSH as a risk factor in ovarian carcinogenesis. PMID:19444906

  6. Studies on the structure of the follicle-stimulating hormone receptor using photoaffinity labeling procedures

    SciTech Connect

    Smith, R.A.

    1985-01-01

    The general objective of this project was to study the structure of the follicle stimulating hormone (FSH) receptor using affinity labeling methods. A low density fraction derived from homogenates of bovine testis was found to contain high affinity and low capacity receptors specific for FSH. Electron microscopic examination of the fraction revealed structure resembling multilamellar membranous vesicles (MV). For photoaffinity labeling of the FSH receptors in MV, an azidobenzoyl-/sup 125/I-analog of human FSH was prepared (/sup 125/I-AB-hFSH) and binding of specific FSH receptors was studied. /sup 125/I-AB-hFSH binding of receptors was inhibited in a dose dependent manner by unlabeled hFSH, and binding was not prevented by structurally-related human chorionic gonadotropin (hCG). The formation of photocrosslinked protein of relative molecular mass (M/sub r/) 54,000, 64,000, 76,000, 84,000, 97,000 and 116,000 was found to be inhibited by unlabeled hFSH in a dose related manner, and to be dependent on photoactivation of the FSH derivative. The interpretation of the photoaffinity labeling experiments was that three proteins associated with the FSH receptor were photoaffinity labeled. Analysis by indirect means suggested that the three proteins were assembled to form oligomeric complexes, and based on the intensities and composition of the oligomeric species, spatial relationships of the polypeptides with respect to each other on the membrane surface were deduced. The results of photoaffinity labeling suggest the FSH receptor is composed of three subunits of M/sub r/ 38,000, 48,000, and 81,000 and exists in the membrane in part as a M/sub r/ 330,000 dimer.

  7. Rescue from dominant follicle atresia by follicle-stimulating hormone in mice.

    PubMed

    Zhou, X L; Teng, Y; Cao, R; Fu, H; Xiong, K; Sun, W X; Zhu, C C; Huang, X J; Xiao, P; Liu, H L

    2013-01-01

    We investigated the effects of follicle-stimulating hormone (FSH) on atresia of the dominant follicle and changes in relevant apoptosis genes in granulosa cells of dominant follicles regulated by FSH in vivo. Four-week-old mice were administered FSH by intraperitoneal injection to induce follicular maturation. Granulosa cells of dominant follicles were collected at 48, 72, and 96 h after the first FSH injection. Phosphate-buffered saline was injected as a control. The mRNA levels of relevant granulosa cell apoptosis genes were examined by real-time quantitative polymerase chain reaction, and apoptosis of granulosa cells in dominant ovarian follicles was determined by the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Apoptosis in granulosa cells of dominant follicles was almost TUNEL-negative at 48, 72-66, 72, and 96-90 h after the first FSH injection, but granulosa cell apoptosis in dominant follicles was clearly detected at 96, 102, and 102-96 h by TUNEL. The BIM, caspase-3, and caspase-9 mRNA expression levels were significantly lower after FSH treatment at 72-66 and 96-90 h, compared with that at 72 and 96 h (P < 0.05). Caspase-8 and FasL mRNA expressions did not respond to FSH. FSH rescued granulosa cells from apoptosis when the relevant apoptosis genes were upregulated in early atretic follicles. FSH did not rescue granulosa cells from apoptosis if the DNA was cut into fragments by endonucleases. Thus, the rescue by FSH of granulosa cells from apoptosis and dominant follicle atresia may be accomplished by inhibition of apoptosis in mitochondria. PMID:24065650

  8. Leptin concentrations in the follicular phase of spontaneous cycles and cycles superovulated with follicle stimulating hormone.

    PubMed

    Messinis, I E; Milingos, S; Zikopoulos, K; Kollios, G; Seferiadis, K; Lolis, D

    1998-05-01

    It has been reported that oestradiol may play a role in the production of leptin from adipocytes. To investigate this relationship further, nine normally ovulating women were studied during two menstrual cycles, i.e. an untreated spontaneous cycle and a cycle treated with follicle stimulating hormone (FSH) from cycle day 2 until the day of human chorionic gonadotrophin (HCG) injection. Serum leptin values on cycle day 2 did not differ significantly between the spontaneous and the FSH cycles. In the spontaneous cycles, leptin values declined gradually and significantly up to day 7 and then increased progressively up to the day of luteinizing hormone (LH) surge onset, at which point they achieved the highest values. In the FSH cycles, serum leptin values increased gradually and significantly up to day 6, remaining stable thereafter, and were in the midfollicular phase significantly higher than in the spontaneous cycles. Significant positive correlations were found between mean values of leptin and mean values of oestradiol during the second half of the follicular phase in the spontaneous cycles and during the first half in the FSH cycles. A significant negative correlation was found between these two parameters in the spontaneous cycles during the first half of the follicular phase. Serum leptin levels were significantly higher in the midluteal than in the follicular phase in both cycles. These results demonstrate for the first time significant changes in leptin values during the follicular phase of the human menstrual cycle and a significant increase during superovulation induction with FSH. It is suggested that oestradiol may be involved in the regulation of leptin production in women. PMID:9647537

  9. The frequency of follicle stimulating hormone receptor gene polymorphisms in Iranian infertile men with azoospermia

    PubMed Central

    Gharesi-Fard, Behrouz; Ghasemi, Zahra; Shakeri, Saeed; Behdin, Shabnam; Aghaei, Fatemeh; Malek-Hosseini, Zahra

    2015-01-01

    Background: Azoospermia is the medical condition of a man not having any measurable level of sperm in his semen. Follicle stimulating hormone (FSH) is a member of the glycoprotein hormone family that plays an important role in human reproduction because of its essential role in normal spermatogenesis. Various Single Nucleotide Polymorphisms (SNPs) have been reported within FSH receptor (FSHR) gene that may affect the receptor function. Objective: The present study aimed to investigate the correlation between two FSHR SNPs at positions A919G, A2039G, and susceptibility to azoospermia in a group of Iranian azoospermic men. The association between FSH levels within the sera and A919G and A2039G alleles and genotypes were also investigated. Materials and Methods: This case control study was performed on 212 men with azoospermia (126 non-obstructive and 86 obstructive) and 200 healthy Iranian men. Two FSHR gene SNPs were genotyped using PCR-RFLP method. The relationship between FSH levels within the sera and A919G and A2039G alleles and genotypes were also investigated. Results: Statistical analysis indicated that at A919G position, AA genotype and A allele were more frequent in obstructive azoospermia cases compared to non-obstructive or normal men (p=0.001). Regarding A2039G polymorphisms, no significant difference was observed between both azoospermia groups and the controls. The mean level of serum FSH was higher in the non-obstructive men compared to the obstructive patients (23.8 versus 13.8, respectively, p= 0.04). Conclusion: The results of the present study indicated that the genetic polymorphisms in the FSHR gene might increase the susceptibility to azoospermia in Iranian men. PMID:26730241

  10. Differential effects of follicle-stimulating and luteinizing hormones on testosterone production by mouse testes.

    PubMed

    Dalterio, S L; Suter, D E; Schwartz, N B; Mayfield, D; Rettori, V B

    1986-07-01

    In adult mice, direct intratesticular injection of ovine follicle-stimulating hormone (o-FSH-13; AFP 2846-C, from NIAMDD, less than 1% LH contamination) at 10, 100 or 1000 ng significantly elevated concentrations of testosterone (T) within the testis. These effects were rapid, with peak values attained by 15 min, and transient, with return to values comparable to that in the contralateral, saline-injected testis within 90 min. Intratesticular injection of FSH (1 microgram) significantly increased testicular T levels in 15- and 60-day old mice. This contrasted with the effects of intratesticular administration of human chorionic gonadotropin (hCG), which stimulated T production significantly at 30 days of age through adulthood. In adult mice, the equivalent LH to the possible contamination in the FSH preparation (1 ng) had no effect. Intratesticular injection of 10 ng LH produced comparable stimulation to that by 100 ng FSH (approximately 7-fold). Systemic pre-treatment with a charcoal-treated porcine follicular fluid (PFF) extract for 2 days reduced plasma FSH levels [86 +/- 17 (5) vs 700 +/- 8 (6); P less than 0.05], but had no effect on plasma LH. Twenty-four hours after the last treatment, the response to intratesticular injection of hCG (2.5 mIU), FSH (100 ng) or LH (10 ng) was also significantly attenuated in these mice. Intratesticular injection of PFF had no direct effect on testicular T levels. In vitro T production in the presence of hCG, LH or FSH were differentially affected by the concentrations of calcium (Ca2+) or magnesium (Mg2+) in the incubation media. The stimulatory effects of FSH were apparent at significantly lower levels of Ca2+ or Mg2+, than were those of LH or hCG. The results of these studies indicate that FSH is capable of stimulating testicular T production. Furthermore, the responsiveness to FSH is qualitatively different than that to LH/hCG in terms of the age pattern, as well as the dependence on Ca2+ or Mg2+. In addition, plasma FSH

  11. Biopotency in vitro and metabolic clearance rates of five pituitary preparations of follicle stimulating hormone.

    PubMed

    Phillips, D J; Hudson, N L; Lun, S; Condell, L A; McNatty, K P

    1993-01-01

    Five pituitary preparations of follicle stimulating hormone (FSH), namely NIDDK-oFSH-17, Bioscan oFSH, Ovagen, Folltropin-V and F.S.H.-P., were examined for biological activity in terms of their potency in an in vitro bioassay, receptor assay and heterologous radioimmunoassay and in terms of their metabolic clearance rates. In the three assays, Bioscan oFSH was the most potent (P < 0.05) (3- to 5-fold the potency of NIDDK-oFSH-17), with Ovagen being 25-50% the potency of the NIDDK standard (P < 0.05). Folltropin-V and F.S.H.-P. had the lowest potencies in all three assays. For each preparation, the ratio of activities between the assays was not consistent, suggesting that the preparations behaved differently in each assay. In 9 of 10 cases, potency estimates in the heterologous radioimmunoassay were greater than those in the in vitro bioassay or receptor assay. Polyacrylamide gel electrophoresis of the preparations showed banding consistent with the molecular weight of FSH, but also indicated that the preparations were contaminated with other proteins to varying extents. The half-lives of these preparations when injected into the bloodstream of mature female mice were 28.0, 8.6, 13.4, 11.6 and 17.4 min for NIDDK-oFSH-17, Bioscan oFSH, Ovagen, Folltropin-V and F.S.H.-P. respectively. The slopes of the decay rates were significantly different from each other (P < 0.05) except between Ovagen and Folltropin-V. The results of these studies show that a number of widely available FSH preparations have differing biopotencies. Moreover, the biopotency of a preparation in vitro is not related to its metabolic clearance rate, and not all FSH preparations behave identically in different assays. Measures of biopotency in vitro combined with those of metabolic clearance rate may provide useful information on the properties of FSH preparations used for research purposes and for superovulation of farmed livestock. PMID:8265802

  12. Serum follicle-stimulating hormone levels predict time to development of castration-resistant prostate cancer

    PubMed Central

    Hoare, Dylan; Skinner, Thomas A.A.; Black, Angela; Robert Siemens, D.

    2015-01-01

    Introduction: Treatment of advancing prostate cancer focuses on blocking the activation of the androgen receptor with resultant prolonged perturbation of the hypothalamic-pituitary-gonadal axis. Androgen deprivation therapy (ADT) is marked, however, by eventual progression to castration- resistant prostate cancer (CRPC). Emerging evidence has postulated that follicle-stimulating hormone (FSH) may lead to proliferative and mutagenic responses of prostate cancer. We investigated the association of serum FSH and time to castration resistance. Methods: This was a single-centre retrospective study assessing serum FSH levels of patients undergoing ADT for advancing prostate cancer. The primary outcome was time of ADT initiation to the development of CRPC. For each patient on treatment and with castrate levels of testosterone, the maximum FSH value between ADT commencement and CRPC was identified and recorded. FSH was analyzed as a continuous and categorical variable. Cox multivariate regression in a step-wise fashion was used to explore the association between FSH levels and time to CRPC. Results: From a database of 323 prostate cancer patients actively managed with ADT, 103 men had a documented FSH value while castrate, with 45 men progressing to CRPC. The mean ± standard deviation maximum FSH value of these patients was 6.66 ± 4.22 mIU/mL (range: 1.5–28.1). The mean duration from ADT commencement to CRPC was 3.03 ± 0.34 years (range: 0.36–9.71). Univariate analysis suggested a trend of a negative correlation between FSH values and time to castrate resistance. A FSH value of less than or equal to the lowest tertile (4.8 mIU/mL) was associated with a longer time to CRPC (hazard ratio 0.46; p = 0.006). In the Cox regression analysis, elevated FSH was associated with a shorter duration time to CRPC (p = 0.03). Conclusions: This retrospective, single-centre study would suggest there may be an association between serum FSH levels and time to CRPC for men treated

  13. Metabolism of testosterone by human granulosa cells in culture: influence of follicle-stimulating hormone and luteinizing hormone

    SciTech Connect

    Moon, Y.S.; Duleba, A.; Leung, P.C.; Gomel, V.

    1982-03-15

    Human granulosa cells were isolated from follicles (8 to 15 mm) and cultivated for 24 hours in the presence or absence of follicle-stimulating hormone (NIH-FSH-HS-1, 1 microgram/ml) and luteinizing hormone (NIAMDD-hLH-1, 1 microgram/ml). Testosterone -4-14C was added subsequently to all cultures for 4-, 6-, and 24-hour periods. Of the seven metabolites of testosterone studied, 17 beta-estradiol (E2) and estrone (E1) were the major products. In all patients, levels of E2 were three to ten times higher than those of E1. Production of E2, but not E1, was stimulated by either follicle-stimulating hormone (FSH) or luteinizing hormone (LH). The cells of the largest follicle (15 mm) showed greater response to LH than to FSH. Production of the other C19 and C18 metabolites was very low or negligible. These results further suggest that FSH regulates the aromatization of testosterone in human granulosa cells, and that LH may have the same effect on the matured follicle during the preovulatory period.

  14. Effect of inter-cycle interval on oocyte production in humans in the presence of the weak androgen DHEA and follicle stimulating hormone: a case-control study

    PubMed Central

    2014-01-01

    Background In various animal models androgens have been demonstrated to enhance follicle stimulating hormone (FSH) activity on granulosa cells during small growing follicle stages. To assess whether similar synergism may also exist in humans we investigated women on androgen (dehydroepiandrosterone, DHEA) supplementation with varying concomitant FSH exposure. Methods In a case controlled cohort study we determine if time interval between IVF cycles of IVF treatment with FSH had an effect on ovarian response to ovulation induction in women supplemented with DHEA. Among 85 women with known low functional ovarian reserve (LFOR), supplemented with DHEA, and undergoing at least 3 consecutive IVF cycles, 68 demonstrated short (<120 days) intervals between repeated cycles (Group 1) and were, therefore, considered to have consistent FSH exposure. In contrast 17 women (Group 2) demonstrated long (> = 120 days) intervals between repeated cycles and, therefore, were considered to demonstrate inconsistent FSH exposure. Trends in oocyte yields were compared between these groups, utilizing mixed model repeated measures ANOVA, adjusted for initial age and FSH dose. Results Only women in Group I demonstrated a linear increase in oocyte yields across their three cycles of treatments (F = 7.92; df 1, 68.6; p = 0.017). Moreover, the analysis revealed a significant interaction between the two patient groups and cycle number for retrieved oocytes (F = 6.32, df = 2, 85.9, p = 0.003). Conclusions This study offers preliminary confirmatory evidence that repeated short interval exposure to androgens in combination with FSH improves human FOR. A higher level of evidence will require prospectively randomized studies. PMID:25048047

  15. Neural alterations from lead exposure in zebrafish.

    PubMed

    Roy, Nicole M; DeWolf, Sarah; Schutt, Alexius; Wright, Ashia; Steele, Latina

    2014-01-01

    Lead was used extensively as a gas additive and pesticide, in paints, batteries, lead shot, pipes, canning and toy manufacturing. Although uses of lead have been restricted, lead persists in our environment especially in older homes, and generally in soil and water. Although extensive studies have determined that fetal and childhood exposures to lead have been associated with childhood and adolescent memory impairments and learning disabilities, there are limited studies investigating early neural and morphological effects that may lead to these behavioral and learning abnormalities. Here we utilize the zebrafish vertebrate model system to study early effects of lead exposure on the brain. We treat embryos with 0.2mM lead for 24, 48 and 72 h and analyze neural structures through live imagery and transgenic approaches. We find structural abnormalities in the hindbrain region as well as changes in branchiomotor neuron development and altered neural vasculature. Additionally, we find areas of increased apoptosis. We conclude that lead is developmentally neurotoxic to a specific region of the brain, the hindbrain and is toxic to branchiomotor neurons residing in rhombomeres 2 through 7 of the hindbrain and hindbrain central artery vasculature. PMID:25242292

  16. Daily Exposure to Dust Alters Innate Immunity

    PubMed Central

    Sahlander, Karin; Larsson, Kjell; Palmberg, Lena

    2012-01-01

    Pig farmers are exposed to organic material in pig barns on a daily basis and have signs of an ongoing chronic airway inflammation and increased prevalence of chronic inflammatory airway diseases, predominantly chronic bronchitis. Interestingly, the inflammatory response to acute exposure to organic dust is attenuated in farmers. The aim of the study was to closer characterize innate immunity features in blood and airways in farmers and in naïve, non-exposed, controls. The expression of pattern recognition receptors (TLR2, TLR4 and CD14) whose ligands are abundant in pig barn dust and adhesion proteins (CD11b, CD62L and CD162L) on blood and sputum neutrophils in pig farmers and soluble TLR2 and CD14 (sTLR2 and sCD14) in blood and sputum were assessed in pig farmers and previously unexposed controls. The release of pro-inflammatory cytokines from blood cells stimulated with LPS ex vivo was measured in the absence and presence of anti-ST2. We also examined, in a separate study population, serum levels of soluble ST2 (sST2), before and after exposure in a pig barn and a bronchial LPS challenge. Farmers had signs of ongoing chronic inflammation with increased number of blood monocytes, and decreased expression of CD62L and CD162 on blood neutrophils. Farmers also had lower levels of sTLR2 and sCD14 in sputum and reduced expression of CD14 on sputum neutrophils than controls. Exposure to organic dust and LPS induced increase of serum sST2 in controls but not in farmers. In conclusion, farmers have signs of local and systemic inflammation associated with altered innate immunity characteristics. PMID:22355383

  17. Exposure to Environmental Ozone Alters Semen Quality

    PubMed Central

    Sokol, Rebecca Z.; Kraft, Peter; Fowler, Ian M.; Mamet, Rizvan; Kim, Elizabeth; Berhane, Kiros T.

    2006-01-01

    Idiopathic male infertility may be due to exposure to environmental toxicants that alter spermatogenesis or sperm function. We studied the relationship between air pollutant levels and semen quality over a 2-year period in Los Angeles, California, by analyzing repeated semen samples collected by sperm donors. Semen analysis data derived from 5,134 semen samples from a sperm donor bank were correlated with air pollutant levels (ozone, nitrogen dioxide, carbon monoxide, and particulate matter < 10 μm in aerodynamic diameter) measured 0–9, 10–14, and 70–90 days before semen collection dates in Los Angeles between January 1996 and December 1998. A linear mixed-effects model was used to model average sperm concentration and total motile sperm count for the donation from each subject. Changes were analyzed in relationship to biologically relevant time points during spermatogenesis, 0–9, 10–14, and 70–90 days before the day of semen collection. We estimated temperature and seasonality effects after adjusting for a base model, which included donor’s date of birth and age at donation. Forty-eight donors from Los Angeles were included as subjects. Donors were included if they collected repeated semen samples over a 12-month period between January 1996 and December 1998. There was a significant negative correlation between ozone levels at 0–9, 10–14, and 70–90 days before donation and average sperm concentration, which was maintained after correction for donor’s birth date, age at donation, temperature, and seasonality (p < 0.01). No other pollutant measures were significantly associated with sperm quality outcomes. Exposure to ambient ozone levels adversely affects semen quality. PMID:16507458

  18. Polymorphism of follicle stimulating hormone beta (FSHβ) subunit gene and its association with litter traits in giant panda.

    PubMed

    Huang, Xiaoyu; Li, Desheng; Wang, Jiwen; Huang, Yan; Han, Chunchun; Zhang, Guiquan; Huang, Zhi; Wu, Honglin; Wei, Ming; Wang, Guosong; Hu, Haiping; Deng, Tao; He, Tao; Zhou, Yingming; Song, Shixian; Luo, Bo; Zhang, Heming

    2013-11-01

    The different SSCP patterns of the follicle stimulating hormone beta (FSHβ) gene amplified by three pairs of primers were sequenced. Comparisons among the three nucleotide sequences of three genotypes indicated that three base substitutions (A213T, A91G, and A89C) were detected in FSHβ gene, which A213T substitution led to one amino acids mutation (Lys > Met), and the other two substitutions were synonymous mutations. The AA, AB and BB genotypes patterns obtained by FSHβ primer1 had evident relation with the litter traits, but the SSCP genotypes patterns obtained by FSHβ primer2 and primer3 had no evident relation with the litter traits in giant panda. The giant panda with AA and AB genotype had the largest litter size and multiparity rate compared with the BB genotypes (P < 0.05). We speculated that the giant pandas with the A allele have better litter traits than those with the B allele. PMID:24057246

  19. Luteinizing hormone and follicle stimulating hormone synergy: A review of role in controlled ovarian hyper-stimulation

    PubMed Central

    Raju, Gottumukkala Achyuta Rama; Chavan, Rahul; Deenadayal, Mamata; Gunasheela, Devika; Gutgutia, Rohit; Haripriya, Geetha; Govindarajan, Mirudhubashini; Patel, Nayana Hitesh; Patki, Ameet Shashikant

    2013-01-01

    Luteinizing hormone (LH) in synergy with follicle stimulating hormone (FSH) stimulates normal follicular growth and ovulation. FSH is frequently used in assisted reproductive technology (ART). Recent studies have facilitated better understanding on the complementary role of the LH to FSH in regulation of the follicle; however, role of LH in stimulation of follicle, optimal dosage of LH in stimulation and its importance in advanced aged patients has been a topic of discussion among medical fraternity. Though the administration of exogenous LH with FSH is obligatory for controlled ovarian stimulation in patients with hypogonadotropic hypogonadism, there is still a paucity of information of its usage in other patient population. In this review we looked in to the multiple roles that LH plays complementary to FSH to better understand the LH requirement in patients undergoing ART. PMID:24672160

  20. Follicle-stimulating hormone receptor (FSHR) alternative skipping of exon 2 or 3 affects ovarian response to FSH

    PubMed Central

    Karakaya, Cengiz; Guzeloglu-Kayisli, Ozlem; Hobbs, Rebecca J.; Gerasimova, Tsilya; Uyar, Asli; Erdem, Mehmet; Oktem, Mesut; Erdem, Ahmet; Gumuslu, Seyhan; Ercan, Deniz; Sakkas, Denny; Comizzoli, Pierre; Seli, Emre; Lalioti, Maria D.

    2014-01-01

    Genes critical for fertility are highly conserved in mammals. Interspecies DNA sequence variation, resulting in amino acid substitutions and post-transcriptional modifications, including alternative splicing, are a result of evolution and speciation. The mammalian follicle-stimulating hormone receptor (FSHR) gene encodes distinct species-specific forms by alternative splicing. Skipping of exon 2 of the human FSHR was reported in women of North American origin and correlated with low response to ovarian stimulation with exogenous follicle-stimulating hormone (FSH). To determine whether this variant correlated with low response in women of different genetic backgrounds, we performed a blinded retrospective observational study in a Turkish cohort. Ovarian response was determined as low, intermediate or high according to retrieved oocyte numbers after classifying patients in four age groups (<35, 35–37, 38–40, >40). Cumulus cells collected from 96 women undergoing IVF/ICSI following controlled ovarian hyperstimulation revealed four alternatively spliced FSHR products in seven patients (8%): exon 2 deletion in four patients; exon 3 and exons 2 + 3 deletion in one patient each, and a retention of an intron 1 fragment in one patient. In all others (92%) splicing was intact. Alternative skipping of exons 2, 3 or 2 + 3 were exclusive to low responders and was independent of the use of agonist or antagonist. Interestingly, skipping of exon 3 occurs naturally in the ovaries of domestic cats—a good comparative model for human fertility. We tested the signaling potential of human and cat variants after transfection in HEK293 cells and FSH stimulation. None of the splicing variants initiated cAMP signaling despite high FSH doses, unlike full-length proteins. These data substantiate the occurrence of FSHR exon skipping in a subgroup of low responders and suggest that species-specific regulation of FSHR splicing plays diverse roles in mammalian ovarian function. PMID

  1. Plasma levels of follicle-stimulating and luteinizing hormones during the reproductive cycle of wild and cultured Senegalese sole (Solea senegalensis).

    PubMed

    Chauvigné, François; Fatsini, Elvira; Duncan, Neil; Ollé, Judith; Zanuy, Silvia; Gómez, Ana; Cerdà, Joan

    2016-01-01

    The intensive culture of the Senegalese sole (Solea senegalensis) is hampered by the low or null fertilization rates exhibited by the first generation (F1) of reared males. To investigate the regulation of the reproductive processes in this species by the pituitary gonadotropins follicle-stimulating and luteinizing hormones (Fsh and Lh, respectively), we developed a highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) for Lh measurements. Quantification of the Fsh and Lh plasma levels in cultured sole using the Lh ELISA developed here, and a previously developed ELISA for Fsh, indicated that in both males and females circulating Fsh steadily increased during autumn and winter and prior to the major spawning in spring, whereas an Lh surge occurred specifically during spawning. The increase in Fsh was associated with a rise of plasma levels of the steroid hormones testosterone (T), 11-ketotestosterone (11-KT) and estradiol-17β (E2), but that of Lh was concomitant with a strong decline of the levels of E2 in females and of 11-KT in males, possibly reflecting a rapid steroidogenic shift promoting the final maturation of gametes. Comparison of the plasma levels of gonadotropins and steroids between wild and F1 fish during autumn and spring revealed that F1 males showed significantly lower plasma Lh titres compared to wild males, whereas the levels of T and 11-KT were similar or more elevated in the F1 fish. These data suggest that an impaired Lh secretion during spawning, and perhaps altered Lh-mediated mechanisms in the testis, may be underlying causes for the low reproductive performance of Senegalese sole F1 males. PMID:26419696

  2. Evaluation of an immunoenzymometric assay (IEMA) using automated system for determination of luteinizing hormone and follicle stimulating hormone.

    PubMed

    Fonseca, E; Mason, M; Galván, R E; Pascoe, D; Ochoa, R; Hernández, M; Zárate, A

    1997-01-01

    It has been proposed that automated systems for immunoenzymometric assay (IEMA) may substitute traditional radioimmunoassay (RIA) for measurement of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in blood due to the advantage of being more rapid, higher sensitivity, lower cost and not requiring radioactive reagents. The study was designed to evaluate both systems using serum samples to determine luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations. The automatic system (ES-300) for IEMA utilized two monoclonal antibodies, one of them on the solid phase was the specific extractant for the antigen, and the other was a peroxidase labeled antibody which recognizes a different epitope in the antigen molecule, specifically bound in linear proportion to the antigen concentration. Blood samples were obtained from patients who were treated at the hospital for various clinical problems ("problem group") as well as blood samples from patients in whom FSH and LH concentrations were already known ("high", "medium" and "low" levels) by previous RIA ("control group"). IEMA showed a higher sensitivity, 0.42 and 0.96 mIU/ml for FSH and LH, respectively, whereas RIA was 1.95 mIU/ml for both hormones. Intra- and interassay coefficient of variation were below 10% within the range of 15-150 mIU/ml for FSH and 5-100 mIU/ml for LH; however, the coefficient of variation was 15-25% at lower concentrations of FSH and LH. Accuracy of IEMA was evaluated by recovery percentage, thus when high and medium concentrations of FSH and LH were analyzed the recovery was between 99-104%. On the other hand, the recovery was 110% when low levels of FSH and LH were used. In conclusion, IEMA resulted reliable when FSH and LH concentrations are in the middle and high range; likewise, the detection limit of IEMA was lower than RIA, particularly for FSH. On the bases of these results, IEMA showed several advantages over RIA, but its reliability diminishes when serum

  3. An unbalanced translocation unmasks a recessive mutation in the follicle-stimulating hormone receptor (FSHR) gene and causes FSH resistance

    PubMed Central

    Kuechler, Amla; Hauffa, Berthold P; Köninger, Angela; Kleinau, Gunnar; Albrecht, Beate; Horsthemke, Bernhard; Gromoll, Jörg

    2010-01-01

    Follicle-stimulating hormone (FSH) mediated by its receptor (FSHR) is pivotal for normal gametogenesis. Inactivating FSHR mutations are known to cause hypergonadotropic hypogonadism with disturbed follicular maturation in females. So far, only very few recessive point mutations have been described. We report on a 17-year-old female with primary amenorrhea, hypergonadotropic hypogonadism and disturbed folliculogenesis. Chromosome analysis detected a seemingly balanced translocation 46,XX,t(2;8)(p16.3or21;p23.1)mat. FSHR sequence analysis revealed a novel non-synonymous point mutation in exon 10 (c.1760C>A, p.Pro587His), but no wild-type allele. The mutation was also found in the father, but not in the mother. Furthermore, molecular-cytogenetic analyses of the breakpoint region on chromosome 2 showed the translocation to be unbalanced, containing a deletion with one breakpoint within the FSHR gene. The deletion size was narrowed down by array analysis to approximately 163 kb, involving exons 9 and 10 of the FSHR gene. Functional studies of the mutation revealed the complete lack of signal transduction presumably caused by a changed conformational structure of transmembrane helix 6. To our knowledge, this is the first description of a compound heterozygosity of an inactivating FSHR point mutation unmasked by a partial deletion. This coincidence of two rare changes caused clinical signs consistent with FSH resistance. PMID:20087398

  4. Androgen receptor and miRNA-126* axis controls follicle-stimulating hormone receptor expression in porcine ovarian granulosa cells.

    PubMed

    Du, Xing; Li, Qiqi; Pan, Zengxiang; Li, Qifa

    2016-08-01

    Androgen, which acts via the androgen receptor (AR), plays crucial roles in mammalian ovarian function. Recent studies showed that androgen/AR signaling regulates follicle-stimulating hormone receptor (FSHR) expression in follicles; however, the detailed mechanism underlying this regulation remained unknown. Here, we demonstrate that AR and miR-126* cooperate to inhibit FSHR expression and function in pig follicular granulosa cells (pGCs). In pGCs, overexpression of AR decreased, whereas knockdown increased, FSHR mRNA and protein expression; however, neither manipulation affected FSHR promoter activity. Using a dual-luciferase reporter assay, we found that the FSHR gene is a direct target of miR-126*, which inhibits FSHR expression and increases the rate of AR-induced apoptosis in pGCs. Collectively, our data show for the first time that the AR/miR-126* axis exerts synergetic effects in the regulation of FSHR expression and apoptosis in pGCs. Our findings thus define a novel pathway, AR/miR-126*/FSHR, that regulates mammalian GC functions. PMID:27222597

  5. Weight loss results in a small decrease in follicle stimulating hormone in overweight glucose-intolerant postmenopausal women

    PubMed Central

    Kim, Catherine; Randolph, John F.; Golden, Sherita H.; Labrie, Fernand; Kong, Shengchun; Nan, Bin; Barrett-Connor, Elizabeth

    2014-01-01

    Structured Abstract Objective To examine the impact of a weight loss intervention upon follicle stimulating hormone (FSH) levels in postmenopause. Design and Methods Participants were postmenopausal, overweight, glucose-intolerant women not using exogenous estrogen (n=382) in the Diabetes Prevention Program. Women were randomized to intensive lifestyle change (ILS) with the goals of weight reduction of at least 7% of initial weight and 150 minutes per week of moderate intensity exercise, metformin 850 mg, or placebo administered twice a day. Results Randomization to ILS led to small increases in FSH between baseline and 1-year follow-up vs. placebo (2.3 IU/l vs. -0.81 IU/l, p<0.01). Increases in FSH were correlated with decreases in weight (r=-0.165, p<0.01) and E2 (r=-0.464, p<0.0001) after adjustment for age, race/ethnicity, and randomization arm. Changes in FSH were still significantly associated with changes in weight even after adjustment for E2 levels. Metformin users had reductions in weight but non-significant changes in FSH and E2 levels vs. placebo. Conclusions Weight loss leads to small increases in FSH among overweight, postmenopausal women, potentially through pathways mediated by endogenous estrogen as well as other pathways. PMID:25294746

  6. Protection from radiation-induced damage of spermatogenesis in the rhesus monkey (Macaca mulatta) by follicle-stimulating hormone

    SciTech Connect

    van Alphen, M.M.; van de Kant, H.J.; de Rooij, D.G.

    1989-02-01

    In adult rhesus monkeys a two- to threefold increase in the number of spermatogonia was found at Day 75 after 1 Gy of X-irradiation when the animals were pretreated with two intramuscular injections of follicle-stimulating hormone (FSH) each day. Also the percentage of cross-sections of seminiferous tubules showing spermatogonia (repopulation index) was much higher when FSH was given before irradiation. At 75 days postirradiation the repopulation index was 39 +/- 10% after irradiation alone and 81 +/- 11% when FSH pretreatment was applied. The pretreatment with two injections of FSH each day during 16 days caused an increase in the number of proliferating A spermatogonia. In view of earlier results in the mouse, where proliferating spermatogonial stem cells appeared more radioresistant than quiescent ones, it is suggested that the protective effects of FSH treatment are caused by the increase in the proliferative activity of the A spermatogonia and consequently of the spermatogonial stem cells. The results indicate that in the rhesus monkey the maximal protective effect of FSH is reached after a period of treatment between 7 and 16 days.

  7. Quantification of follicle stimulating hormone (follitropin alfa): is in vivo bioassay still relevant in the recombinant age?

    PubMed

    Driebergen, R; Baer, G

    2003-01-01

    Quantification of follicle-stimulating hormone (FSH) for clinical use has traditionally involved the use of in vivo bioassays, particularly the Steelman-Pohley bioassay. This assay has limited precision, requires large numbers of laboratory animals and involves cumbersome procedures for data generation and interpretation. Recent advances in manufacturing procedures for recombinant human FSH (r-hFSH) have resulted in a preparation (follitropin alfa; Gonal-F) that is highly consistent in both isoform profile and glycan species distribution. As a result, follitropin alfa can be reliably quantified using an optimised size exclusion high-performance liquid chromatography (SE-HPLC) method, and vials can be filled by mass. Preliminary clinical studies suggest that the fill-by-mass process results in a product that delivers a more consistent clinical response and is more effective than follitropin alfa vials filled by bioassay in women undergoing controlled ovarian stimulation. Non-bioassay methods such as SE-HPLC are likely to become increasingly important for quality testing and regulatory purposes, provided that the manufacturing process is well controlled and produces a protein of highly consistent physico-chemical properties. PMID:12661779

  8. Vasoactive intestinal peptide enhanced aromatase activity in the neonatal rat ovary before development of primary follicles or responsiveness to follicle-stimulating hormone

    SciTech Connect

    George, F.W.; Ojeda, S.R.

    1987-08-01

    The authors have investigated the factors that regulate aromatase activity in fetal-neonatal rat ovaries. Ovarian aromatase activity (assessed by measuring the amount of /sup 3/H/sub 2/O formed from (1..beta..-/sup 3/H)testosterone) is low prior to birth and increases to values greater than 30 pmol/hr per mg of protein between days 8 and 12 after birth. The appearance of ovarian aromatase coincides with the development of primordial follicles. Fetal-neonatal ovaries maintained in serum-free organ culture do not develop aromatase activity at the expected time. Ovine follicle-stimulating hormone, ovine luteinizing hormone, or their combination failed to induce the enzyme activity in cultured fetal ovaries, whereas follicle-stimulating hormone is effective in preventing the decline in aromatase activity when postnatal day 8 ovaries are placed in culture. In contrast to follicle-stimulating hormone, dibutyryl-cAMP markedly enhances ovarian aromatase in cultured fetal ovaries. Likewise, enhancement of endogenouse cAMP formation with forskolin or cholera toxin caused an increase in enzyme activity within 24 hr. Vasoactive intestinal peptide, a peptide known to occur in ovarian nerves, caused a dose-dependent increase in aromatase activity in fetal ovaries prior to folliculogenesis. Of related peptides tested, only the peptide having N-terminal histidine and C-terminal isoleucine amide was capable of inducing aromatase activity in fetal ovaries. The fact that VIP can induce aromatase activity in fetal rat ovaries prior to follicle formation and prior to responsiveness to follicle-stimulating hormone suggests that this neuropeptide may play a critical role in ovarian differentiation.

  9. Genetically Determined Dosage of Follicle-Stimulating Hormone (FSH) Affects Male Reproductive Parameters

    PubMed Central

    Grigorova, Marina; Punab, Margus; Ẑilaitienė, Birutė; Erenpreiss, Juris; Ausmees, Kristo; Matuleviĉius, Valentinas; Tsarev, Igor; Jørgensen, Niels

    2011-01-01

    Context: The detailed role of FSH in contributing to male testicular function and fertility has been debated. We have previously identified the association between the T-allele of the FSHB promoter polymorphism (rs10835638; G/T, −211 bp from the mRNA start) and significantly reduced male serum FSH. Objective: In the current study, the T-allele carriers of the FSHB −211 G/T single nucleotide polymorphism represented a natural model for documenting downstream phenotypic consequences of insufficient FSH action. Design and Subjects: We genotyped rs10835638 in the population-based Baltic cohort of young men (n = 1054; GG carriers, n = 796; GT carriers, n = 244; TT carriers, n = 14) recruited by Andrology Centres in Tartu, Estonia; Riga, Latvia; and Kaunas, Lithuania. Marker-trait association testing was performed using linear regression (additive, recessive models) adjusted by age, body mass index, smoking, and recruitment center. Results: Serum hormones directly correlated with the T-allele dosage of rs10835638 included FSH (additive model, P = 1.11 × 10−6; T-allele effect, −0.41 IU/liter), inhibin-B (P = 2.16 × 10−3; T-allele effect, −14.67 pg/ml), and total testosterone (P = 9.30 × 10−3; T-allele effect, −1.46 nmol/liter). Parameters altered only among TT homozygotes were reduced testicular volume (recessive model, P = 1.19 × 10−4; TT genotype effect, −9.47 ml) and increased serum LH (P = 2.25 × 10−2; TT genotype effect, 1.07 IU/liter). The carrier status of rs10835638 alternative genotypes did not affect sperm motility and morphology, calculated free testosterone, serum SHBG, and estradiol concentrations. Conclusion: We showed for the first time that genetically determined low FSH may have wider downstream effects on the male reproductive system, including impaired testes development, altered testicular hormone levels (inhibin-B, total testosterone, LH), and affected male reproductive potential. PMID:21733993

  10. Follicle-stimulating hormone-induced rescue of cumulus cell apoptosis and enhanced development ability of buffalo oocytes.

    PubMed

    Jain, A; Jain, T; Kumar, P; Kumar, M; De, S; Gohain, M; Kumar, R; Datta, T K

    2016-04-01

    The effect of follicle-stimulating hormone (FSH) on apoptotic status of cumulus cells, expression of proapoptotic and antiapoptotic genes, and development rate of in vitro fertilization-produced buffalo embryos were investigated. FSH supplementation in in vitro maturation-medium resulted in a dose-dependent reduction in the expression of proapoptotic genes namely, BCL2-associated X protein (BAX), cytochrome c, and caspase-3 and increase in the expression of antiapoptotic genes such as B-cell lymphoma 2 (BCL2) and X-linked inhibitor of apoptosis protein (XIAP) in cumulus cells of mature oocyte. Cumulus expansion, oocyte maturation, cleavage, and blastocyst development rates were significantly higher (P < 0.05) in 5 and 10-μg/mL FSH-supplemented groups as compared with control. Significant increase in the expression of FSH receptor messenger RNA was also found with 5 and 10-μg/mL FSH (P < 0.05). Terminal deoxynucleotidyl transferase dUTP nick end labeling assay confirmed that the population of apoptotic cumulus cells of matured oocytes was reduced in the FSH-treated groups as compared with control (P < 0.05). In conclusion, our data suggest that FSH may attenuate apoptosis in cumulus cells via mitochondria-dependent apoptotic pathway by increasing XIAP expression, resulting in a more favorable ratio of BCL2/BAX expression and decreasing the cytochrome c and caspase-3 expression, eventually contributing to developmental competence of oocytes. The information generated will help in improving the in vitro embryo production program in buffalo. PMID:26774556

  11. Follicle Stimulating Hormone (FSH) Dosage Based on Body Weight Enhances Ovulatory Responses and Subsequent Embryo Production in Goats

    PubMed Central

    Rahman, M. R.; Rahman, M. M.; Wan Khadijah, W. E.; Abdullah, R. B.

    2014-01-01

    An experiment was conducted to evaluate the efficacy of porcine follicle stimulating hormone (pFSH) dosage based on body weight (BW) on ovarian responses of crossbred does. Thirty donor does were divided into 3 groups getting pFSH dosages of 3, 5, and 8 mg pFSH per kg BW, respectively, and were named as pFSH-3, pFSH-5 and pFSH-8, respectively. Estrus was synchronized by inserting a controlled internal drug release (CIDR) device and a single injection of prostaglandin F2α (PGF2α). The pFSH treatments were administered twice a day through 6 decreasing dosages (25, 25, 15, 15, 10, and 10% of total pFSH amount; decreasing daily). Ovarian responses were evaluated on Day 7 after CIDR removal. After CIDR removal, estrus was observed 3 times in a day and pFSH treatments were initiated at 2 days before the CIDR removal. All does in pFSH-5 and pFSH-8 showed estrus signs while half of the does in pFSH-3 showed estrus signs. No differences (p>0.05) were observed on the corpus luteum and total ovarian stimulation among the treatment groups, while total and transferable embryos were higher (p<0.05) in pFSH-5 (7.00 and 6.71) than pFSH-3 (3.00 and 2.80) and pFSH-8 (2.00 and 1.50), respectively. In conclusion, 5 mg pFSH per kg BW dosage gave a higher number of embryos than 3 and 8 mg pFSH per kg BW dosages. The results indicated that the dosage of pFSH based on BW is an important consideration for superovulation in goats. PMID:25178370

  12. Impacts of incorporation of follicle stimulating hormone into an estrous synchronization protocol for timed artificial insemination of crossbred beef cattle.

    PubMed

    Gentry, G T; Walker, R S; Gentry, L R

    2016-05-01

    One-hundred-eighty crossbred beef cows and 66 crossbred beef heifers across three locations were stratified by body weight (BW), body condition score (BCS), and age (within location) to evaluate administration of follicle stimulating hormone (FSH) on Day 2 using a modified 7-day CO-Synch plus CIDR(®) protocol (Day 0=CIDR insertion) with timed-artificial insemination (TAI) at 72h (cows) or 54h (heifers) following CIDR removal. Estrous response following CIDR removal was determined using an Estrotect patch and TAI and final pregnancy rates were determined by transrectal ultrasonography 42-45days following TAI and ≥45days following removal of clean-up bulls. Estrous response rate, TAI and final pregnancy rates for cows were not affected (P≥0.65) by treatment. Cows that exhibited estrus had greater (P<0.01) TAI pregnancy rate (66%) than cows not exhibiting estrus (38%). There was an estrous response by postpartum length interaction (P=0.02) where cows exhibiting estrus and ≥55days postpartum had greater TAI pregnancy rates (75%) compared to cows not exhibiting estrus and <55days postpartum (39%) or ≥55days postpartum (28%). For heifers, timed AI (P=0.46) and final pregnancy rates (P=0.45) were similar across treatments and estrous response had no effect (P=0.30) on TAI pregnancy rates. In conclusion, the addition of FSH to the CO-Synch plus CIDR estrous synchronization protocol did not increase TAI pregnancy rates in beef cows or heifers. However, a positive estrous response to the synchronization protocol was associated with increased TAI pregnancy rates in cows. PMID:26968244

  13. Production and characterization of monoclonal antibodies against recombinant tethered follicle-stimulating hormone from Japanese eel Anguilla japonica.

    PubMed

    Kim, Dae-Jung; Park, Chae-Won; Kim, Dong-Wan; Park, Hong-Kyu; Byambaragchaa, Munkhzaya; Lee, Nam-Sil; Hong, Sun-Mee; Seo, Mi-Young; Kang, Myung-Hwa; Min, Kwan-Sik

    2016-07-01

    We prepared monoclonal antibodies (mAbs) against a recombinant tethered follicle-stimulating hormone (rec-FSH) from Japanese eel Anguilla japonica that was produced in Escherichia coli. Positive hybridomas (clones eFA-C5, eFA-C10, eFA-C11, eFA-C12, eFA-C13, and eFB-C14) were selected by using the eel FSH antigen in ELISA, and anti-eel FSH mAbs were purified from culture supernatants by performing affinity chromatography. Three of the 6mAbs were characterized and their isotypes were identified as IgG2b (eFA-C5 and eFA-C11) and IgG1 (eFB-C14). In western blotting assays, the mAbs recognized the antigen as a 24.3-kDa band, and further detected bands of 34 and 32kDa in the supernatants of CHO cells transfected with cDNA encoding tethered eel FSHβ/α and LHβ/α, respectively. PNase F-mediated deglycosylation of the recombinant proteins resulted in a drastic reduction in their molecular weight, to 7-9kDa. The mAbs eFA-C5 and eFA-C11 recognized the eel FSHα-subunit that is commonly encoded among glycoprotein hormones, whereas eFB-C14 recognized the eel FSHβ-subunit, and immunohistochemical analysis revealed that the staining by these mAbs was specifically localized in the eel pituitary. We also established an ELISA system for detecting rec-tethered FSHβ/α and LHβ/α produced from CHO cell lines. Measurement of biological activities in vitro revealed that only weak activity of rec-FSHβ/α was detected. The activity of rec-LHβ/α was found to be increased in a dose-dependent manner for eel oocyte maturation. PMID:27174750

  14. Differential thermal stability of human, bovine and ovine Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) quaternary structures.

    PubMed

    Haj Hassan, Maya; Cahoreau, Claire; Jégot, Gwenhael; Jouanny, Camille; Mariot, Julie; Lecompte, François; Klett, Danièle; Combarnous, Yves

    2015-02-01

    Quaternary structure of human, bovine and ovine Follicle-Stimulating Hormones (hFSH, bFSH and oFSH) and Luteinizing Hormone was assessed in sandwich ELISAs using monoclonal anti-oFSHβ or anti-oLHβ antibodies, respectively, for capture and a biotinylated anti-hFSHα (α4 epitope) for detection. Neither free subunit gave any signal in this assay so that it was possible to measure the residual heterodimeric fraction after thermal treatment of the gonadotropins under study. The hormones were subjected to 5-min heating between 37 and 90 °C before rapid cooling in melting ice before ELISA. The data show half-dissociation of natural and recombinant human and ovine FSH preparations between 68 and 74 °C whereas bovine FSH preparations exhibited lower stability in these conditions with half-dissociation between 61 and 64 °C. Moreover, whereas all human and bovine as well as most ovine FSH preparations were fully dissociated at temperatures above 80 °C, one natural oFSH and one recombinant hLH preparations contained an important fraction that resisted dissociation even at 93 °C and retained in vitro bioactivity. This suggests the existence of gonadotropin αβ heterodimer with covalently linked subunits. Similarly, about 20% of the recombinant hLH preparation was also found withstand heat denaturation and also probably to have cross-linked subunits. The origin and chemical nature of these inter-subunit bonds remain to be determined. PMID:24732063

  15. Ascorbic acid treatment elevates follicle stimulating hormone and testosterone plasma levels and enhances sperm quality in albino Wistar rats

    PubMed Central

    Okon, Uduak Akpan; Utuk, Ikponoabasi Ibanga

    2016-01-01

    Background: Infertility issues have been linked to the effect of oxidative reaction in the reproductive system. This study evaluated the effect of ascorbic acid, on fertility parameters of male albino Wistar rats was studied. Materials and Methods: Eighteen albino Wistar rats weighed between 178 g and 241 g were used, randomly assigned into three groups. Group 1 was the control group; oral gavaged 5 ml of distilled water; Groups 2 and 3 were administered medium dose (250 mg/kg) and high dose of ascorbic acid (400 mg/kg), respectively; twice daily for 21 days. Blood samples were obtained by cardiac puncture, and blood serum was obtained for hormonal assay, and the testes were harvested for sperm analysis. Results: Follicle stimulating hormone levels significantly increased in the high-dose group as compared to both the control and medium dose groups. Luteinizing hormone levels in the medium dose group decreased significantly as compared to the control group. Testosterone significantly increased in both the medium- and high-dose groups as compared to the control group. Sperm motility increased significantly in the high-dose group as compared to both control and medium-dose groups. Percentage sperm concentration decreased significantly in the medium-dose group when compared to the control and increased significantly in the high-dose group as compared to the medium-dose group. For percentage normal morphology, there was a dose-dependent increase in the test groups when compared to control group. Conclusion: These results are indicative of a positive influence of ascorbic acid on male fertility modulators and may therefore, serve as a potential adjuvant treatment for male infertility cases. PMID:27185976

  16. Follicle-stimulating hormone increases the intramuscular fat content and expression of lipid biosynthesis genes in chicken breast muscle*

    PubMed Central

    Cui, Xiao-yan; Li, Ying-ying; Liu, Ran-ran; Zhao, Gui-ping; Zheng, Mai-qing; Li, Qing-he; Wen, Jie

    2016-01-01

    Intramuscular fat (IMF) is a crucial factor in the quality of chicken meat. The genetic basis underlying it is complex. Follicle-stimulating hormone (FSH), well-known as an effector in reproductive tissues, was recently discovered to stimulate abdominal fat accumulation in chicken. The effect of FSH on IMF accumulation and the underlying molecular regulatory mechanisms controlling both IMF and abdominal fat deposition in vivo are largely unknown. In this study, two groups of chickens were treated with chicken FSH or a placebo. The lipid content of breast muscle, abdominal fat volume, and serum concentrations of FSH were examined. Related genes implicated in breast muscle and abdominal fat accumulation were also investigated. Compared to the control group, the triglyceride (TG) content of breast muscle and the percentage of abdominal fat in FSH-treated chickens were significantly increased by 64.9% and 56.5% (P<0.01), respectively. The FSH content in the serum of FSH-treated chickens was 2.1 times than that of control chickens (P<0.01). Results from quantitative real-time polymerase chain reaction (qRT-PCR) assays showed that relative expression levels of fatty acid synthase (FAS), lipoprotein lipase (LPL), diacylglycerol acyltransferase 2 (DGAT2), adipocyte fatty acid binding protein (A-FABP), and peroxisome proliferator-activated receptor γ (PPARγ) were significantly upregulated in breast muscle following FSH treatment (P<0.01). Treatment with FSH also significantly increased relative expression levels of FAS, LPL, DGAT2, A-FABP, and PPARγ in abdominal fat tissue (P<0.05). The results of principal component analysis (PCA) for gene expression (breast muscle and abdominal fat) showed that the control and FSH treatment groups were well separated, which indicated the reliability of the data. This study demonstrates that FSH plays an important role in IMF accumulation in female chickens, which likely involves the regulation of biosynthesis genes related to lipid

  17. Follicle-Stimulating Hormone and Estradiol Interact to Stimulate Glutathione Synthesis in Rat Ovarian Follicles and Granulosa Cells1

    PubMed Central

    Hoang, Yvonne D.; Nakamura, Brooke N.; Luderer, Ulrike

    2009-01-01

    Glutathione (GSH), the most abundant intracellular nonprotein thiol, is critical for many cellular functions. The rate-limiting step in GSH synthesis is catalyzed by glutamate cysteine ligase (GCL), a heterodimer composed of a catalytic (GCLC) and a modifier (GCLM) subunit. The tissue-specific regulation of GSH synthesis is poorly understood. We showed previously that gonadotropin hormones regulate ovarian GSH synthesis. In the present study, we sought to clarify the ovarian cell type-specific effects of follicle-stimulating hormone (FSH) and estradiol on GSH synthesis. Immature female rats were treated with estradiol to stimulate development of small antral follicles. Granulosa cells (GCs) from these follicles or whole follicles were cultured in serum-free media, with or without FSH and 17beta-estradiol. The GSH and GCLC protein and mRNA levels increased in GCs treated with FSH alone. The effects of FSH on GCLC and GCLM protein and mRNA levels, GCL enzymatic activity, and GSH concentrations in GCs were significantly enhanced by the addition of estradiol. Estradiol alone had no effects on GSH. Dibromo-cAMP mimicked and protein kinase A (PKA) inhibitors prevented FSH stimulation of GCL subunit protein levels. In cultured small antral follicles, FSH stimulated estradiol synthesis and robustly increased GCL subunit mRNA and protein levels and GSH concentrations. The GCL subunit mRNA expression increased in both the granulosa cells and theca cells of follicles with FSH stimulation. These data demonstrate that maximal stimulation of GSH synthesis by FSH in granulosa cells and follicles requires estradiol. Without estradiol, FSH causes lesser increases in GCL subunit expression via a PKA-dependent pathway. PMID:19516019

  18. Effect of estradiol-17β on follicle-stimulating hormone secretion and egg-laying performance of Japanese quail.

    PubMed

    Çiftci, H B

    2012-12-01

    The aim of this study was to measure the effect of estradiol-17β (E2) injection on follicle-stimulating hormone (FSH) secretion and egg-laying performance of Japanese quail. Female Japanese quail were housed in cages and fed ad libitum. After a 7-day adaptation period, the birds were randomly assigned to three groups, that is, one control group and two test groups. The birds were weighed, before every injection. The control group was subcutaneously injected with 0.2 ml sesame oil-ethanol mixture, whereas test groups were injected, twice in a week, with 0.2 ml sesame oil-ethanol mixture containing 0.1 or 0.2 mg E2 along the study. One day after the first injection, egg number, egg weight, eggshell strength and food conception were daily recorded. On the last day of the experiment, the birds were injected and 3 h later seven birds from each group were randomly selected for bleeding. Blood samples (2 ml/bird) were collected from the jugular vein for the measurements of serum concentrations of E2, FSH, calcium (Ca) and phosphorus (P). E2 injection did not cause any significant changes in serum FSH concentrations, daily egg laid/bird, food conception/bird, serum concentrations of the Ca and the P. Egg weight was significantly increased in the 0.1 mg E2-injected group as compared with the control and 0.2 mg E2-injected groups. Eggshell strength in the 0.2 mg E2-injected group was significantly high as compared with the control, whereas the difference between the 0.1 mg E2- and 0.2 mg E2-injected groups was not statistically important. These results show that serum FSH concentration was not increased even when slightly suppressed by subcutaneous injection of 0.1 or 0.2 mg E2. Different doses of E2 have different functions. The increase in BWs in the 0.1 mg E2-injected group was a result of the dose effect, which probably increased growth hormone secretion from the pituitary or IGF-1 synthesis from the liver or both. The dose, 0.2 mg E2, was ineffective in increasing the

  19. POSTNATAL ALTERATIONS IN DEVELOPMENT RESULTING FROM PRENATAL EXPOSURE TO PESTICIDES

    EPA Science Inventory

    Alterations in the developmental processes of embryos resulting from exposure to chemicals are not limited to morphological abnormalities that can be observed in the near term fetus. In the research on the developmental toxicology of pesticides the authors have noted morphologica...

  20. Responses of luteinizing hormone, follicle-stimulating hormone, and prolactin to prolonged administration of the dopamine antagonist in normal women and women with low-weight amenorrhea.

    PubMed

    Larsen, S

    1981-06-01

    The responses of luteinizing hormone, follicle-stimulating hormone, and prolactin to prolonged administration of the dopamine receptor antagonist metoclopramide (5 mg twice daily) were investigated in six normal women and six women with low-weight amenorrhea (LWA). In contrast to the normal group, the LWA group showed no significant changes in the mean basal prolactin level or the mean prolactin response to stimulation with thyrotropin-releasing hormone, but there was an significant elevation of the mean net increase in luteinizing hormone after stimulation with gonadotropin-releasing hormone. On the basis of these data, the possibility of increased central dopaminergic activity in women with LWA is discussed. PMID:6788608

  1. Molecular analysis of the koala reproductive hormones and their receptors: gonadotrophin-releasing hormone (GnRH), follicle-stimulating hormone β and luteinising hormone β with localisation of GnRH.

    PubMed

    Busby, E R; Soeta, S; Sherwood, N M; Johnston, S D

    2014-12-01

    During evolution, reproductive hormones and their receptors in the brain-pituitary-gonadal axis have been altered by genetic mechanisms. To understand how the neuroendocrine control of reproduction evolved in mammals, it is important to examine marsupials, the closest group to placental mammals. We hypothesised that at least some of the hormones and receptors found in placental mammals would be present in koala, a marsupial. We examined the expression of koala mRNA for the reproductive molecules. Koala cDNAs were cloned from brain for gonadotrophin-releasing hormones (GnRH1 and GnRH2) or from pituitary for GnRH receptors, types I and II, follicle-stimulating hormone (FSH)β and luteinising hormone (LH)β, and from gonads for FSH and LH receptors. Deduced proteins were compared by sequence alignment and phylogenetic analysis with those of other vertebrates. In conclusion, the koala expressed mRNA for these eight putative reproductive molecules, whereas at least one of these molecules is missing in some species in the amniote lineage, including humans. In addition, GnRH1 and 2 are shown by immunohistochemistry to be expressed as proteins in the brain. PMID:25200132

  2. Alterations in cognitive and psychological functioning after organic solvent exposure

    SciTech Connect

    Morrow, L.A.; Ryan, C.M.; Hodgson, M.J.; Robin, N. )

    1990-05-01

    Exposure to organic solvents has been linked repeatedly to alterations in both personality and cognitive functioning. To assess the nature and extent of these changes more thoroughly, 32 workers with a history of exposure to mixtures of organic solvents and 32 age- and education-matched blue-collar workers with no history of exposure were assessed with a comprehensive battery of neuropsychological tests. Although both groups were comparable on measures of general intelligence, significant differences were found in virtually all other cognitive domains tested (Learning and Memory, Visuospatial, Attention and Mental Flexibility, Psychomotor Speed). In addition, Minnesota Multiphasic Personality Inventories of exposed workers indicated clinically significant levels of depression, anxiety, somatic concerns and disturbances in thinking. The reported psychological distress was unrelated to degree of cognitive deficit. Finally, several exposure-related variables were associated with poorer performance on tests of memory and visuospatial ability.

  3. Gene Expression Profiling of Biological Pathway Alterations by Radiation Exposure

    PubMed Central

    Lee, Kuei-Fang; Weng, Julia Tzu-Ya; Hsu, Paul Wei-Che; Chi, Yu-Hsiang; Chen, Ching-Kai; Liu, Ingrid Y.; Chen, Yi-Cheng; Wu, Lawrence Shih-Hsin

    2014-01-01

    Though damage caused by radiation has been the focus of rigorous research, the mechanisms through which radiation exerts harmful effects on cells are complex and not well-understood. In particular, the influence of low dose radiation exposure on the regulation of genes and pathways remains unclear. In an attempt to investigate the molecular alterations induced by varying doses of radiation, a genome-wide expression analysis was conducted. Peripheral blood mononuclear cells were collected from five participants and each sample was subjected to 0.5 Gy, 1 Gy, 2.5 Gy, and 5 Gy of cobalt 60 radiation, followed by array-based expression profiling. Gene set enrichment analysis indicated that the immune system and cancer development pathways appeared to be the major affected targets by radiation exposure. Therefore, 1 Gy radioactive exposure seemed to be a critical threshold dosage. In fact, after 1 Gy radiation exposure, expression levels of several genes including FADD, TNFRSF10B, TNFRSF8, TNFRSF10A, TNFSF10, TNFSF8, CASP1, and CASP4 that are associated with carcinogenesis and metabolic disorders showed significant alterations. Our results suggest that exposure to low-dose radiation may elicit changes in metabolic and immune pathways, potentially increasing the risk of immune dysfunctions and metabolic disorders. PMID:25276823

  4. Effects of new sports tennis type exercise on aerobic capacity, follicle stimulating hormone and N-terminal telopeptide in the postmenopausal women

    PubMed Central

    Shin, Hyun-Jae; Lee, Ha-Yan; Cho, Hye-Young; Park, Yun-Jin; Moon, Hyung-Hoon; Lee, Sung-Hwan; Lee, Sung-Ki; Kim, Myung-Ki

    2014-01-01

    Menopause is characterized by rapid decreases in bone mineral density, aerobic fitness, muscle strength, and balance. In the present study, we investigated the effects of new sports tennis type exercise on aerobic capacity, follicle stimulating hormone (FSH) and N-terminal telopeptide (NTX) in the postmenopausal women. Subjects were consisted of 20 postmenopausal women, who had not menstruated for at least 1 yr and had follicle-stimulating hormone levels > 35 mIU/L, estradiol levels< 40 pg/mL. The subjects were randomly divided into two groups: control group (n= 10), new sports tennis type exercise group (n= 10). New sports tennis type exercise was consisted of warm up (10 min), new sports tennis type exercise (40 min), cool down (10 min) 3 days a per week for 12 weeks. The aerobic capacities were increased by 12 weeks new sports tennis type exercise. New sports tennis type exercise significantly increased FSH and NTx levels, indicating biochemical markers of bone formation and resorption. These findings indicate that 12 weeks of new sports tennis type exercise can be effective in prevention of bone loss and enhancement of aerobic capacity in postmenopausal women. PMID:24877043

  5. Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes

    PubMed Central

    Fang, Xiefan; Mei, Wenbin; Barbazuk, William B.; Rivkees, Scott A.

    2014-01-01

    Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20–60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3–65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes. PMID:25354728

  6. Produced water exposure alters bacterial response to biocides.

    PubMed

    Vikram, Amit; Lipus, Daniel; Bibby, Kyle

    2014-11-01

    Microbial activity during the holding and reuse of wastewater from hydraulic fracturing operations, termed produced water, may lead to issues with corrosion, sulfide release, and fouling. Biocides are applied to control biological activity, often with limited efficacy, which is typically attributed to chemical interactions with the produced water. However, it is unknown whether there is a biologically driven mechanism to biocide tolerance in produced water. Here, we demonstrate that produced water exposure results in an enhanced tolerance against the typically used biocide glutaraldehyde and increased susceptibility to the oxidative biocide hypochlorite in a native and a model bacteria and that this altered resistance is due to the salinity of the produced water. In addition, we elucidate the genetic response of the model organism Pseudomonas fluorescens to produced water exposure to provide a mechanistic interpretation of the altered biocide resistance. The RNA-seq data demonstrated the induction of genes involved in osmotic stress, energy production and conversion, membrane integrity, and protein transport following produced water exposure, which facilitates bacterial survival and alters biocide tolerance. Efforts to fundamentally understand biocide resistance mechanisms, which enable the optimization of biocide application, hold significant implications for greening of the fracturing process through encouraging produced water recycling. Specifically, these results suggest the necessity of optimizing biocide application at the level of individual shale plays, rather than historical experience, based upon produced water characteristics and salinity. PMID:25279933

  7. Perinatal exposure to polychlorinated biphenyls alters social behaviors in rats

    PubMed Central

    Jolous-Jamshidi, Banafsheh; Cromwell, Howard C.; McFarland, Ashley M.; Meserve, Lee A.

    2014-01-01

    Perinatal exposure to polychlorinated biphenyls (PCBs) leads to significant alterations of neural and hormonal systems. These alterations have been shown to impair motor and sensory development. Less is known about the influence of PCB exposure on developing emotional and motivational systems involved in social interactions and social learning. The present study examined the impact of perinatal PCB exposure (mixture of congeners 47 and 77) on social recognition in juvenile animals, conspecific-directed investigation in adults and on neural and hormonal systems involved in social functions. We used a standard habituation–dishabituation paradigm to evaluate juvenile recognition and a social port paradigm to monitor adult social investigation. Areal measures of the periventricular nucleus (PVN) of the hypothalamus were obtained to provide correlations with related hormone and brain systems. PCB exposed rats were significantly impaired in social recognition as indicated by persistent conspecific-directed exploration by juvenile animals regardless of social experience. As adults, PCB exposure led to a dampening of the isolation-induced enhancement of social investigation. There was not a concomitant alteration of social investigation in pair-housed PCB exposed animals at this stage of development. Interestingly, PVN area was significantly decreased in juvenile animals exposed to PCB during the perinatal period. Shifts in hypothalamic regulation of hormones involved in social behavior and stress could be involved in the behavioral changes observed. Overall, the results suggest that PCB exposure impairs context or experience-dependent modulation of social approach and investigation. These types of social-context deficits are similar to behavioral deficits observed in social disorders such as autism and other pervasive developmental disorders. PMID:20813172

  8. Perinatal exposure to polychlorinated biphenyls alters social behaviors in rats.

    PubMed

    Jolous-Jamshidi, Banafsheh; Cromwell, Howard C; McFarland, Ashley M; Meserve, Lee A

    2010-11-30

    Perinatal exposure to polychlorinated biphenyls (PCBs) leads to significant alterations of neural and hormonal systems. These alterations have been shown to impair motor and sensory development. Less is known about the influence of PCB exposure on developing emotional and motivational systems involved in social interactions and social learning. The present study examined the impact of perinatal PCB exposure (mixture of congeners 47 and 77) on social recognition in juvenile animals, conspecific-directed investigation in adults and on neural and hormonal systems involved in social functions. We used a standard habituation-dishabituation paradigm to evaluate juvenile recognition and a social port paradigm to monitor adult social investigation. Areal measures of the periventricular nucleus (PVN) of the hypothalamus were obtained to provide correlations with related hormone and brain systems. PCB exposed rats were significantly impaired in social recognition as indicated by persistent conspecific-directed exploration by juvenile animals regardless of social experience. As adults, PCB exposure led to a dampening of the isolation-induced enhancement of social investigation. There was not a concomitant alteration of social investigation in pair-housed PCB exposed animals at this stage of development. Interestingly, PVN area was significantly decreased in juvenile animals exposed to PCB during the perinatal period. Shifts in hypothalamic regulation of hormones involved in social behavior and stress could be involved in the behavioral changes observed. Overall, the results suggest that PCB exposure impairs context or experience-dependent modulation of social approach and investigation. These types of social-context deficits are similar to behavioral deficits observed in social disorders such as autism and other pervasive developmental disorders. PMID:20813172

  9. Chronic bisphenol A exposure alters behaviors of zebrafish (Danio rerio).

    PubMed

    Wang, Ju; Wang, Xia; Xiong, Can; Liu, Jian; Hu, Bing; Zheng, Lei

    2015-11-01

    The adult zebrafish (Danio rerio) were exposed to treated-effluent concentration of bisphenol A (BPA) or 17β-estradiol (E2) for 6 months to evaluate their effects on behavioral characteristics: motor behavior, aggression, group preference, novel tank test and light/dark preference. E2 exposure evidently dampened fish locomotor activity, while BPA exposure had no marked effect. Interestingly, BPA-exposed fish reduced their aggressive behavior compared with control or E2. Both BPA and E2 exposure induced a significant decrease in group preference, as well as a weaker adaptability to new environment, exhibiting lower latency to reach the top, more entries to the top, longer time spent in the top, fewer frequent freezing, and fewer erratic movements. Furthermore, the circadian rhythmicity of light/dark preference was altered by either BPA or E2 exposure. Our results suggest that chronic exposure of treated-effluent concentration BPA or E2 induced various behavioral anomalies in adult fish and enhanced ecological risk to wildlife. PMID:26204572

  10. Sperm counts and serum follicle-stimulating hormone levels before and after radiotherapy and chemotherapy in men with testicular germ cell cancer

    SciTech Connect

    Berthelsen, J.G.

    1984-02-01

    Sperm counts were low (median, 15 X 10(6) per ejaculate) and serum follicle-stimulating hormone (FSH) levels were moderately elevated (median, 31 IU/l) after unilateral orchiectomy and immediately before radiotherapy and chemotherapy in 34 patients with seminomas and 20 patients with nonseminomatous germ cell tumors. The scattered radiation (0.2 to 1.3 Gray (Gy)) reaching the remaining testicle during radiotherapy caused azoospermia in more than two thirds of the patients. A median of 540 days elapsed after the end of treatment before spermatozoa were again found in semen samples, while a median of 1250 days passed before the pretreatment sperm count was reached. One to 5 years after treatment, sperm counts were still low (median, 6 X 10(6) per ejaculate) and serum FSH was elevated (median, 61 IU/l). The adjuvant chemotherapy given to the 20 patients with nonseminomatous tumors did not appear to affect restitution appreciably.

  11. Assembly and structural characterization of an authentic complex between human follicle stimulating hormone and a hormone-binding ectodomain of its receptor

    PubMed Central

    Fan, Qing R.; Hendrickson, Wayne A.

    2007-01-01

    Follicle stimulating hormone (FSH) is secreted from the pituitary gland to regulate reproduction in vertebrates. FSH signals through a G-protein coupled receptor (FSHR) on the target cell surface. We describe here the strategy to produce a soluble FSH-FSHR complex that involves the co-secretion of a truncated FSHR ectodomain (FSHRHB) and a covalently-linked FSHαβ heterodimer from baculovirus-infected insect cells. FSH binds to FSHRHB with a high affinity comparable to that for the full-length receptor. The crystal structure of the FSH-FSHRHB complex provides explanations for the high affinity and specificity of FSH interaction with FSHR, and it shows an unexpected dimerization of these complexes. Here we also compare the crystal structure with theoretical models of the FSH-FSHR binding mode. We conclude that the FSH-FSHRHB structure gives an authentic representation of FSH binding to intact FSHR. PMID:17045735

  12. Radiation Exposure Alters Expression of Metabolic Enzyme Genes In Mice

    NASA Technical Reports Server (NTRS)

    Wotring, Virginia E.; Mangala, L. S.; Zhang, Y.; Wu, H.

    2010-01-01

    Most pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Because of the importance of the liver in drug metabolism it is important to understand the effects of spaceflight on the enzymes of the liver. Exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. This study is an effort to examine the effects of adaptive mechanisms that may be triggered by early exposure to low radiation doses. Using procedures approved by the JSC Animal Care & Use Committee, C57 male mice were exposed to Cs-137 in groups: controls, low dose (50 mGy), high dose (6Gy) and a fourth group that received both radiation doses separated by 24 hours. Animals were anesthetized and sacrificed 4 hours after their last radiation exposure. Livers were removed immediately and flash-frozen in liquid nitrogen. Tissue was homogenized, RNA extracted and purified (Absolutely RNA, Agilent). Quality of RNA samples was evaluated (Agilent Bioanalyzer 2100). Complementary DNA was prepared from high-quality RNA samples, and used to run RT-qPCR screening arrays for DNA Repair and Drug Metabolism (SuperArray, SABiosciences/Qiagen; BioRad Cfx96 qPCR System). Of 91 drug metabolism genes examined, expression of 7 was altered by at least one treatment condition. Genes that had elevated expression include those that metabolize promethazine and steroids (4-8-fold), many that reduce oxidation products, and one that reduces heavy metal exposure (greater than 200-fold). Of the 91 DNA repair and general metabolism genes examined, expression of 14 was altered by at least one treatment condition. These gene expression changes are likely homeostatic and could lead to development of new radioprotective countermeasures.

  13. Vanadium Exposure-Induced Neurobehavioral Alterations among Chinese Workers

    PubMed Central

    Li, Hong; Zhou, Dinglun; Zhang, Qin; Feng, Chengyong; Zheng, Wei; He, Keping; Lan, Yajia

    2014-01-01

    Vanadium-containing products are manufactured and widely used in the modern industry. Yet the neurobehavioral toxicity due to occupational exposure to vanadium remained elusive. This cross-sectional study was designed to examine the neurotoxic effects of occupational vanadium exposure. A total of 463 vanadium-exposed workers (exposed group) and 251 non-exposed workers (control group) were recruited from a Steel and Iron Group in Sichuan, China. A WHO-recommended neurobehavioral core test battery (NCTB) and event-related auditory evoked potentials test (P300) were used to assess the neurobehavioral functions of all study subjects. A general linear model was used to compare outcome scores between the two groups while controlling for possible confounders. The exposed group showed a statistically significant neurobehavioral alteration more than the control group in the NCTB tests. The exposed workers also exhibited an increased anger-hostility, depression-dejection and fatigue-inertia on the profile of mood states (p<0.05). Performances in the Simple Reaction Time, Digit Span, Benton Visual Retention and Pursuit Aiming were also poorer among exposed workers as compared to unexposed control workers(p<0.05). Some of these poor performances in tests were also significantly related to workers’ exposure duration. P300 latencies were longer in the exposed group than in the control (p<0.05). Longer mean reaction times and more counting errors were also found in the exposed workers (p<0.05). Given the findings of our study and the limitations of neurobehavioral workplace testing, we found evidence of altered neurobehavioral outcomes by occupational exposure to vanadium. PMID:23500660

  14. Prenatal exposure to aflatoxin B1: developmental, behavioral, and reproductive alterations in male rats

    NASA Astrophysics Data System (ADS)

    Supriya, Ch.; Reddy, P. Sreenivasula

    2015-06-01

    Previous studies have shown that aflatoxin B1 (AfB1) inhibits androgen biosynthesis as a result of its ability to form a high-affinity complex with the steroidogenic acute regulatory protein. The results of the present study demonstrate the postnatal effects of in utero exposure to AfB1 in the rat. Pregnant Wistar rats were given 10, 20, or 50 μg AfB1/kg body weight daily from gestation day (GD) 12 to GD 19. At parturition, newborns were observed for clinical signs and survival. All animals were born alive and initially appeared to be active. Male pups from control and AfB1-exposed animals were weaned and maintained up to postnatal day (PD) 100. Litter size, birth weight, sex ratio, survival rate, and crown-rump length of the pups were significantly decreased in AfB1-exposed rats when compared to controls. Elapsed time (days) for testes to descend into the scrotal sac was significantly delayed in experimental pups when compared to control pups. Behavioral observations such as cliff avoidance, negative geotaxis, surface rightening activity, ascending wire mesh, open field behavior, and exploratory and locomotory activities were significantly impaired in experimental pups. Body weights and the indices of testis, cauda epididymis, prostate, seminal vesicles, and liver were significantly reduced on PD 100 in male rats exposed to AfB1 during embryonic development when compared with controls. Significant reduction in the testicular daily sperm production, epididymal sperm count, and number of viable, motile, and hypo-osmotic tail coiled sperm was observed in experimental rats. The levels of serum testosterone and activity levels of testicular hydroxysteroid dehydrogenases were significantly decreased in a dose-dependent manner with a significant increase in the serum follicle-stimulating hormone and luteinizing hormone in experimental rats. Deterioration in the testicular and cauda epididymal architecture was observed in experimental rats. The results of fertility

  15. Prenatal exposure to aflatoxin B1: developmental, behavioral, and reproductive alterations in male rats.

    PubMed

    Supriya, Ch; Reddy, P Sreenivasula

    2015-06-01

    Previous studies have shown that aflatoxin B1 (AfB1) inhibits androgen biosynthesis as a result of its ability to form a high-affinity complex with the steroidogenic acute regulatory protein. The results of the present study demonstrate the postnatal effects of in utero exposure to AfB1 in the rat. Pregnant Wistar rats were given 10, 20, or 50 μg AfB1/kg body weight daily from gestation day (GD) 12 to GD 19. At parturition, newborns were observed for clinical signs and survival. All animals were born alive and initially appeared to be active. Male pups from control and AfB1-exposed animals were weaned and maintained up to postnatal day (PD) 100. Litter size, birth weight, sex ratio, survival rate, and crown-rump length of the pups were significantly decreased in AfB1-exposed rats when compared to controls. Elapsed time (days) for testes to descend into the scrotal sac was significantly delayed in experimental pups when compared to control pups. Behavioral observations such as cliff avoidance, negative geotaxis, surface rightening activity, ascending wire mesh, open field behavior, and exploratory and locomotory activities were significantly impaired in experimental pups. Body weights and the indices of testis, cauda epididymis, prostate, seminal vesicles, and liver were significantly reduced on PD 100 in male rats exposed to AfB1 during embryonic development when compared with controls. Significant reduction in the testicular daily sperm production, epididymal sperm count, and number of viable, motile, and hypo-osmotic tail coiled sperm was observed in experimental rats. The levels of serum testosterone and activity levels of testicular hydroxysteroid dehydrogenases were significantly decreased in a dose-dependent manner with a significant increase in the serum follicle-stimulating hormone and luteinizing hormone in experimental rats. Deterioration in the testicular and cauda epididymal architecture was observed in experimental rats. The results of fertility

  16. Sertoli Cell-specific Expression of Metastasis-associated Protein 2 (MTA2) Is Required for Transcriptional Regulation of the Follicle-stimulating Hormone Receptor (FSHR) Gene during Spermatogenesis*

    PubMed Central

    Zhang, Shun; Li, Wei; Zhu, Chuchao; Wang, Xiaohong; Li, Zhen; Zhang, Jinshan; Zhao, Jie; Hu, Jing; Li, Teng; Zhang, Yuanqiang

    2012-01-01

    The effect of follicle-stimulating hormone (FSH) on spermatogenesis is modulated at a fundamental level by controlling the number of competent receptors present at the surface of Sertoli cells (SCs). One underlying mechanism is the down-regulation of the expression levels of the FSH receptor (FSHR) gene after exposure to FSH. Here we report that metastasis-associated protein 2 (MTA2), a component of histone deacetylase and nucleosome-remodeling complexes, as a gene product induced directly by testosterone or indirectly by FSH, is exclusively expressed in SCs. Stimulation of SCs with FSH is accompanied by up-regulation of MTA2 expression and enhancement of deacetylase activity. This effect requires the integrity of functional androgen receptor. Furthermore, MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. Abolishment of endogenous MTA2 by siRNA treatment disrupted the desensitization of the FSH response and thereafter impaired the FSH-dependent secretory function of SCs. From a clinical standpoint, deregulated expression of MTA2 in SCs of human pathological testes negatively correlates to the deregulated level of serum FSH. Overall, our present results provide the first evidence that the FSH/androgen receptor/MTA2 cascade may serve as an indispensable negative feedback mechanism to modulate the transduction events of SCs in response to FSH. These data also underscore an unexpected reproductive facet of MTA2, which may operate as a novel integrator linking synergistic actions of FSH and androgen signaling in SCs. PMID:23086931

  17. DNA methylation alterations in response to pesticide exposure in vitro

    PubMed Central

    Zhang, Xiao; Wallace, Andrew D.; Du, Pan; Kibbe, Warren A.; Jafari, Nadereh; Xie, Hehuang; Lin, Simon; Baccarelli, Andrea; Soares, Marcelo Bento; Hou, Lifang

    2013-01-01

    Although pesticides are subject to extensive carcinogenicity testing before regulatory approval, pesticide exposure has repeatedly been associated with various cancers. This suggests that pesticides may cause cancer via non-mutagenicity mechanisms. The present study provides evidence to support the hypothesis that pesticide-induced cancer may be mediated in part by epigenetic mechanisms. We examined whether exposure to 7 commonly used pesticides (i.e., fonofos, parathion, terbufos, chlorpyrifos, diazinon, malathion, and phorate) induces DNA methylation alterations in vitro. We conducted genome-wide DNA methylation analyses on DNA samples obtained from the human hematopoietic K562 cell line exposed to ethanol (control) and several OPs using the Illumina Infinium HumanMethylation27 BeadChip. Bayesian-adjusted t-tests were used to identify differentially methylated gene promoter CpG sites. In this report, we present our results on three pesticides (fonofos, parathion, and terbufos) that clustered together based on principle component analysis and hierarchical clustering. These three pesticides induced similar methylation changes in the promoter regions of 712 genes, while also exhibiting their own OP-specific methylation alterations. Functional analysis of methylation changes specific to each OP, or common to all three OPs, revealed that differential methylation was associated with numerous genes that are involved in carcinogenesis-related processes. Our results provide experimental evidence that pesticides may modify gene promoter DNA methylation levels, suggesting that epigenetic mechanisms may contribute to pesticide-induced carcinogenesis. Further studies in other cell types and human samples are required, as well as determining the impact of these methylation changes on gene expression. PMID:22847954

  18. Predator exposure alters stress physiology in guppies across timescales.

    PubMed

    Fischer, Eva K; Harris, Rayna M; Hofmann, Hans A; Hoke, Kim L

    2014-02-01

    In vertebrates, glucocorticoids mediate a wide-range of responses to stressors. For this reason, they are implicated in adaptation to changes in predation pressure. Trinidadian guppies (Poecilia reticulata) from high-predation environments have repeatedly and independently colonized and adapted to low-predation environments, resulting in parallel changes in life history, morphology, and behavior. We validated methods for non-invasive waterborne hormone sample collection in this species, and used this technique to examine genetic and environmental effects of predation on basal glucocorticoid (cortisol) levels. To examine genetic differences, we compared waterborne cortisol levels in high- and low-predation fish from two distinct population pairs. We found that fish from high-predation localities had lower cortisol levels than their low-predation counterparts. To isolate environmental influences, we compared waterborne cortisol levels in genetically similar fish reared with and without exposure to predator chemical cues. We found that fish reared with predator chemical cues had lower waterborne cortisol levels than those reared without. Comparisons of waterborne and whole-body cortisol levels demonstrated that populations differed in overall cortisol levels in the body, whereas rearing conditions altered the release of cortisol from the body into the water. Thus, evolutionary history with predators and lifetime exposure to predator cues were both associated with lower cortisol release, but depended on distinct physiological mechanisms. PMID:24370688

  19. Effective Mobilization of Very Small Embryonic-Like Stem Cells and Hematopoietic Stem/Progenitor Cells but Not Endothelial Progenitor Cells by Follicle-Stimulating Hormone Therapy

    PubMed Central

    Zbucka-Kretowska, Monika; Eljaszewicz, Andrzej; Lipinska, Danuta; Grubczak, Kamil; Rusak, Malgorzata; Mrugacz, Grzegorz; Dabrowska, Milena; Ratajczak, Mariusz Z.; Moniuszko, Marcin

    2016-01-01

    Recently, murine hematopoietic progenitor stem cells (HSCs) and very small embryonic-like stem cells (VSELs) were demonstrated to express receptors for sex hormones including follicle-stimulating hormone (FSH). This raised the question of whether FSH therapy at clinically applied doses can mobilize stem/progenitor cells in humans. Here we assessed frequencies of VSELs (referred to as Lin−CD235a−CD45−CD133+ cells), HSPCs (referred to as Lin−CD235a−CD45+CD133+ cells), and endothelial progenitor cells (EPCs, identified as CD34+CD144+, CD34+CD133+, and CD34+CD309+CD133+ cells) in fifteen female patients subjected to the FSH therapy. We demonstrated that FSH therapy resulted in statistically significant enhancement in peripheral blood (PB) number of both VSELs and HSPCs. In contrast, the pattern of responses of EPCs delineated by different cell phenotypes was not uniform and we did not observe any significant changes in EPC numbers following hormone therapy. Our data indicate that FSH therapy mobilizes VSELs and HSPCs into peripheral blood that on one hand supports their developmental origin from germ lineage, and on the other hand FSH can become a promising candidate tool for mobilizing HSCs and stem cells with VSEL phenotype in clinical settings. PMID:26635885

  20. Effective Mobilization of Very Small Embryonic-Like Stem Cells and Hematopoietic Stem/Progenitor Cells but Not Endothelial Progenitor Cells by Follicle-Stimulating Hormone Therapy.

    PubMed

    Zbucka-Kretowska, Monika; Eljaszewicz, Andrzej; Lipinska, Danuta; Grubczak, Kamil; Rusak, Malgorzata; Mrugacz, Grzegorz; Dabrowska, Milena; Ratajczak, Mariusz Z; Moniuszko, Marcin

    2016-01-01

    Recently, murine hematopoietic progenitor stem cells (HSCs) and very small embryonic-like stem cells (VSELs) were demonstrated to express receptors for sex hormones including follicle-stimulating hormone (FSH). This raised the question of whether FSH therapy at clinically applied doses can mobilize stem/progenitor cells in humans. Here we assessed frequencies of VSELs (referred to as Lin(-)CD235a(-)CD45(-)CD133(+) cells), HSPCs (referred to as Lin(-)CD235a(-)CD45(+)CD133(+) cells), and endothelial progenitor cells (EPCs, identified as CD34(+)CD144(+), CD34(+)CD133(+), and CD34(+)CD309(+)CD133(+) cells) in fifteen female patients subjected to the FSH therapy. We demonstrated that FSH therapy resulted in statistically significant enhancement in peripheral blood (PB) number of both VSELs and HSPCs. In contrast, the pattern of responses of EPCs delineated by different cell phenotypes was not uniform and we did not observe any significant changes in EPC numbers following hormone therapy. Our data indicate that FSH therapy mobilizes VSELs and HSPCs into peripheral blood that on one hand supports their developmental origin from germ lineage, and on the other hand FSH can become a promising candidate tool for mobilizing HSCs and stem cells with VSEL phenotype in clinical settings. PMID:26635885

  1. Interleukin 1. alpha. inhibits prostaglandin E sub 2 release to suppress pulsatile release of luteinizing hormone but not follicle-stimulating hormone

    SciTech Connect

    Rettori, V.; McCann, S.M. ); Gimeno, M.F. ); Karara, A. ); Gonzalez, M.C. )

    1991-04-01

    Interleukin 1{alpha} (IL-1{alpha}), a powerful endogenous pyrogen released from monocytes and macrophages by bacterial endotoxin, stimulates corticotropin, prolactin, and somatotropin release and inhibits thyrotropin release by hypothalamic action. The authors injected recombinant human IL-1{alpha} into the third cerebral ventricle, to study its effect on the pulsatile release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in conscious, freely moving, ovariectomized rats. Intraventricular injection of 0.25 pmol of IL-1{alpha} caused an almost immediate reduction of plasma LH concentration. To determine the mechanism of the suppression of LH release, mediobasal hypothalamic fragments were incubated in vitro with IL-1{alpha} (10 pM) and the release of LH-releasing hormone (LHRH) and prostaglandin E{sub 2} into the medium was measured by RIA in the presence or absence of nonrepinephrine. 1{alpha} reduced basal LHRH release and blocked LHRH release induced by nonrepinephrine. In conclusion, IL-1{alpha} suppresses LH but not FSH release by an almost complete cessation of pulsatile release of LH in the castrated rat. The mechanism of this effect appears to be by inhibition of prostaglandin E{sub 2}-mediated release of LHRH.

  2. Comparison of recombinant human follicle stimulating hormone (rhFSH), human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) on semen parameters after varicocelectomy: a randomized clinical trial

    PubMed Central

    Amirzargar, Mohammad Ali; Yavangi, Mahnaz; Basiri, Abbass; Hosseini Moghaddam, Sayyed Mahdi; Babbolhavaeji, Hooshang; Amirzargar, Nasibeh; Amirzargar, Hossein; Moadabshoar, Leila

    2012-01-01

    Background: The most frequent physical finding in infertile men is varicocele, in which one of the mechanisms that can affect seminal parameters is oxidative stress. Objective: Our study aimed, for the first time, to compare the efficacy of recombinant human follicle-stimulating hormone (rhFSH), human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) on sperm parameters and fertility after varicocelectomy. Materials and Methods: 113 infertile men with varicocele were divided into four groups. Group A received HCG 5000 IU weekly, group B received HMG 75 IU three times a week, group C received rhFSH 75 IU three times a week and group D received no medical treatment after varicocelectomy. Results: After three months, in group A sperm morphology improved (p=0.007), causing a 32% pregnancy rate. In group B, sperm motility (p=0.023) and morphology (p=0.014) improved, causing a 57% pregnancy rate. In group C, all of the investigated semen parameters increased (p<0.05), causing a 62.5% pregnancy rate. Only rhFSH improved sperm concentrations to >20×106 mL (p=0.027). In group D, sperm morphology increased (p=0.038), but other parameters remained unchanged and no pregnancies occurred. Conclusion: It can be concluded that drugs can reduce induction time for spermatogenesis and fertility in comparison with varicocelectomy alone. For these purposes, rhFSH is more effective than other drugs. PMID:25246910

  3. Follicle-stimulating Hormone Activates Extracellular Signal-regulated Kinase but Not Extracellular Signal-regulated Kinase Kinase through a 100-kDa Phosphotyrosine Phosphatase*

    PubMed Central

    Cottom, Joshua; Salvador, Lisa M.; Maizels, Evelyn T.; Reierstad, Scott; Park, Youngkyu; Carr, Daniel W.; Davare, Monika A.; Hell, Johannes W.; Palmer, Stephen S.; Dent, Paul; Kawakatsu, Hisaaki; Ogata, Masato; Hunzicker-Dunn, Mary

    2006-01-01

    In this report we sought to elucidate the mechanism by which the follicle-stimulating hormone (FSH) receptor signals to promote activation of the p42/p44 extracellular signal-regulated protein kinases (ERKs) in granulosa cells. Results show that the ERK kinase MEK and upstream intermediates Raf-1, Ras, Src, and L-type Ca2+ channels are already partially activated in vehicle-treated cells and that FSH does not further activate them. This tonic stimulatory pathway appears to be restrained at the level of ERK by a 100-kDa phosphotyrosine phosphatase that associates with ERK in vehicle-treated cells and promotes dephosphorylation of its regulatory Tyr residue, resulting in ERK inactivation. FSH promotes the phosphorylation of this phosphotyrosine phosphatase and its dissociation from ERK, relieving ERK from inhibition and resulting in its activation by the tonic stimulatory pathway and consequent translocation to the nucleus. Consistent with this premise, FSH-stimulated ERK activation is inhibited by the cell-permeable protein kinase A-specific inhibitor peptide Myr-PKI as well as by inhibitors of MEK, Src, a Ca2+ channel blocker, and chelation of extracellular Ca2+. These results suggest that FSH stimulates ERK activity in immature granulosa cells by relieving an inhibition imposed by a 100-kDa phosphotyrosine phosphatase. PMID:12493768

  4. Association of four new single-nucleotide polymorphisms in follicle-stimulating hormone receptor and zona pellucida glycoprotein with reproductive traits in pigs.

    PubMed

    Yuan, J F; Jafer, O; Affara, N A; Gong, Y Z; Yang, L G; Liu, J; Moaeen-Ud-Din, M; Li, W M; Zhang, S J

    2007-10-01

    Two new single-nucleotide polymorphisms (SNPs) (C1166T and G1190A) were discovered in the follicle-stimulating hormone receptor (FSHR) gene and two (G261A and T302C) in the zona pellucida glycoprotein (ZP3) gene. These SNPs were genotyped in three Chinese domestic purebred sow lines (42 Small Meishan, 46 Qingping and 41 Jinhua sows) and three European purebred sow lines (225 Duroc, 195 Large White and 65 Landrace sows) by using SNP chips. Phenotypic data including the functional teat number (i.e. milk-producing teats, TN) and number of piglets born alive per litter (NBA). These traits were tested for association with the genotypes of four SNPs. The association analysis revealed genotype of G261A in the ZP3 gene was significantly (P < 0.01) associated with overall NBA and NBA at later parities (NBA2+) but not with NBA at first parity (NBA1). There was a significant (P < 0.05) difference between sows with genotype GG (14.83 ± 0.18) and AA (14.26 ± 0.09) in TN at position 261 in the ZP3 gene. No significant associations were observed for the SNPs in the FSHR gene with NBA or TN in our populations. The results showed that the new SNPs in the ZP3 gene may be an effective potential marker to be used in conjunction with traditional selection methods. PMID:22444880

  5. Haplotype Structure of FSHB, the Beta-Subunit Gene for Fertility-Associated Follicle-Stimulating Hormone: Possible Influence of Balancing Selection

    PubMed Central

    Grigorova, M; Rull, K; Laan, M

    2007-01-01

    Follicle-stimulating hormone (FSH) is essential for human reproduction. The unique functions of this hormone are provided by the FSH receptor-binding beta-subunit encoded by the FSHB gene. Resequencing and genotyping of FSHB in three European, two Asian and one African population, as well as in the great apes (chimpanzee, gorilla, orangutan), revealed low diversity and significant excess of polymorphisms with intermediate frequency alleles. Statistical tests for FSHB showed deviations from neutrality in all populations suggesting a possible effect of balancing selection. Two core haplotypes were identified (carried by 76-96.6% of each population's sample), the sequences of which are clearly separated from each other. As fertility most directly affects an organism's fitness, the carriers of these haplotypes have apparently had more success in human history to contribute to the next generation. There is a preliminary observation suggesting that the second most frequent FSHB haplotype may be associated with rapid conception success in females. Interestingly, the same haplotype is related to an ancestral FSHB variant shared with the ancestor of the great apes. The determination of the functional consequence of the two core FSHB variants may have implications for understanding and regulating human fertility, as well as in assisting infertility treatments. PMID:17227474

  6. Frequency-Dependent Regulation of Follicle-Stimulating Hormone β by Pulsatile Gonadotropin-Releasing Hormone Is Mediated by Functional Antagonism of bZIP Transcription Factors ▿

    PubMed Central

    Ciccone, Nick A.; Xu, Shuyun; Lacza, Charlemagne T.; Carroll, Rona S.; Kaiser, Ursula B.

    2010-01-01

    Oscillatory synthesis and secretion of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), under the control of pulsatile hypothalamic gonadotropin-releasing hormone (GnRH), is essential for normal reproductive development and fertility. The molecular mechanisms by which various patterns of pulsatile GnRH regulate gonadotrope responsiveness remain poorly understood. In contrast to the α and LHβ subunit genes, FSHβ subunit transcription is preferentially stimulated at low rather than high frequencies of pulsatile GnRH. In this study, mutation of a cyclic AMP response element (CRE) within the FSHβ promoter resulted in the loss of preferential GnRH stimulation at low pulse frequencies. We hypothesized that high GnRH pulse frequencies might stimulate a transcriptional repressor(s) to attenuate the action of CRE binding protein (CREB) and show that inducible cAMP early repressor (ICER) fulfills such a role. ICER was not detected under basal conditions, but pulsatile GnRH stimulated ICER to a greater extent at high than at low pulse frequencies. ICER binds to the FSHβ CRE site to reduce CREB occupation and abrogates both maximal GnRH stimulation and GnRH pulse frequency-dependent effects on FSHβ transcription. These data suggest that ICER production antagonizes the stimulatory action of CREB to attenuate FSHβ transcription at high GnRH pulse frequencies, thereby playing a critical role in regulating cyclic reproductive function. PMID:20008557

  7. Analysis of the Relationship between Estradiol and Follicle-Stimulating Hormone Concentrations and Polymorphisms of Apolipoprotein E and LeptinGenes in Women Post-Menopause

    PubMed Central

    Rył, Aleksandra; Jasiewicz, Andrzej; Grzywacz, Anna; Adler, Grażyna; Skonieczna-Żydecka, Karolina; Rotter, Iwona; Sipak-Szmigiel, Olimpia; Rumianowski, Bogdan; Karakiewicz, Beata; Jurczak, Anna; Parczewski, Miłosz; Urbańska, Anna; Grabowska, Marta; Laszczyńska, Maria

    2016-01-01

    Background: Menopause is the permanent cessation of menstruation due to loss of ovarian follicular activity. A review of the available literature indicates that correlations between the changes that take place in a woman’s body after menopause and different genetic variants are still being sought. Methods: The study was conducted in 252 women who had completed physiological menopause. The women were divided into groups according to the time elapsed since menopause. The total concentrations of estradiol and follicle-stimulating hormone were determined by means of electrochemiluminescence. The apolipoprotein E (APOE) and lepitn (LEP) genotypes were determined by real-time PCR and polymerase chain reaction–restriction fragment length polymorphism, respectively. Results: We observed that people with the APOE3/E3 genotype entered menopause insignificantly later compared to other genotypes. Additionally, in the group of patients with the APOE3/E3 genotypes, differences in the E2 concentration were significantly related to the time since their last menstruation. There is no association found in the literature between these polymorphisms of the LEP gene and hormones. Conclusions: To date, attempts to formulate a model describing the association between E2 and FSH concentration with the polymorphisms of various genes of menopause in women have not been successful. This relationship is difficult to study because of the number of nongenetic factors. Environmental factors can explain variation in postmenopausal changes in hormone levels. PMID:27240396

  8. Gankyrin facilitates follicle-stimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1α/cyclin D1 pathway.

    PubMed

    Chen, J; Bai, M; Ning, C; Xie, B; Zhang, J; Liao, H; Xiong, J; Tao, X; Yan, D; Xi, X; Chen, X; Yu, Y; Bast, R C; Zhang, Z; Feng, Y; Zheng, W

    2016-05-12

    Gankyrin is a regulatory subunit of the 26kD proteasome complex. As a novel oncoprotein, gankyrin is expressed aberrantly in cancers from several different sites and has been shown to contribute to oncogenesis in endometrial and cervical carcinomas. Neither gankyrin's contribution to the development of epithelial ovarian cancer nor its interaction with follicle-stimulating hormone (FSH)-driven proliferation in ovarian cancer has been studied. Here we have found that gankyrin is overexpressed in ovarian cancers compared with benign ovarian cystadenomas and that gankyrin regulates FSH upregulation of cyclin D1. Importantly, gankyrin regulates PI3K/AKT signaling by downregulating PTEN. Prolonged AKT activation by FSH stimulation of the FSH receptor (FSHR) promotes gankyrin expression, which, in turn, enhances AKT activation by inhibiting PTEN. Overexpression of gankyrin decreases hypoxia inducible factor-1α (HIF-1α) protein levels, but has little effect on HIF-1α mRNA levels, which could be attributed to gankyrin mediating HIF-1α protein stability via the ubiquitin-proteasome pathway. Reduction in HIF-1α protein stability led to attenuation of the binding with cyclin D1 promoter, resulted in abolishment of the negative regulation of cyclin D1 by HIF-1α, which promotes proliferation of ovarian cancer cells. Our results document that gankyrin regulates HIF-1α protein stability and cyclin D1 expression, ultimately mediating FSH-driven ovarian cancer cell proliferation. PMID:26364616

  9. Effects of 3, 5, 3'-triiodothyronine (t3) and follicle stimulating hormone on apoptosis and proliferation of rat ovarian granulosa cells.

    PubMed

    Zhang, Cheng; Guo, Li; Zhu, Baochang; Feng, Yun; Yu, Shangyu; An, Na; Wang, Xiaoxia

    2013-10-31

    Thyroid hormone (TH) is important for normal reproductive functions and dysregulation of TH support is associated with reproductive disorders. We have previously reported that 3,5,3'-triiodothyronine (T₃) increases follicle stimulating hormone (FSH)-induced preantral follicle growth in vitro. Interaction of hormones with apoptosis and proliferation of granulosa cells is poorly understood. The present study investigated the role and the mechanism of T₃ and/or FSH on granulosa cell apoptosis and proliferation. Granulosa cells harvested from DES-primed immature rats were exposed to T₃ (1 nM) and/or FSH (100 ng/ml) for 24-48 h. We demonstrated by TUNEL assays that the hormones prevented cells from C8-ceramide-induced apoptosis. The Src/PI3K/Akt pathway was involved in the regulation of granulosa cell survival. While ineffective alone, T₃ significantly enhanced the proliferating cell nuclear antigen (PCNA) content of FSH-induced granulosa cells, consistent with the cell number pattern after treatment. Moreover, the action of the hormones on cell proliferation was also shown to be mediated by the Src/PI3K/Akt pathway. Taken together, these results suggest that T₃ potentiates the cell survival action of FSH through inhibiting cell apoptosis and promoting cell proliferation. Moreover, the protective and survival effects of hormones are mediated by the activation of Src/PI3K/Akt pathway. PMID:24032715

  10. Reduction of dehydroepiandrosterone sulfate synthesis in women with polycystic ovary syndrome by human menopausal gonadotropin but not purified urinary follicle stimulating hormone: a comparative pilot study.

    PubMed

    Turkmen, S; Backstrom, T; Idil, M

    2004-08-01

    We aimed to compare the effects of two different gonadotropins on steroid production in patients with polycystic ovary syndrome (PCOS). The study group comprised 20 infertile patients diagnosed with PCOS who were accepted into in vitro fertilization-embryo transfer and gamete intra-Fallopian transfer programs. Ten patients were consecutively allocated to a purified urinary follicle stimulating hormone (FSH) administration group while the other ten received human menopausal gonadotropin (hMG). All patients were pretreated with a gonadotropin releasing hormone-agonist. The patients were followed by daily vaginal ultrasonography until at least two follicles reached a diameter of 17 mm or an estradiol value of at least 100 pg/ml per follicle. To induce ovulation, human chorionic gonadotropin was given. On the 3rd day of menstruation, serum estradiol, luteinizing hormone (LH), FSH, total testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), insulin-like growth factor-I and insulin were measured. These same parameters were measured again on the day of follicle aspiration in both serum and follicular fluid. In both groups, the serum levels of estradiol and androstenedione were raised significantly, and on aspiration day the serum level of DHEAS was significantly raised in the FSH group but not in the hMG group. Our findings suggest that in PCOS patients exogenous hMG induces a different steroid synthesis pattern compared to pure FSH, hypothetically by reduction of the delta-5 steroid synthesis pathway in the adrenals and/or in the ovary. PMID:15624268

  11. Profile of follitropin alpha/lutropin alpha combination for the stimulation of follicular development in women with severe luteinizing hormone and follicle-stimulating hormone deficiency

    PubMed Central

    Rinaldi, Leonardo; Selman, Helmy

    2016-01-01

    A severe gonadotropin deficiency together with chronic estradiol deficiency leading to amenorrhea characterizes patients suffering from hypogonadotropic hypogonadism. Administration of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to these patients has been shown to be essential in achieving successful stimulation of follicular development, ovulation, and rescue of fertility. In recent years, the availability of both recombinant FSH (rFSH) and recombinant LH (rLH) has provided a new therapeutic option for the stimulation of follicular growth in hypopituitary–hypogonadotropic women (World Health Organization Group I). In this article, we review the data reported in the literature to highlight the role and the efficacy of using recombinant gonadotropins, rFSH and rLH, in the treatment of women with severe LH/FSH deficiency. Although the studies on this issue are limited and the experiences available in the literature are few due to the small number of such patients, it is clearly evident that the recombinant gonadotropins rFSH and rLH are efficient in treating patients affected by hypogonadotropic hypogonadism. The results observed in the studies reported in this review suggest that recombinant gonadotropins are able to induce proper follicular growth, oocyte maturation, and eventually pregnancy in this group of women. Moreover, the clinical use of recombinant gonadotropins in this type of patients has given more insight into some endocrinological aspects of ovarian function that have not yet been fully understood. PMID:27307766

  12. Cytoskeletal and mitochondrial properties of bovine oocytes obtained by Ovum Pick-Up: the effects of follicle stimulation and in vitro maturation.

    PubMed

    Somfai, Tamás; Matoba, Satoko; Inaba, Yasushi; Nakai, Michiko; Imai, Kei; Nagai, Takashi; Geshi, Masaya

    2015-12-01

    Follicle stimulation by follicular stimulating hormone (FSH) is known to improve developmental competence of bovine oocytes obtained by Ovum Pick-Up (OPU); however, the exact factors in oocytes affected by this treatment have remained unclear. We compared in vitro matured (IVM) oocytes obtained at the immature stage from cows by OPU either without or with stimulation with FSH (non-stimulated and stimulated OPU, respectively) to those obtained by superstimulation and in vivo maturation in terms of cytoskeleton morphology, mitochondrial distribution, intracellular adenosine triphosphate (ATP) content and H2 O2 levels at the metaphase-II stage and intracellular Ca(2+) levels after in vitro fertilization (IVF). Confocal microscopy after immunostaining revealed reduced size of the meiotic spindle, associated with increased tendencies of microfilament degradation and insufficient mitochondrial re-distribution in non-stimulated OPU-derived IVM oocytes compared with those collected by stimulated OPU, which in turn resembled in vivo matured oocytes. However, there was no difference in mitochondrial functions between oocytes obtained by stimulated or non-stimulated OPU in terms of ATP content, cytoplasmic H2 O2 levels, base Ca(2+) levels and the frequencies and amplitudes of Ca(2+) oscillations after IVF. Larger size of metaphase spindles in oocytes obtained by stimulated OPU may reflect and potentially contribute to their high developmental competence. PMID:26154026

  13. Alterations in the laryngeal mucosa after exposure to asbestos.

    PubMed Central

    Kambic, V; Radsel, Z; Gale, N

    1989-01-01

    The laryngeal mucosa of 195 workers in an asbestos cement factory (Salonit Anhovo, Yugoslavia) and in a control group was examined. The factory manufactures asbestos cement products containing about 13% of asbestos (8% amosite, 12% crocidolite, and 80% chrysotile) of different provenance. Alterations in the laryngeal mucosa were more frequent in the factory workers than in the control group. The changes, mostly consistent with chronic laryngitis, were closely related to the degree of workplace pollution and less so to the duration of employment Ten workers exhibiting the most severe clinical changes underwent biopsy, the results of which showed histomorphological changes characteristic of hyperplastic chronic laryngitis. Four tissue specimens were examined also by scanning electron microscopy and in three of them asbestos fibres were found on the epithelial surface. No case of laryngeal carcinoma was identified. On the basis of our results it is thought that asbestos related changes of the larynx should receive more attention and that the use of the term "laryngeal asbestosis" is justified. The clinical picture is non-specific but in view of their frequency such changes should be considered a consequence of exposure to asbestos. Images PMID:2489023

  14. Suppression of male reproduction in rats after exposure to sodium fluoride during early stages of development

    NASA Astrophysics Data System (ADS)

    Reddy, P. Sreedhar; Pushpalatha, T.; Reddy, P. Sreenivasula

    2007-07-01

    Sodium fluoride (NaF), a widespread natural pollutant was given to sperm-positive female rats throughout gestation and lactation at a dose of 4.5 and 9.0 ppm via drinking water. The neonates were allowed to grow up to 90 days on tap water, and then sperm parameters, testicular steroidogenic marker enzyme activity levels, and circulatory hormone levels were studied. The sperm count, sperm motility, sperm coiling (hypoosmotic swelling test), and sperm viability were decreased in experimental rats when compared with controls. The activity levels of testicular steroidogenic marker enzymes (3β hydroxysteroid dehydrogenase and 17β hydroxysteroid dehydrogenase) were significantly decreased in experimental animals indicating decreased steroidogenesis. The serum testosterone, follicle stimulating hormone and luteinizing hormone levels were also significantly altered in experimental animals. Our data indicate that exposure to NaF during gestation and lactation affects male reproduction in adult rats by decreasing spermatogenesis and steroidogenesis.

  15. Molecular characterization of the Chinese alligator follicle-stimulating hormone β subunit (FSHβ) and its expression during the female reproductive cycle.

    PubMed

    Zhang, Rui; Zhang, Shengzhou; Zhu, Xue; Zhou, Yongkang; Wu, Xiaobing

    2015-05-01

    The Chinese alligator Alligator sinensis is an endangered species endemic to China, it has a highly specialized reproductive pattern with low fecundity. Up to date, little is known about the regulation of its female reproductive cycle. Follicle-stimulating hormone (FSH), a glycoprotein hormone, plays a key role in stimulating and regulating ovarian follicular development and egg production. In this study, the complete FSHβ cDNA from the ovary of the Chinese alligator was obtained for the first time, it consists of 843-bp nucleotides, including 120-bp nucleotides of the 5'-untranslated region (UTR), 396-bp of the open reading frame, and 3'-UTR of 327-bp nucleotides. It encodes a 131-amino acid precursor molecule of FSHβ with a signal peptide of 18 amino acids followed by a mature protein of 113 amino acids. Its deduced amino acid sequence shares high identities with the American alligator (100%) and birds (89-92%). Phylogenetic tree analysis of the FSHβ amino acid sequence indicated that alligators cluster into the bird branch. Tissue distribution analyses indicated that FSHβ mRNA is expressed in ovary, intestine and liver with the highest level in the ovary, while not in stomach, pancreas, heart, thymus and thyroid. Expression of FSHβ in ovary increases in May (breeding prophase) and peaks in July (breeding period), it is maintained at high levels through September, then decreases significantly in November (post-reproductive period) and remains relatively low from January to March (hibernating period). These temporal changes of FSHβ expression implicated that it might play an important role in promoting ovarian development during the female reproductive cycle. PMID:25626184

  16. Kinetic study of internalization and degradation of sup 131 I-labeled follicle-stimulating hormone in mouse Sertoli cells and its relevance to other systems

    SciTech Connect

    Shimizu, A.; Kawashima, S. )

    1989-08-15

    The behavior of 131I-labeled follicle-stimulating hormone (FSH) after binding to cell-surface receptors in cultured Sertoli cells of C57BL/6NCrj mice was investigated. Sertoli cells cultured in F12/DME were pulse-labeled with 131I-FSH for 10 min at 4 degrees C, followed by cold chase for various periods of time. After the cold chase Sertoli cells were treated with 0.2 M acetate (pH 2.5) to dissociate membrane-bound 131I-FSH (surface radioactivity). The medium containing radioactivity after cold chase was mixed with 20% trichloroacetic acid, centrifuged, and the radioactivity of the supernatant was measured (degraded hormone). The radiolabeled materials associated with each process (surface binding, internalization, and degradation) were concentrated with ultrafiltration and characterized with gel filtration and/or thin layer chromatography. The effects of lysosomotropic agents, NH4Cl and chloroquine, were studied. The cold chase study at 32 degrees C showed that the surface radioactivity was the largest among the three kinds of radioactivities associated with each process immediately after pulse labeling, but the surface radioactivity rapidly decreased, while the internalized radioactivity increased. The cold chase study at 4 degrees C did not show such time-related changes in radioactivities, and a high level of surface radioactivity constantly persisted. The surface and internalized radioactivities were due to 131I-FSH, and the degraded radioactivity was mainly due to (131I)monoiodotyrosine. When Sertoli cells were cultured with lysosomotropic agents, the internalized radioactivity increased, while the degraded radioactivity decreased. Based on these observations, a kinetic model was proposed and the relationships among the surface, internalized, and degraded radioactivities and cold chase time were calculated algebraically.

  17. Effects of follicle-stimulating hormone and 17beta-estradiol on proliferation of chicken embryonic ovarian germ cells in culture.

    PubMed

    Xie, Meina; Zhang, Caiqiao; Zeng, Weidong; Mi, Yuling

    2004-12-01

    The effects of follicle-stimulating hormone (FSH) and 17beta-estradiol (E2) on chicken ovarian germ cell proliferation were evaluated through a germ-somatic cell coculture model. Ovarian cells from the left ovaries of 18-day-old chicken embryos were cultured in serum-free McCoy's 5A medium at 39 degrees C and challenged with FSH (0.25-1.0 IU/mL) or E2 (10(-8)-10(-5) M) alone and in combination for 48 h. The number of germ cells was counted, and the proliferating cells were immunolocalized by a specific antibody against proliferating cell nuclear antigen (PCNA). The labeling index (LI) was determined for germ cells. Results revealed that germ cells could survive and kept proliferating under support of somatic cells. Germ cells were localized by expression of a specific antibody for stem cell factor receptor c-kit. Both FSH (0.25-1.0 IU/mL) and E2 (10(-7)-10(-5) M) alone induced a marked increase in germ cell number (P<0.05), and PCNA-LI of germ cells was greater in FSH-treated groups (0.25-1.0 IU/mL) and E2-treated groups (10(-8)-10(-5) M), compared with vehicle-treated group (P<0.05). Furthermore, FSH manifested a synergistic effect with E2 (10(-6)-10(-5) M) in stimulating germ cell proliferation. These results indicate that FSH might interact with estrogen to promote ovarian germ cell proliferation in embryonic chickens near hatching. PMID:15596398

  18. Molecular cloning of LIM homeodomain transcription factor Lhx2 as a transcription factor of porcine follicle-stimulating hormone beta subunit (FSHβ) gene.

    PubMed

    Kato, Takako; Ishikawa, Akio; Yoshida, Saishu; Sano, Yoshiya; Kitahara, Kousuke; Nakayama, Michie; Susa, Takao; Kato, Yukio

    2012-01-01

    We cloned the LIM-homeodomain protein LHX2 as a transcription factor for the porcine follicle-stimulating hormone β subunit gene (Fshβ) by the Yeast One-Hybrid Cloning System using the upstream region of -852/-746 bases (b) from the transcription start site, called Fd2, as a bait sequence. The reporter assay in LβT2 and CHO cells revealed the presence of an LHX2-responsive region other than Fd2. A potential LHX2 binding sequence was confirmed as AATTAAT containing a consensus homeodomain binding core sequence AATT by Systematic Evolution of Ligands by Exponential Enrichment analysis. DNase I footprinting demonstrated three AATTAAT sequences located at regions -835/-829, -818/-812 and -806/-800 b in the Fd2 region and 12 binding sites in the distal and proximal regions mostly containing an AATT-core sequence. RT-PCR analysis of Lhx2 expression during porcine fetal and postnatal pituitary development showed a gradual increase from fetal day (f) 40 to postnatal day (p) 8 followed by a slight decrease to p230, suggesting that LHX2 may play its role largely in the late fetal and postnatal periods. The analyses of Lhx2 expression in pituitary tumor-derived cell lines showed their expressions in cell lines including αT31, LβT2 and others. Since LHX2 was previously identified as a transcription factor for Cga and the in vitro experiments in the present study suggested that LHX2 regulated the expression of Fshβ, it is possible that LHX2 controls the synthesis of FSH at the transcription level. PMID:22134063

  19. Growth hormone, luteinizing hormone, and follicle-stimulating hormone regulation by neuropeptide Y in both sexes of the cichlid fish, Cichlasoma dimerus.

    PubMed

    Di Yorio, M P; Delgadin, T H; Pérez Sirkin, D I; Vissio, P G

    2015-08-01

    Neuropeptide Y (NPY) is considered the most potent orexigenic peptide, increasing before meal time and during fasting. In teleost, most studies on NPY action upon growth hormone (GH) and luteinizing hormone (LH) were conducted in females or group of animals without sex discrimination. The aim of this study was to evaluate whether NPY modulates the expression and release of GH and gonadotropins in both sexes of Cichlasoma dimerus. By double-label immunofluorescence, we first determined the association between NPY fibers and pituitary cells. In addition, we performed in vitro studies to evaluate the effect of NPY on GH and gonadotropins expression by real-time PCR, and release by Western blot, in males and females separately. Contacts between NPY fibers and GH and follicle-stimulating hormone (FSH)-producing cells were detected, indicating possible functional relationships. We observed an increase in GH release in the culture medium at 2 nM for males (p = 0.043) and 20 nM for females (p = 0.028). Pituitary FSH release was stimulated at 20 nM (p = 0.026) and 200 nM (p = 0.033) for males and females, respectively. Finally, NPY only increased β-LH mRNA expression at 20 nM in females (p = 0.028) and its release at 2 nM (p = 0.049) and 200 nM for males (p = 0.005) and 200 nM for females (p = 0.018). In conclusion, NPY acts as a GH-, LH- and FSH-releasing factor, in a dose- and sex-dependent way. PMID:25869217

  20. Metabolism of energy substrates of in vitro and in vivo derived embryos from ewes synchronized and super ovulated with norgestomet and porcine follicle stimulating hormone

    PubMed Central

    2012-01-01

    The synchronization and ovulatory responses of Sangsari cross bred ewes and metabolism of energy substrates in 8-cell stage embryos to hatched blastocysts stage produced in vitro or in vivo were investigated. Ewes were assigned randomly to receive 37.5 IU of porcine follicle stimulating hormone (FSH-P) daily for the 3 days preceding implant removal (Day 0). Synchronization of estrus was carried out using a 1.5 mg norgestomet (Crestar) ear implant for 12 days. Ewes in estrus were mated two to three times with rams of proven fertility. At the time of first mating each ewe was administered 1000 IU of human chorionic gonadotrophin (hCG) to induce ovulation. Surgical embryo recovery was performed on Days 4 and 6 after onset of estrus (Day 0) and recovered embryos were subjected to comparative metabolism studies with in vitro derived embryos at the same stage of development. The number of corpora lutea (CL), unovulated follicles and overall ovarian activity were recorded for each ewe during the breeding and non-breeding seasons. While the pattern of oxidation was similar among in vitro and in vivo derived embryos, a low pyruvate to lactate ratio was the preferred substrate of embryos derived in vitro. A high level of production of CO2 and lactate resulted from a stress response to the suboptimal culture environment. The first marked increase in the metabolism of glucose by ovine embryos was detected in compact morula stage, but there was no significant increase in the oxidation of glucose after the morula stage. Two different concentrations of glucose were compared, but this did not affect metabolism. However, the rate of incorporation and metabolism of glucose tended to be higher at the 0.56 mmol/L glucose dosage. PMID:23157819

  1. Follicle-stimulating hormone potentiates the steroidogenic activity of chorionic gonadotropin and the anti-apoptotic activity of luteinizing hormone in human granulosa-lutein cells in vitro.

    PubMed

    Casarini, Livio; Riccetti, Laura; De Pascali, Francesco; Nicoli, Alessia; Tagliavini, Simonetta; Trenti, Tommaso; La Sala, Giovanni Battista; Simoni, Manuela

    2016-02-15

    Luteinizing hormone (LH) and choriogonadotropin (hCG) are glycoprotein hormones regulating ovarian function and pregnancy, respectively. Since these molecules act on the same receptor (LHCGR), they were traditionally assumed as equivalent in assisted reproduction techniques (ART), although differences between LH and hCG were demonstrated at molecular and physiological level. In this study, we demonstrated for the first time that co-treatment with a follicle-stimulating hormone (FSH) dose in the ART therapeutic range potentiates different LH- and hCG-dependent responses in vitro, measured in terms of cAMP, phospho-CREB, -ERK1/2 and -AKT activation, gene expression, progesterone and estradiol production in human granulosa-lutein cells (hGLC). We show that in the presence of FSH, hCG biopotency is about 5-fold increased, in the presence of FSH, in terms of cAMP activation. Accordingly, CREB phosphorylation and steroid production is increased under hCG and FSH co-treatment. LH effects, evaluated as steroidogenic cAMP/PKA pathway activation, do not change in the presence of FSH, which, however, increases LH-dependent ERK1/2 and AKT, but not CREB phosphorylation, resulting in anti-apoptotic effects. The different modulatory activity of FSH on LH and hCG action in vitro corresponds to their different physiological functions, reflecting proliferative effects exerted by LH during the follicular phase and before trophoblast development, and the high steroidogenic potential of hCG requested to sustain pregnancy from the luteal phase onwards. PMID:26690776

  2. CREB coactivator CRTC2/TORC2 and its regulator calcineurin crucially mediate follicle-stimulating hormone and transforming growth factor β1 upregulation of steroidogenesis.

    PubMed

    Fang, Wei-Ling; Lee, Ming-Ting; Wu, Leang-Shin; Chen, Yun-Ju; Mason, Jian; Ke, Ferng-Chun; Hwang, Jiuan-Jiuan

    2012-06-01

    In vitro and in vivo studies implicate that follicle-stimulating hormone (FSH) and transforming growth factor β1 (TGFβ1) play crucial physiological roles in regulating ovarian granulosa cell function essential to fertility control in females. FSH induces cAMP and calcium signaling, thereby activating transcription factor CREB to upregulate steroidogenic gene expression, and TGFβ1 greatly enhances FSH-stimulated steroidogenesis. A CREB coactivator CRTC2/TORC2 was identified to function as a cAMP and calcium-sensitive coincidence sensor. This led us to explore the role of CRTC2 and its regulator calcineurin in FSH and TGFβ1-stimulated steroidogenesis. Primary culture of granulosa cells from gonadotropin-primed immature rats was used. Immunoblotting analysis shows that FSH rapidly and transiently induced dephosphorylation/activation of CRTC2, and FSH + TGFβ1 additionally induced late-phase CRTC2 dephosphorylation. Immunofluorescence analysis further confirms FSH ± TGFβ1 promoted CRTC2 nuclear translocation. Using selective inhibitors, we demonstrate that FSH activated CRTC2 in a PKA- and calcineurin-dependent manner, and TGFβ1 acting through its type I receptor (TGFβRI)-modulated FSH action in a calcineurin-mediated and PKA-independent fashion. Next, we investigated the involvement of calcineurin and CRTC2 in FSH and TGFβ1-stimulated steroidogenesis. Calcineurin and TGFβRI inhibitor dramatically reduced the FSH ± TGFβ1-increased progesterone synthesis and protein levels of StAR, P450scc, and 3β-HSD enzyme. Furthermore, chromatin-immunoprecipitation and immunoprecipitation analyses demonstrate that FSH ± TGFβ1 differentially increased CRTC2, CREB, and CBP binding to these steroidogenic genes, and CREB nuclear association with CRTC2 and CBP. In all, this study reveals for the first time that CRTC2 and calcineurin are critical signaling mediators in FSH and TGFβ1-stimulated steroidogenesis in ovarian granulosa cells. PMID:21826657

  3. Follicle-stimulating hormone receptor (FSHR) in Chinese alligator, Alligator sinensis: molecular characterization, tissue distribution and mRNA expression changes during the female reproductive cycle.

    PubMed

    Zhang, Rui; Zhang, Shengzhou; Zhu, Xue; Zhou, Yongkang; Wu, Xiaobing

    2015-05-01

    The follicle-stimulating hormone (FSH) plays a central role in vertebrate reproduction, with the actions of FSH mediated by FSH receptors (FSHRs) on the granulosa cells of the ovary. The present study reports the cloning and characterization of FSHR in Chinese alligator, Alligator sinensis (caFSHR), and its tissue distribution and mRNA expression changes during the reproductive cycle. The mature protein of caFSHR displays typical features of the glycoprotein hormone receptor family, but also contains some remarkable differences when compared with other vertebrate FSHRs. The deduced amino acid sequence of the caFSHR shares identity of 85% with Chinese softshell turtle, 84-87% with birds, 77-78% with mammals, 67-73% with amphibians and 51-58% with fishes. Phylogenetic tree analysis of the FSHR amino acid sequence indicated that alligators cluster into the bird branch. Tissue expression analysis showed that caFSHR was not only expressed in the ovary, but also in the stomach, intestine, pancreas liver and oviduct at similar levels, while it was not detectable in heart, thymus or thyroid. Expression of caFSHR in the ovary is high in May (breeding prophase) and peaks in July during the breeding period, where it is maintained at high levels through September (breeding anaphase). Expression decreases significantly in November (hibernating period) and then remains relatively low from January to March (hibernating period). These temporal changes in FSHR expression suggest that it plays an important role in promoting ovarian development during the female reproductive cycle of Chinese alligator. PMID:25765682

  4. The preparation and application of N-terminal 57 amino acid protein of the follicle-stimulating hormone receptor as a candidate male contraceptive vaccine

    PubMed Central

    Xu, Cheng; Li, Ying-Chun; Yang, Hua; Long, Yan; Chen, Min-Jian; Qin, Yu-Feng; Xia, Yan-Kai; Song, Ling; Gu, Ai-Hua; Wang, Xin-Ru

    2014-01-01

    Follicle-stimulating hormone receptor (FSHR), which is expressed only on Sertoli cells and plays a key role in spermatogenesis, has been paid attention for its potential in male contraception vaccine research and development. This study introduces a method for the preparation and purification of human FSHR 57-amino acid protein (FSHR-57aa) as well as determination of its immunogenicity and antifertility effect. A recombinant pET-28a(+)-FSHR-57aa plasmid was constructed and expressed in Escherichia coli strain BL21 Star™ (DE3) and the FSHR-57aa protein was separated and collected by cutting the gel and recovering activity by efficient refolding dialysis. The protein was identified by Western blot and high-performance liquid chromatography analysis with a band of nearly 7 kDa and a purity of 97.4%. Male monkeys were immunized with rhFSHR-57aa protein and a gradual rising of specific serum IgG antibody was found which reached a plateau on day 112 (16 weeks) after the first immunization. After mating of one male with three female monkeys, the pregnancy rate of those mated with males immunized against FSHR-57aa was significantly decreased while the serum hormone levels of testosterone and estradiol were not disturbed in the control or the FSHR-57aa groups. By evaluating pathological changes in testicular histology, we found that the blood-testis barrier remained intact, in spite of some small damage to Sertoli cells. In conclusion, our study demonstrates that the rhFSHR-57aa protein might be a feasible male contraceptive which could affect sperm production without disturbing hormone levels. PMID:24713829

  5. Follicle-stimulating Hormone Regulates Pro-apoptotic Protein Bcl-2-interacting Mediator of Cell Death-Extra Long (BimEL)-induced Porcine Granulosa Cell Apoptosis*

    PubMed Central

    Wang, Xian-Long; Wu, Yi; Tan, Lu-Bin; Tian, Zhen; Liu, Jing-Hao; Zhu, De-Sheng; Zeng, Shen-Ming

    2012-01-01

    The pro-apoptotic protein Bim (B-cell lymphoma-2 (Bcl-2)-interacting modulator of cell death) has recently been identified and shown to promote cell death in response to several stimuli. In this report, we investigated the role of Bim in porcine follicular atresia. Initially, Bim cDNA was cloned and characterized from porcine ovarian tissue. Porcine Bim had three alternative splicing variants (Bim-extra long, Bim-long, and Bim-short), all containing the consensus Bcl-2 homology 3 domain. We then found the Bim-extra long (BimEL) protein, the most abundant isoform of Bim, was strongly expressed and co-localized with apoptotic (TUNEL-positive) granulosa cells from porcine atretic follicles. Furthermore, overexpression of BimEL triggered apoptosis in granulosa cells. In primary granulosa cell cultures under basal conditions, we observed that BimEL expression was dampened by treatment with follicle-stimulating hormone (FSH). The role of the PI3K/Akt pathway in the regulation of repression was clarified by the use of the PI3K inhibitor, LY294002, and by transfection with Akt siRNA. Forkhead Box Protein O3a (FoxO3a), a well defined transcriptional activator of Bim, was phosphorylated at Ser-253 and inactivated after FSH stimulation. Also, FSH abolished FoxO3a nuclear accumulation in response to LY294002. Finally, chromatin immunoprecipitation assays demonstrated that FoxO3a directly bound and activated the bim promoter. Taken together, we conclude that BimEL induces porcine granulosa cell apoptosis during follicular atresia, and its expression is regulated by FSH via the PI3K/Akt/FoxO3a pathway. PMID:22235114

  6. Control of gonadotrophin secretion by steroid hormones in castrated male transsexuals. I. Effects of oestradiol infusion on plasma levels of follicle-stimulating hormone and luteinizing hormone.

    PubMed

    Goh, H H; Chew, P C; Karim, S M; Ratnam, S S

    1980-02-01

    Twenty-four infusions of oestradiol (E2) in graded doses ranging from 0--200 micrograms administered over a period of 7 hours were carried out in eleven healthy male transsexuals who had undergone sex reassignment at least 3 months previously. Plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and E2 were analysed by radioimmunoassay, while sex hormone binding globulin (SHBG) was measured using 3H-testosterone as the saturating ligand. Infusion of 5--200 micrograms of E2 raised plasma E2 to levels ranging from 38.4--367.8 pg/ml which present 83%--800% of levels found in a control group of sixty-three normal males. SHBG capacity remained unchanged at all doses of E2 studied. No change in plasma levels of FSH and LH was observed in control infusions and infusion of 5 micrograms of E2. From 10 micrograms-200 micrograms, suppression of plasma levels of FSH was noted at the 5--7 hour period. The suppression increased up to 20 micrograms and thereafter the levels of FSH remained constant. On the other hand, the suppression of LH increased up to the highest E2 dose (200 micrograms) studied. Further, significant suppression of LH occurred earlier than the 5--7 hours as the dose of E2 increased. These observations are consistent with the conclusions that: (1) E2 plays a part in the regulation of secretion of FSH and LH in men; and (2) at doses higher than physiological, E2 exerts a differential effect on the secretion of FSH and LH. PMID:6772356

  7. The preparation and application of N-terminal 57 amino acid protein of the follicle-stimulating hormone receptor as a candidate male contraceptive vaccine.

    PubMed

    Xu, Cheng; Li, Ying-Chun; Yang, Hua; Long, Yan; Chen, Min-Jian; Qin, Yu-Feng; Xia, Yan-Kai; Song, Ling; Gu, Ai-Hua; Wang, Xin-Ru

    2014-01-01

    Follicle-stimulating hormone receptor (FSHR), which is expressed only on Sertoli cells and plays a key role in spermatogenesis, has been paid attention for its potential in male contraception vaccine research and development. This study introduces a method for the preparation and purification of human FSHR 57-amino acid protein (FSHR-57aa) as well as determination of its immunogenicity and antifertility effect. A recombinant pET-28a(+)-FSHR-57aa plasmid was constructed and expressed in Escherichia coli strain BL21 Star TM (DE3) and the FSHR-57aa protein was separated and collected by cutting the gel and recovering activity by efficient refolding dialysis. The protein was identified by Western blot and high-performance liquid chromatography analysis with a band of nearly 7 kDa and a purity of 97.4%. Male monkeys were immunized with rhFSHR-57aa protein and a gradual rising of specific serum IgG antibody was found which reached a plateau on day 112 (16 weeks) after the first immunization. After mating of one male with three female monkeys, the pregnancy rate of those mated with males immunized against FSHR-57aa was significantly decreased while the serum hormone levels of testosterone and estradiol were not disturbed in the control or the FSHR-57aa groups. By evaluating pathological changes in testicular histology, we found that the blood-testis barrier remained intact, in spite of some small damage to Sertoli cells. In conclusion, our study demonstrates that the rhFSHR-57aa protein might be a feasible male contraceptive which could affect sperm production without disturbing hormone levels. PMID:24713829

  8. Intracerebroventricular infusion of neuropeptide Y up-regulates synthesis and accumulation of luteinizing hormone but not follicle stimulating hormone in the pituitary cells of prepubertal female lambs.

    PubMed

    Wańkowska, Marta; Lerrant, Yannick; Wójcik-Gładysz, Anna; Starzec, Anna; Counis, Raymond; Polkowska, Jolanta

    2002-02-01

    Neuropeptide Y (NPY) is a putative neuroregulator of the reproductive axis in the central nervous system. In this study we evaluated the effects of central infusion of exogenous NPY on the secretory activity of pituitary gonadotrophic cells in prepubertal lambs. Immature female Merino sheep (n=12) were infused of Ringer solution (control) or 50 microg of NPY to the third ventricle for 5 min and then slaughtered 3 h later. Immunoreactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) cells were localised by immunohistochemistry using antibody raised against LHbeta and FSHbeta. Messenger RNA analyses were performed by in situ hybridisation using sense and antisense riboprobes produced from beta subunits of LH and FSH cDNA clones. The results were generated by computer image analysis to determine the area fraction occupied by immunoreactive and/or hybridising cells and optical density for immunostaining and hybridisation signal. LH in the blood plasma was determined by radioimmunoassay. It was found, that in the lambs infused with NPY the area fraction and optical density for immunoreactive LH cells and mRNA LHbeta-expressing cells increased significantly (P<0.001), compared to the vehicle-infused animals. The concentration of LH in the blood plasma did not differ between control and treated groups. The NPY infusions had no effect on the immunoreactivity of FSH cells or on expression of mRNA for FSHbeta. In conclusion we suggest that NPY may be an important component of mechanisms stimulating the synthesis and storage but not the release of LH in the pituitary gonadotrophs from prepubertal female sheep. In addition, this effect is specific for LH, no such effect was apparent on FSH. PMID:11841917

  9. Efficacy of corifollitropin alfa followed by recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist protocol for Korean women undergoing assisted reproduction

    PubMed Central

    Park, Hyo Young; Lee, Min Young; Jeong, Hyo Young; Rho, Yong Sook; Song, Sang Jin

    2015-01-01

    Objective To evaluate the effect of a gonadotropin-releasing hormone (GnRH) antagonist protocol using corifollitropin alfa in women undergoing assisted reproduction. Methods Six hundred and eighty-six in vitro fertilization-embryo transfer (IVF)/intracytoplasmic sperm injection (ICSI) cycles were analyzed. In 113 cycles, folliculogenesis was induced with corifollitropin alfa and recombinant follicle stimulating hormone (rFSH), and premature luteinizing hormone (LH) surges were prevented with a GnRH antagonist. In the control group (573 cycles), premature LH surges were prevented with GnRH agonist injection from the midluteal phase of the preceding cycle, and ovarian stimulation was started with rFSH. The treatment duration, quality of oocytes and embryos, number of embryo transfer (ET) cancelled cycles, risk of ovarian hyperstimulation syndrome (OHSS), and the chemical pregnancy rate were evaluated in the two ovarian stimulation protocols. Results There were no significant differences in age and infertility factors between treatment groups. The treatment duration was shorter in the corifollitropin alfa group than in the control group. Although not statistically significant, the mean numbers of matured (86.8% vs. 85.1%) and fertilized oocytes (84.2% vs. 83.1%), good embryos (62.4% vs. 60.3%), and chemical pregnancy rates (47.2% vs. 46.8%) were slightly higher in the corifollitropin alfa group than in the control group. In contrast, rates of ET cancelled cycles and the OHSS risk were slightly lower in the corifollitropin alfa group (6.2% and 2.7%) than in the control group (8.2% and 3.5%), although these differences were also not statistically significant. Conclusion Although no significant differences were observed, the use of corifollitropin alfa seems to offer some advantages to patients because of its short treatment duration, safety, lower ET cancellation rate and reduced risk of OHSS. PMID:26161335

  10. Correlation analysis for follicle-stimulating hormone and C-terminal cross-linked telopetides of type i collagen in menopausal transition women with osteoporosis

    PubMed Central

    Wang, Bing; Song, Yang; Chen, Yan; Wang, En-Sheng; Zheng, Dan; Qu, Fan; Zhou, Jian-Hong

    2015-01-01

    The sudden drop in estrogen in post-menopausal women can lead to osteoporosis. About one in three women aged more than 50 years experienced an osteoporotic fracture. The aim of this study is to explore function of follicle-stimulating hormone (FSH) in bone metabolism and osteoporosis in menopausal transition women. 164 cases of women in menopausal transition were included, and which were divided into three groups, including < 40 years group, 40-50 years group and > 50 years group. All of patients must with empty stomach, and 5 ml blood was collected from median cubital vein between second day to ninth day in menstruation period. Examination of FSH and C-terminal cross-linked telopetides of type I collagen (CTx) was performed by using ECLIA assay. The results indicated that CTx levels were distinguished among the different aged group, with the increasing level following with the increased age. FSH level in both of < 40 years and 40-50 years old women were positively correlated with CTx level (P < 0.05). The spearman rank correlation analysis results also showed that there were no significant correlation between CTx level and FSH level in > 50 years old women. There were significant differences for the CTx level between 0-40 mIU/ml group and > 40 40 mIU/ml group in all of the three ages group (P < 0.05). In conclusion, it’s clinically significant for the combining examination of FSH and CTx in menopausal transition women, which could observe the bone metabolize changes quickly and sensitively, and prevent or therapy the osteoporosis in a further step. PMID:25932182

  11. Predicting pregnancy in women undergoing in-vitro fertilization with basal serum follicle stimulating hormone levels between 10.0 and 11.9 IU/L

    PubMed Central

    Levin, Dan; Jun, Sunny H.; Dahan, Michael H.

    2015-01-01

    Objective To evaluate the results of the in vitro fertilization (IVF) cycle outcomes in women whose borderline basal follicle stimulating hormone (FSH) levels were between 10.0 and 11.9 IU/L and to analyze the predictors of pregnancy in this population. Material and Methods A prospective cohort study was performed at an academic teaching hospital; participants were infertile couples in which the women were undergoing IVF treatment and had borderline basal highest FSH levels between 10.0 and 11.9 IU/L. Statistical modeling was performed to determine risk factors for pregnancy and clinical pregnancy. Results A clinical pregnancy rate of 26.5% per cycle and 35% per patient was found in the study population. Among all subjects and non-intracytoplasmic sperm injection (ICSI) subjects, younger age, higher gravidity, higher number of mature follicles on day of Human Chorionic gonadotrophin (hCG) triggering, higher number of oocytes retrieved, and number of embryos produced were significant discriminators between individuals who conceived and those who did not. However, only the number of embryos predicted those who had a clinical pregnancy when compared with those who did not. Higher gravidity, and basal estradiol (E2) levels, and lower maximum basal FSH levels predicted clinical pregnancy in non-ICSI patients. Among ICSI patients, the only predictor of pregnancy was a thicker endometrium. A trend towards higher pregnancy rates was noted in ICSI patients. Conclusion We showed that pregnancy rates per cycle and per patient in this population were not significantly different than those in patients with a basal FSH level below 10.0 IU/L. Preliminary evidence suggests that ICSI is the fertilization method of choice in these patients. PMID:25788842

  12. Multicenter, noninterventional, post-marketing surveillance study to evaluate dosing of recombinant human follicle-stimulating hormone using the redesigned follitropin alfa pen in women undergoing ovulation induction

    PubMed Central

    Nawroth, Frank; Tandler-Schneider, Andreas; Bilger, Wilma

    2015-01-01

    This prospective, noninterventional, post-marketing surveillance study evaluated doses of recombinant human follicle-stimulating hormone (r-hFSH) using the redesigned follitropin alfa pen in women who were anovulatory or oligomenorrheic and undergoing ovulation induction (OI) alone or OI with intrauterine insemination. The primary endpoint was the proportion of patients who achieved monofollicular or bifollicular development (defined as one or two follicles ≥15 mm). Secondary endpoints included characteristics of ovulation stimulation treatment, such as mean total and mean daily r-hFSH doses. Data were analyzed for 3,193 patients from 30 German fertility centers. The proportion of patients with monofollicular or bifollicular development was 71.1% (n=2,270 of a total of 3,193 patients; intent-to-treat population). The mean±standard deviation total and daily doses of r-hFSH were 696.9±542.5 IU and 61.7±29.4 IU, respectively. The three doses prescribed most frequently were: 37.5 IU (n=703 from N=3,189; 22.0%), 50.0 IU (n=1,056 from N=3,189; 33.1%), and 75.0 IU (n=738 from N=3,189; 23.1%) on the first day of stimulation; and 37.5 IU (n=465 from N=3,189; 14.6%), 50.0 IU (n=922 from N=3,189; 28.9%), and 75.0 IU (n=895 from N=3,189; 28.1%) on the last day of stimulation. This noninterventional, post-marketing surveillance study found that monofollicular or bifollicular development was achieved in 71% of patients studied and the small dose increment (12.5 IU) of the redesigned follitropin alfa pen allowed individualized treatment of women undergoing OI. PMID:25926755

  13. Decreased bone mineral density in rats rendered follicle-deplete by an ovotoxic chemical correlates with changes in follicle-stimulating hormone and inhibin A.

    PubMed

    Lukefahr, A L; Frye, J B; Wright, L E; Marion, S L; Hoyer, P B; Funk, J L

    2012-03-01

    Bone loss during perimenopause, an estrogen-sufficient period, correlates with elevated serum follicle-stimulating hormone (FSH) and decreased inhibins A and B. Utilizing a recently described ovotoxin-induced animal model of perimenopause characterized by a prolonged estrogen-replete period of elevated FSH, we examined longitudinal changes in bone mineral density (BMD) and their association with FSH. Additionally, serum inhibin levels were assessed to determine whether elevated FSH occurred secondary to decreased ovarian inhibin production and, if so, whether inhibins also correlated with BMD. BMD of the distal femur was assessed using dual-energy X-ray absorptiometry (DXA) over 19 months in Sprague-Dawley rats treated at 1 month with vehicle or 4-vinylcyclohexene diepoxide (VCD, 80 or 160 mg/kg daily). Serum FSH, inhibins A and B, and 17-ß estradiol (E(2)) were assayed and estrus cyclicity was assessed. VCD caused dose-dependent increases in FSH that exceeded values occurring with natural senescence, hastening the onset and prolonging the duration of persistent estrus, an acyclic but E(2)-replete period. VCD decreased serum inhibins A and B, which were inversely correlated with FSH (r(2) = 0.30 and 0.12, respectively). In VCD rats, significant decreases in BMD (5-13%) occurred during periods of increased FSH and decreased inhibins, while BMD was unchanged in controls. In skeletally mature rats, FSH (r(2) = 0.13) and inhibin A (r(2) = 0.15) correlated with BMD, while inhibin B and E(2) did not. Thus, for the first time, both the hormonal milieu of perimenopause and the association of dynamic perimenopausal changes in FSH and inhibin A with decreased BMD have been reproduced in an animal model. PMID:22249524

  14. Decreased Bone Mineral Density in Rats Rendered Follicle-Deplete by an Ovotoxic Chemical Correlates with Changes in Follicle-Stimulating Hormone and Inhibin A

    PubMed Central

    Lukefahr, A. L.; Frye, J. B.; Wright, L. E.; Marion, S. L.; Hoyer, P. B.; Funk, J. L.

    2012-01-01

    Bone loss during perimenopause, an estrogen-sufficient period, correlates with elevated serum follicle-stimulating hormone (FSH) and decreased inhibins A and B. Utilizing a recently described ovotoxin-induced animal model of perimenopause characterized by a prolonged estrogen-replete period of elevated FSH, we examined longitudinal changes in bone mineral density (BMD) and their association with FSH. Additionally, serum inhibin levels were assessed to determine whether elevated FSH occurred secondary to decreased ovarian inhibin production and, if so, whether inhibins also correlated with BMD. BMD of the distal femur was assessed using dual-energy X-ray absorptiometry (DXA) over 19 months in Sprague-Dawley rats treated at 1 month with vehicle or 4-vinylcyclohexene diepoxide (VCD, 80 or 160 mg/kg daily). Serum FSH, inhibins A and B, and 17-ß estradiol (E2) were assayed and estrus cyclicity was assessed. VCD caused dose-dependent increases in FSH that exceeded values occurring with natural senescence, hastening the onset and prolonging the duration of persistent estrus, an acyclic but E2-replete period. VCD decreased serum inhibins A and B, which were inversely correlated with FSH (r2 = 0.30 and 0.12, respectively). In VCD rats, significant decreases in BMD (5–13%) occurred during periods of increased FSH and decreased inhibins, while BMD was unchanged in controls. In skeletally mature rats, FSH (r2 = 0.13) and inhibin A (r2 = 0.15) correlated with BMD, while inhibin B and E2 did not. Thus, for the first time, both the hormonal milieu of perimenopause and the association of dynamic perimenopausal changes in FSH and inhibin A with decreased BMD have been reproduced in an animal model. PMID:22249524

  15. Pubertal development in the male pig: effects of treatment with a long-acting gonadotropin-releasing hormone agonist on plasma luteinizing hormone, follicle stimulating hormone and testosterone.

    PubMed Central

    Trudeau, V L; Meijer, J C; Erkens, J H; van de Wiel, D F; Wensing, C J

    1992-01-01

    The effects of a long-acting gonadotropin-releasing hormone (GnRH) agonist, [D-Trp6]-GnRH (GnRH-A) on developmental profiles of plasma luteinizing hormone (LH), follicle stimulation hormone (FSH) and testosterone (T), and pituitary responsiveness to exogenous GnRH were studied in male Dutch Landrace x Large White crossbred pigs from 1 to 30 wk of age. Group 1 control animals (control; n = 12) were injected subcutaneously in the neck with vehicle at 1 and 16 wk of age. Group 2 animals (early treatment; n = 10) were injected with 600 micrograms [D-Trp6]-GnRH at 1 wk and with vehicle at 16 wk. Group 3 animals (late treatment; n = 8) were injected with vehicle and 3 mg GnRH-A at 1 and 16 wk, respectively. Group 4 animals (early plus late treatment; n = 9) were injected at both 1 and 16 wk with GnRH-A. Blood was collected by brachiocephalic puncture at weekly or biweekly intervals, and through brachiocephalic cannulae, to determine longitudinal profiles of LH, FSH and T, and plasma gonadotropin responses to intravenous injection of GnRH (0.1 microgram/kg), respectively. In control animals, LH and FSH declined over the first 5 wk of postnatal life and peaked again at 10-14 wk. Levels of both hormones were basal from 18 to 30 wk. Plasma T was high in the first week, declined progressively over the next few weeks and remained low until 24 wk when a transient increment was noted. The LH and FSH responses to acute GnRH stimulation were similar at 7 and 14 wk and declined significantly at 23 wk of age.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1534270

  16. CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FAILS TO ALTER BRAINSTEM AUDITORY EVOKED RESPONSE (BAERS) IN RATS.

    EPA Science Inventory

    Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Cholinergic transmission is involved in auditory structures in the periphery and the brainstem and is altered following chlorpyrifos exposure. This study e...

  17. CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FAILS TO ALTER FLASH OR PATTERN REVERSAL EVOKED POTENTIALS IN RATS.

    EPA Science Inventory

    Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Visual disturbances are often reported following exposure to xenobiotics, and cholinesterase-inhibiting compounds have been reported to alter visual functi...

  18. FINE PARTICLE EXPOSURE IS ASSOCIATED WITH ALTERED VENTRICULAR REPOLARIZATION

    EPA Science Inventory

    Exposure to fine airborne particulate matter (PM2.5) has previously been associated with cardiac events, especially in older people with cardiovascular disease and in diabetics. This study examined the cardiac effects of short-term exposures to ambient PM2.5 in a prospective pane...

  19. NEONATAL CHIORDECONE EXPOSURE ALTERS BEHAVIORAL SEX DIFFERENTIATION IN FEMALE HAMSTERS

    EPA Science Inventory

    The present study was designed in order to determine if exposure to the weakly estrogenic pesticide Chlordecone during a critical period of behavioral sex differentiation of the brain could masculinize and defeminize the behavior of female hamsters.

  20. In utero and postnatal exposure to arsenic alters pulmonary structure and function

    SciTech Connect

    Lantz, R. Clark Chau, Binh; Sarihan, Priyanka; Witten, Mark L.; Pivniouk, Vadim I.; Chen, Guan Jie

    2009-02-15

    In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures to arsenic (100 ppb or less in drinking water) were found to alter airway reactivity to methacholine challenge in 28 day old pups. Removal of mice from arsenic exposure 28 days after birth did not reverse the alterations in sensitivity to methacholine. In addition, adult mice exposed to similar levels of arsenic in drinking water did not show alterations. Therefore, alterations in airway reactivity were irreversible and specific to exposures during lung development. These functional changes correlated with protein and gene expression changes as well as morphological structural changes around the airways. Arsenic increased the whole lung levels of smooth muscle actin in a dose dependent manner. The level of smooth muscle mass around airways was increased with arsenic exposure, especially around airways smaller than 100 {mu}m in diameter. This increase in smooth muscle was associated with alterations in extracellular matrix (collagen, elastin) expression. This model system demonstrates that in utero and postnatal exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary structure and function in the adults.

  1. Developmental timing of perchlorate exposure alters threespine stickleback dermal bone

    PubMed Central

    Furin, Christoff G.; von Hippel, Frank A.; Postlethwait, John; Buck, C. Loren; Cresko, William A.; O’Hara, Todd M.

    2015-01-01

    Adequate levels of thyroid hormone are critical during development and metamorphosis, and for maintaining metabolic homeostasis. Perchlorate, a common contaminant of water sources, inhibits thyroid function in vertebrates. We utilized threespine stickleback (Gasterosteus aculeatus) to determine if timing of perchlorate exposure during development impacts adult dermal skeletal phenotypes. Fish were exposed to water contaminated with perchlorate (30 mg/L or 100 mg/L) beginning at 0, 3, 7, 14, 21, 42, 154 or 305 days post fertilization until sexual maturity at one year of age. A reciprocal treatment moved stickleback from contaminated to clean water on the same schedule providing for different stages of initial exposure and different treatment durations. Perchlorate exposure caused concentration-dependent significant differences in growth for some bony traits. Continuous exposure initiated within the first 21 days post fertilization had the greatest effects on skeletal traits. Exposure to perchlorate at this early stage can result in small traits or abnormal skeletal morphology of adult fish which could affect predator avoidance and survival. PMID:25753171

  2. Follicle Stimulating Hormone and Anti-Müllerian Hormone per Oocyte in Predicting in vitro Fertilization Pregnancy in High Responders: A Cohort Study

    PubMed Central

    Weghofer, Andrea; Kim, Ann; Barad, David H.; Gleicher, Norbert

    2012-01-01

    Background Follicle stimulating hormone (FSH) and Anti-Müllerian hormone (AMH) are utilized to differentiate between good and poor response to controlled ovarian hyperstimulation. Their respective roles in defining functional ovarian reserve remain, however, to be elucidated. To better understand those we investigated AMH and FSH per oocyte retrieved (AMHo and FSHo). Methodology/Principal Findings Three-hundred and ninety-six women, undergoing first in vitro fertilization cycles, were retrospectively evaluated. Women with oocyte yields >75th percentile for their age group were identified as high responders. In a series of logistic regression analyses, AMHo and FSHo levels were then evaluated as predictive factors for pregnancy potential in high responders. Patients presented with a mean age of 38.0±5.0 years, mean baseline FSH of 11.8±8.7 mIU/mL and mean AMH of 1.6±2.1 ng/mL. Those 88 women, who qualified as high responders, showed mean FSH of 9.7±6.5 mIU/mL, AMH of 3.1±3.1 ng/mL and oocyte yields of 15.8±7.1. Baseline FSH and AMH did not predict pregnancy in high responders. However, a statistically significant association between FSHo and pregnancy was observed in high responders, both after univariate regression (p = 0.02) and when adjusted for age, percentage of usable embryos, and number of embryos transferred (p = 0.03). Rate of useable embryos also significantly affected pregnancy outcome independently of FSHo (p = 0.01). AMHo was also associated with clinical pregnancy chances in high responders (p = 0.03) and remained significant when adjusted for usable embryos and number of embryos transferred (p = 0.04). Conclusions AMHo and FSHo are predictive of pregnancy potential in high responders, but likely reflect different responsibilities in recruitment and maturation of growing follicle cohorts. PMID:22545082

  3. The meiotic response of cumulus cell-enclosed mouse oocytes to follicle-stimulating hormone in the presence of different macromolecules.

    PubMed

    Downs, S M; Dow, M P; Fagbohun, C F

    1991-06-01

    Experiments were carried out to determine the effect of different macromolecules on the follicle-stimulating hormone (FSH)-induced maturation of mouse oocytes in culture. Cumulus cell-enclosed oocytes (CEO) were isolated from gonadotropin-primed mice and maintained in meiotic arrest for 17-18 h with the cAMP analogue, dibutyryl cAMP (dbcAMP). Germinal vesicle breakdown (GVB) was stimulated by the addition of FSH. Medium was supplemented with either no macromolecule or with varying concentrations of polyvinylpyrrolidone (PVP), polyvinylalcohol (PVA), crystallized bovine serum albumin (BSA), or fetal bovine serum (FBS). Oocyte maturation in all FSH-free cultures occurred at a frequency of about 30% or below. High frequencies of maturation were achieved when FSH was added to macromolecule-free medium or to cultures containing PVP, PVA, or BSA. Crystallized BSA was the most effective of these in supporting stimulation of maturation (94% GVB at 3 mg/ml, compared with 72-74% with synthetic polymer-supplemented or macromolecule-free media). The BSA effect was not due to contaminating fatty acids, and a less pure fraction V BSA was not as effective in supporting FSH-induced maturation. FBS suppressed FSH stimulation of maturation in a dose-dependent fashion. Sera from pigs, goats, horses, and rats were also inhibitory, but bovine calf serum (BCS) permitted a high maturation frequency (80% GVB). When added to medium containing either FBS or BCS, crystallized BSA had no effect on FSH-stimulated maturation, but fraction V BSA suppressed maturation in both serum-supplemented media. Under no conditions did FSH stimulate maturation in cumulus cell-free oocytes. These results demonstrate that hormone-induced oocyte maturation is supported in vitro by nonprotein polymers as well as BSA and that the behavior of the oocyte-cumulus cell complex depends on the purity of the BSA sample. In addition, serum contains inhibitory factors that suppress the positive response to FSH. Thus, the

  4. The Correlations of Anti-Mullerian Hormone, Follicle-Stimulating Hormone and Antral Follicle Count in Different Age Groups of Infertile Women

    PubMed Central

    Barbakadze, Ludmila; Kristesashvili, Jenara; Khonelidze, Natalia; Tsagareishvili, Gia

    2015-01-01

    Background The objective of our study was to identify the correlations between the tests currently used in ovarian reserve assessment: anti-Mullerian hormone (AMH), follicle stimulating hormone (FSH) and antral follicle count (AFC) and to distinguish the most reliable markers for ovarian reserve in order to select an adequate strategy for the initial stages of infertility treatment. Materials and Methods In this prospective study, 112 infertile women were assessed. Subjects were divided into three age groups: group I <35 years (n=39), group II 35-40 years (n=31), and group III 41-46 years (n=42). AMH, FSH and AFC were determined on days 2-3 of the patients’ menstrual cycles. Results There was a significantly elevated negative correlation between age and AMH level (rs=-0.67, p<0.0001) and AFC (rs=-0.55, p<0.0001). We observed a significantly positive correlation between age and FSH (rs=0.38, p<0.0001). AMH negatively correlated with FSH (rs=-0.48, p<0.0001) and positively with AFC (r=-0.71, p=0.0001). There was a moderate negative relation between FSH and AFC (r=-0.41, p=0.0001) and moderate positive relation between age and FSH (rs=0.38, p<0.0001). The correlation analysis performed in separate groups showed that AMH and AFC showed a statistically significant positive correlation for group I (r=0.57, p<0.0001), group II (r=0.69, p<0.0001) and group III (r=0.47, p<0.002). A statistically significant correlation between FSH and AMH was detected only in groups I (r=-0.41, p<0.02) and II (r=-0.55, p<0.0001). A statistically significant correlation existed between FSH and AFC only in group III (r=-0.42, p<0.006), as well as between age and AFC only in group I (r=-0.35, p<0.03). Conclusion Currently, AMH should be considered as the more reliable of the ovarian reserve assessments tests compared to FSH. There is a strong positive correlation between serum AMH level and AFC. The use of AMH combined with AFC may improve ovarian reserve evaluation. PMID:25780521

  5. The global effect of follicle-stimulating hormone and tumour necrosis factor α on gene expression in cultured bovine ovarian granulosa cells

    PubMed Central

    2014-01-01

    Background Oocytes mature in ovarian follicles surrounded by granulosa cells. During follicle growth, granulosa cells replicate and secrete hormones, particularly steroids close to ovulation. However, most follicles cease growing and undergo atresia or regression instead of ovulating. To investigate the effects of stimulatory (follicle-stimulating hormone; FSH) and inhibitory (tumour necrosis factor alpha; TNFα) factors on the granulosa cell transcriptome, bovine ovaries were obtained from a local abattoir and pools of granulosa cells were cultured in vitro for six days under defined serum-free conditions with treatments present on days 3–6. Initially dose–response experiments (n = 4) were performed to determine the optimal concentrations of FSH (0.33 ng/ml) and TNFα (10 ng/ml) to be used for the microarray experiments. For array experiments cells were cultured under control conditions, with FSH, with TNFα, or with FSH plus TNFα (n = 4 per group) and RNA was harvested for microarray analyses. Results Statistical analysis showed primary clustering of the arrays into two groups, control/FSH and TNFα/TNFα plus FSH. The effect of TNFα on gene expression dominated that of FSH, with substantially more genes differentially regulated, and the pathways and genes regulated by TNFα being similar to those of FSH plus TNFα treatment. TNFα treatment reduced the endocrine activity of granulosa cells with reductions in expression of FST, INHA, INBA and AMH. The top-ranked canonical pathways and GO biological terms for the TNFα treatments included antigen presentation, inflammatory response and other pathways indicative of innate immune function and fibrosis. The two most significant networks also reflect this, containing molecules which are present in the canonical pathways of hepatic fibrosis/hepatic stellate cell activation and transforming growth factor β signalling, and these were up regulated. Upstream regulator analyses also predicted TNF, interferons γ and

  6. Gonadotropin-releasing hormone, estradiol, and inhibin regulation of follicle-stimulating hormone and luteinizing hormone surges: implications for follicle emergence and selection in heifers.

    PubMed

    Haughian, James M; Ginther, O J; Diaz, Francisco J; Wiltbank, Milo C

    2013-06-01

    Mechanisms regulating gonadotropin surges and gonadotropin requirements for follicle emergence and selection were studied in heifers. Experiment 1 evaluated whether follicular inhibins regulate the preovulatory luteinizing hormone (LH)/follicle-stimulating hormone (FSH) surges elicited by gonadotropin-releasing hormone (GnRH) injection (Hour = 0) and the subsequent periovulatory FSH surge. Treatments included control (n = 6), steroid-depleted bovine follicular fluid (bFF) at Hour -4 (n = 6), and bFF at Hour 6 (n = 6). Gonadotropins in blood were assessed hourly from Hours -6 to 36, and follicle growth tracked by ultrasound. Consistent with inhibin independence, bFF at Hour -4 did not impact the GnRH-induced preovulatory FSH surge, whereas treatment at Hour 6 delayed onset of the periovulatory FSH surge and impeded growth of a new follicular wave. Experiment 2 examined GnRH and estradiol (E2) regulation of the periovulatory FSH surge. Treatment groups were control (n = 8), GnRH-receptor antagonist (GnRHr-ant, n = 8), and E2 + GnRHr-ant (n = 4). GnRHr-ant (acyline) did not reduce the concentrations of FSH during the periovulatory surge and early follicle development (<7.0 mm) was unaffected, although subsequent growth of a dominant follicle (>8.0 mm) was prevented by GnRHr-ant. Addition of E2 delayed both the onset of the periovulatory FSH surge and emergence of a follicular wave. Failure to select a dominant follicle in the GnRHr-ant group was associated with reduced concentrations of LH but not FSH. Maximum diameter of F1 in controls (13.3 ± 0.5 mm) was greater than in both GnRHr-ant (7.7 ± 0.3 mm) and E2 + GnRHr-ant (6.7 ± 0.8 mm) groups. Results indicated that the periovulatory FSH surge stems from removal of negative stimuli (follicular E2 and inhibin), but is independent of GnRH stimulation. Emergence and early growth of follicles (until about 8 mm) requires the periovulatory FSH surge but not LH pulses. However, follicular deviation and late-stage growth of

  7. Effectiveness of a recombinant human follicle stimulating hormone on the ovarian follicles, peripheral progesterone, estradiol-17β, and pregnancy rate of dairy cows

    PubMed Central

    Ali, Mohamed; Moustafa M., Zeitoun

    2016-01-01

    Aims: This study aimed at elucidating the effects of recombinant human follicle stimulating hormone (r-hFSH) on the ovarian follicular dynamics, progesterone, estradiol-17β profiles, and pregnancy of dairy cows. Materials and Methods: Three groups (G, n=5 cows) of multiparous dairy cows were used. G1 (C) control cows were given controlled internal drug release (CIDR) and prostaglandin F2α; G2 (L) cows were given low dose (525 IU and G3 (H) cows were given high dose (1800 IU) of r-hFSH on twice daily basis at the last 3 days before CIDR removal. All cows were ultrasonically scanned for follicular growth and dynamics, and blood samples were collected every other day for two consecutive estrus cycles for the determination of estradiol-17β and progesterone. Results: Estrus was observed in all C and L but not in H cows. Dominant follicle was bigger in L compared to C and H cows. Dominant follicle in C (16.00±2.5 mm) and L cows (17.40±2.3 mm) disappeared at 72 h after CIDR removal. However, in H cows, no ovulation has occurred during 7 days post-CIDR removal. Progesterone was not different (p>0.10) among groups, whereas estradiol-17β revealed significant (p<0.01) reduction in H (15.96±2.5 pg/ml) cows compared to C (112.26±26.1 pg/ml) and L (97.49±15.9 pg/ml) cows. Pregnancy rate was higher in L cows (60%) compared with C cows (20%). However, H cows were not artificially inseminated due to non-ovulation. Only a cow of C group has calved one calf, however, 2 of the L cows gave birth of twins and a cow gave single calf. Conclusion: Administration of a low dose (525 IU) of r-hFSH resulted in an optimal size of dominant follicle, normal values of progesterone and estradiol-17β, and 40% twinning rate, howeverusing 1800 IU of r-hFSH, have adverse effects on ovarian follicular dynamics and hormonal profiles with non-pregnancy of dairy cows raised under hot climate. PMID:27536029

  8. Alteration of mammary gland development and gene expression by in utero exposure to arsenic

    PubMed Central

    Parodi, Daniela A.; Greenfield, Morgan; Evans, Claire; Chichura, Anna; Alpaugh, Alexandra; Williams, James; Martin, Mary Beth

    2015-01-01

    Early life exposure to estrogens and estrogen like contaminants in the environment are thought to contribute to the early onset of puberty and consequently increase the risk of developing breast cancer in the exposed female. The results of this study show that in utero exposure to the metalloestrogen arsenite altered mammary gland development prior to its effect on puberty onset. In the prepubertal gland, in utero exposure resulted in an increase in the number of mammosphere-forming cells and an increase in branching, epithelial cells, and density. In the postpubertal gland, in utero exposure resulted in the overexpression of estrogen receptor-alpha (ERα) that was due to the increased and altered response of the ERα transcripts derived from exons O and OT to estradiol. These results suggest that, in addition to advancing puberty onset, in utero exposure to arsenite alters the pre- and postpubertal development of the mammary gland and possibly, the risk of developing breast cancer. PMID:25543096

  9. Radiation Exposure Alters Expression of Metabolic Enzyme Genes in Mice

    NASA Technical Reports Server (NTRS)

    Wotring, V. E.; Mangala, L. S.; Zhang, Y.; Wu, H.

    2011-01-01

    Most administered pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand the effects of spaceflight on the enzymes of the liver and exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. Additionally, it has been previous noted that pre-exposure to small radiation doses seems to confer protection against later and larger radiation doses. This protective power of pre-exposure has been called a priming effect or radioadaptation. This study is an effort to examine the drug metabolizing effects of radioadaptation mechanisms that may be triggered by early exposure to low radiation doses.

  10. Acute neuroactive drug exposures alter locomotor activity in larval zebrafish

    EPA Science Inventory

    In an effort to develop a rapid in vivo screen for EPA's prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after exposure to prototypic drugs that act on the central nervous system. MPTP (1-methyl-4phenyl- 1 ,2,3,6-...

  11. Prenatal cadmium exposure alters postnatal immune cell development and function

    PubMed Central

    Hanson, Miranda L.; Holásková, Ida; Elliott, Meenal; Brundage, Kathleen M.; Schafer, Rosana; Barnett, John B.

    2012-01-01

    Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl2 (10 ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7 weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7 weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2 weeks of age. At 7 weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-γ production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4+FoxP3+CD25+ (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8+CD223+ T cells were markedly decreased in the spleens in all offspring at 7 weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can result in long term detrimental

  12. EXPOSURE OF CULTURED MYOCYTES TO ZINC RESULTS IN ALTERED BEAT RATE AND INTERCELLULAR COMMUNICATION.

    EPA Science Inventory

    Exposure of cultured myocytes to zinc results in altered beat rate and intercellular communication

    Graff, Donald W, Devlin, Robert B, Brackhan, Joseph A, Muller-Borer, Barbara J, Bowman, Jill S, Cascio, Wayne E.

    Exposure to ambient air pollution particulate matter (...

  13. ACUTE EXPOSURE TO MOLINATE ALTERS NEUROENDOCRINE CONTROL OF OVULATION IN THE RAT

    EPA Science Inventory

    Molinate, a thiocarbamate herbicide, has been shown previously to impair reproductive capability in the male rat. In a two-generation study, molinate exposure to female rats resulted in altered pregnancy outcome. However, published data is lacking on the effects of acute exposure...

  14. Prenatal cadmium exposure alters postnatal immune cell development and function

    SciTech Connect

    Hanson, Miranda L.; Holásková, Ida; Elliott, Meenal; Brundage, Kathleen M.; Schafer, Rosana; Barnett, John B.

    2012-06-01

    Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl{sub 2} (10 ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7 weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7 weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2 weeks of age. At 7 weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-γ production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4{sup +}FoxP3{sup +}CD25{sup +} (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8{sup +}CD223{sup +} T cells were markedly decreased in the spleens in all offspring at 7 weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can

  15. Exposure to bisphenol A in young adult mice does not alter ovulation but does alter the fertilization ability of oocytes.

    PubMed

    Moore-Ambriz, Teresita Rocio; Acuña-Hernández, Deyanira Guadalupe; Ramos-Robles, Brenda; Sánchez-Gutiérrez, Manuel; Santacruz-Márquez, Ramsés; Sierra-Santoyo, Adolfo; Piña-Guzmán, Belem; Shibayama, Mineko; Hernández-Ochoa, Isabel

    2015-12-15

    Follicle growth culminates in ovulation, which allows for the expulsion of fertilizable oocytes and the formation of corpora lutea. Bisphenol A (BPA) is present in many consumer products, and it has been suggested that BPA impairs ovulation; however, the underlying mechanisms are unknown. Therefore, this study first evaluated whether BPA alters ovulation by affecting folliculogenesis, the number of corpora lutea or eggs shed to the oviduct, ovarian gonadotropin responsiveness, hormone levels, and estrous cyclicity. Because it has been suggested (but not directly confirmed) that BPA exerts toxic effects on the fertilization ability of oocytes, a second aim was to evaluate whether BPA impacts the oocyte fertilization rate using an in vitro fertilization assay and mating. The possible effects on early zygote development were also examined. Young adult female C57BL/6J mice (39 days old) were orally dosed with corn oil (vehicle) or 50 μg/kgbw/day BPA for a period encompassing the first three reproductive cycles (12-15 days). BPA exposure did not alter any parameters related to ovulation. Moreover, BPA exposure reduced the percentage of fertilized oocytes after either in vitro fertilization or mating, but it did not alter the zygotic stages. The data indicate that exposure to the reference dose of BPA does not impact ovulation but that it does influence the oocyte quality in terms of its fertilization ability. PMID:26493930

  16. Dietary exposure to chlorpyrifos alters core temperature in the rat.

    PubMed

    Gordon, Christopher J; Padnos, Beth K

    2002-08-15

    Administration of the organophosphate pesticide chlorpyrifos (CHP) to the male rat at a dose of 25-80 mg/kg (p.o.) results in hypothermia followed by a delayed fever lasting for several days. These are high doses of CHP that cause marked cholinergic stimulation. It is important to understand if chronic exposure to CHP would evoke changes in thermoregulation that are comparable to the acute administration. Male rats of the Long-Evans strain were subjected to dietary treatment of 0, 1, or 5 mg/(kg day) CHP for 6 months. A limited amount of food was given per day to maintain body weight at 350 g. The constant body weight allowed for the regulation of a consistent dosage of CHP per kg body weight throughout the feeding period. Core temperature (T(a)) and motor activity (MA) were monitored by radio telemetric transmitters implanted in the abdominal cavity. After 5 months of treatment, T(c) and MA were monitored in undisturbed animals for 96 h. CHP at 5 mg/(kg day) led to a slight elevation in T(c) without affecting MA. The rats were then administered a challenge dose of CHP (30 mg/kg, p.o.) while T(c) and MA were monitored. Rats fed the 1 and 5 mg/kg CHP diets showed a significantly greater hypothermic response and reduction in MA following CHP challenge compared to controls. The restricted feeding schedule resulted in marked changes in the pattern of the circadian rhythm. Therefore, in another study, rats were treated ad libitum for 17 days with a CHP diet that resulted in a dosage of 7 mg CHP/(mg day). There was a significant increase in T(c) during the daytime but not during the night throughout most of the treatment period. Overall, chronic CHP was associated with a slight but significant elevation in T(c) and greater hypothermic response to a CHP challenge. This latter finding was unexpected and suggests that chronic exposure to CHP sensitizes the rat's thermoregulatory response to acute CHP exposure. PMID:12135625

  17. Synthetic peptides based upon a three-dimensional model for the receptor recognition site of follicle-stimulating hormone exhibit antagonistic or agonistic activity at low concentrations.

    PubMed Central

    Hage-van Noort, M; Puijk, W C; Plasman, H H; Kuperus, D; Schaaper, W M; Beekman, N J; Grootegoed, J A; Meloen, R H

    1992-01-01

    Follicle-stimulating hormone (follitropin, FSH) belongs to a group of closely related glycoprotein hormones that contain two noncovalently linked dissimilar subunits designated alpha and beta. By using synthetic peptides, several receptor interaction sites in these hormones have been identified; however, the peptides have a reduced potency (lowest effective concentration of 10(-4) to 10(-5) M) relative to the hormone itself (10(-8) to 10(-11) M). This suggests that the peptides represent only a portion of a larger recognition site in the intact hormone that comprises parts of both the beta and the alpha chains. To develop peptides that exhibit FSH-antagonistic activity at low concentrations, we have constructed a three-dimensional model for FSH, which is based on an alignment of both the beta and the alpha chains of glycoprotein hormones with thioredoxin, for which x-ray diffraction data are available. This model resulted in the prediction of a conformational receptor-binding site in FSH, in which (parts of) three earlier proposed binding regions on the FSH molecule [namely, the regions FSH alpha-(34-37), with the amino acid sequence SRAY; FSH beta-(40-43), with the amino acid sequence TRDL; and FSH beta-(87-94), the "determinant loop" with the amino acid sequence CDSDSTDC] are located within 10 A of one another. On the basis of this model, peptides have been synthesized in which two of these binding regions are linked by a synthetic amino acid whose length was derived from the model, Ac-TDSDS-NH-(CH2)5-CO-SRAY-NH2 and Ac-SRAY-NH-(CH2)4-CO-TRDL-NH2. Both peptides inhibited FSH-induced cAMP production in Sertoli cells at 1000-fold lower concentrations (10(-7) M) than the peptides Ac-TRDL-NH2, Ac-SRAY-NH2, or Ac-TDSDS-NH2. In another peptide, Ac-TDSDS-NH-(CH2)5-CO-SRAY-NH-(CH2)4-CO-TRDL-NH2, all three binding regions have been linked. This peptide appeared to be a strong agonist of FSH action, as measured by the ability to stimulate cAMP production, at concentrations

  18. Normal or induced secretory patterns of luteinising hormone and follicle-stimulating hormone in anoestrous gonadotrophin-releasing hormone-immunised and cyclic control heifers.

    PubMed

    Prendiville, D J; Enright, W J; Crowe, M A; Finnerty, M; Roche, J F

    1996-12-16

    The objective was to determine the effect of gonadotrophin-releasing hormone (GnRH), GnRH analogue (GnRH-A) or oestradiol administration on luteinising hormone (LH) and follicle-stimulating hormone (FSH) release in GnRH-immunised anoestrous and control cyclic heifers. Thirty-two heifers (477 +/- 7.1 kg) were immunised against either human serum albumin (HSA; controls; n = 8), or a HSA-GnRH conjugate. On day 70 after primary immunisation, control heifers (n = 4 per treatment; day 3 of cycle) received either (a) 2.5 micrograms GnRH or (b) 2.5 micrograms of GnRH-A (Buserelin) and GnRH-immunised heifers (blocked by GnRH antibody titre; n = 6 per treatment) received either (c) saline, (d) 2.5 micrograms GnRH, (e) 25 micrograms GnRH or (f) 2.5 micrograms GnRH-A, intravenously. On day 105, 1 mg oestradiol was injected (intramuscularly) into control (n = 6) and GnRH-immunised anoestrous heifers with either low (13.4 +/- 1.9% binding at 1:640; n = 6) or high GnRH antibody titres (33.4 +/- 4.8% binding; n = 6). Data were analysed by ANOVA. Mean plasma LH and FSH concentrations on day 69 were higher (P < 0.05) in control than in GnRH-immunised heifers (3.1 +/- 0.16 vs. 2.5 +/- 0.12 ng LH ml-1 and 22.5 +/- 0.73 vs. 17.1 +/- 0.64 ng FSH ml-1, respectively). The number of LH pulses was higher (P < 0.05) in control than in GnRH-immunised heifers on day 69 (3.4 +/- 0.45 and 1.0 +/- 0.26 pulses per 6 h, respectively). On day 70, 2.5 micrograms GnRH increased (P < 0.05) LH concentrations in control but not in GnRH-immunised heifers, while both 25 micrograms GnRH and 2.5 micrograms GnRH-A increased (P < 0.05) LH concentrations in GnRH-immunised heifers, and 2.5 micrograms GnRH-A increased LH in controls. FSH was increased (P < 0.05) in GnRH-immunised heifers following 25 micrograms GnRH and 2.5 micrograms GnRH-A. Oestradiol challenge increased (P < 0.05) LH concentrations during the 13-24 h period after challenge with a greater (P < 0.05) increase in control than in Gn

  19. Exposure to mercury alters early activation events in fish leukocytes.

    PubMed Central

    MacDougal, K C; Johnson, M D; Burnett, K G

    1996-01-01

    Although fish in natural populations may carry high body burdens of both organic and inorganic mercury, the effects of this divalent metal on such lower vertebrates is poorly understood. In this report, inorganic mercury in the form of mercuric chloride (HgCl2) is shown to produce both high-dose inhibition and low-dose activation of leukocytes in a marine teleost fish, Sciaenops ocellatus. Concentrations of inorganic mercury > or = 10 microM suppressed DNA synthesis and induced rapid influx of radiolabeled calcium, as well as tyrosine phosphorylation of numerous cellular proteins. Lower concentrations (0.1-1 microM) of HgCl2 that activated cell growth also induced a slow sustained rise in intracellular calcium in cells loaded with the calcium indicator dye fura-2, but did not produce detectable tyrosine phosphorylation of leukocyte proteins. These studies support the possibility that subtoxic doses of HgCl2 may inappropriately activate teleost leukocytes, potentially altering the processes that regulate the magnitude and specificity of the fish immune response to environmental pathogens. Images Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. PMID:8930553

  20. Developmental exposure to paracetamol causes biochemical alterations in medulla oblongata.

    PubMed

    Blecharz-Klin, Kamilla; Joniec-Maciejak, Ilona; Jawna, Katarzyna; Pyrzanowska, Justyna; Piechal, Agnieszka; Wawer, Adriana; Widy-Tyszkiewicz, Ewa

    2015-09-01

    The effect and safety of prenatal and early life administration of paracetamol - routinely used over-the-counter antipyretic and analgesic medication on monoamines content and balance of amino acids in the medulla oblongata is still unknown. In this study we have determined the level of neurotransmitters in this structure in two-month old Wistar male rats exposed to paracetamol in the dose of 5 (P5, n=10) or 15mg/kg b.w. (P15, n=10) during prenatal period, lactation and till the end of the second month of life. Control group received drinking water (Con, n=10). Monoamines, their metabolites and amino acids concentration in medulla oblongata of rats were determined using high performance liquid chromatography (HPLC) in 60 postnatal day (PND60). This experiment shows that prenatal and early life paracetamol exposure modulates neurotransmission associated with serotonergic, noradrenergic and dopaminergic system in medulla oblongata. Reduction of alanine and taurine levels has also been established. PMID:26233562

  1. Alteration of Rat Fetal Cerebral Cortex Development after Prenatal Exposure to Polychlorinated Biphenyls

    PubMed Central

    Naveau, Elise; Pinson, Anneline; Gérard, Arlette; Nguyen, Laurent; Charlier, Corinne; Thomé, Jean-Pierre; Zoeller, R. Thomas; Bourguignon, Jean-Pierre; Parent, Anne-Simone

    2014-01-01

    Polychlorinated biphenyls (PCBs) are environmental contaminants that persist in environment and human tissues. Perinatal exposure to these endocrine disruptors causes cognitive deficits and learning disabilities in children. These effects may involve their ability to interfere with thyroid hormone (TH) action. We tested the hypothesis that developmental exposure to PCBs can concomitantly alter TH levels and TH-regulated events during cerebral cortex development: progenitor proliferation, cell cycle exit and neuron migration. Pregnant rats exposed to the commercial PCB mixture Aroclor 1254 ended gestation with reduced total and free serum thyroxine levels. Exposure to Aroclor 1254 increased cell cycle exit of the neuronal progenitors and delayed radial neuronal migration in the fetal cortex. Progenitor cell proliferation, cell death and differentiation rate were not altered by prenatal exposure to PCBs. Given that PCBs remain ubiquitous, though diminishing, contaminants in human systems, it is important that we further understand their deleterious effects in the brain. PMID:24642964

  2. PRENATAL EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE ALTERS GENE EXPRESSION IN THE DEVELOPING MURINE HIPPOCAMPUS

    PubMed Central

    Mukhopadhyay, Partha; Horn, Kristin H.; Greene, Robert M.; Pisano, M. Michele

    2010-01-01

    Background Little is known about the effects of passive smoke exposures on the developing brain. Objective The purpose of the current study was to identify changes in gene expression in the murine hippocampus as a consequence of in utero exposure to sidestream cigarette smoke (an experimental equivalent of environmental tobacco smoke (ETS)) at exposure levels that do not result in fetal growth inhibition. Methods A whole body smoke inhalation exposure system was utilized to deliver ETS to pregnant C57BL/6J mice for six hours/day from gestational days 6–17 (gd 6–17) [for microarray] or gd 6–18.5 [for fetal phenotyping]. Results There were no significant effects of ETS exposure on fetal phenotype. However, 61 “expressed” genes in the gd 18.5 fetal hippocampus were differentially regulated (up- or down-regulated by 1.5 fold or greater) by maternal exposure to ETS. Of these 61 genes, 25 genes were upregulated while 36 genes were downregulated. A systems biology approach, including computational methodologies, identified cellular response pathways, and biological themes, underlying altered fetal programming of the embryonic hippocampus by in utero cigarette smoke exposure. Conclusions Results from the present study suggest that even in the absence of effects on fetal growth, prenatal smoke exposure can alter gene expression during the “early” period of hippocampal growth and may result in abnormal hippocampal morphology, connectivity, and function. PMID:19969065

  3. Regionally specific alterations in the low-affinity GABAA receptor following perinatal exposure to diazepam.

    PubMed

    Gruen, R J; Elsworth, J D; Roth, R H

    1990-04-23

    Alterations in a low affinity form of the GABAA receptor were examined with [3H]bicuculline methylchloride in the adult rat following perinatal exposure to diazepam. Perinatal exposure resulted in a significant reduction in [3H]bicuculline binding in the cingulate cortex. A significant decrease in the ability of GABA to displace bound [3H]bicuculline was observed only in the hypothalamus. The results suggest that the effects of perinatal exposure to diazepam are regionally specific and that benzodiazepine receptors and low affinity GABAA receptors are functionally linked during the perinatal period. PMID:2162709

  4. FINE AMBIENT AIR PARTICULAR MATTER EXPOSURE INDUCES MOLECULAR ALTERATIONS INDICATIVE OF CARDIOVASCULAR DISEASE PROGRESSION IN ATHEROSCLEROTIC SUSCEPTIBLE MICE

    EPA Science Inventory

    Epidemiological, clinical, and toxicological studies have demonstrated that exposure to ambient air particulate matter (PM) can alter cardiovascular function and may influence cardiovascular disease (CVD). It has been shown that exposure to concentrated ambient air particles (CA...

  5. Human Ozone (O3) Exposure Alters Serum Profile of Lipid Metabolites

    EPA Science Inventory

    HUMAN OZONE (O3) EXPOSURE ALTERS SERUM PROFILE OF LIPID METABOLITES Miller, D B.1; Kodavanti, U P.2 Karoly, E D.3; Cascio W.E2, Ghio, A J. 21. UNC-Chapel Hill, Chapel Hill, N.C., United States. 2. NHEERL, U.S. EPA, RTP, N.C., United States. 3. METABOLON INC., Durham, N.C., United...

  6. PERINATAL EXPOSURE TO THE PESTICIDE HEPTACHLOR PRODUCES ALTERATIONS IN IMMUNE FUNCTION PARAMETERS IN SPRAGUE DAWLEY RATS

    EPA Science Inventory

    PERINATAL EXPOSURE TO THE PESTICIDE HEPTACHLOR PRODUCES ALTERATIONS IN IMMUNE FUNCTION PARAMETERS IN SPRAGUE DAWLEY RATS. R A Matulka1, AA Rooney3, W Williams2, CB Copeland2, and R J Smialowicz2. 1Curriculum in Toxicology, UNC, Chapel Hill, NC, USA; 2US EPA, ITB, ETD, NHEERL, RT...

  7. ALTERATIONS IN BRAIN PROTEIN KINASE C ISOFORMS FOLLOWING DEVELOPMENTAL EXPOSURE TO POLYCHLORINATED BIPHENYL MIXTURE.

    EPA Science Inventory

    PCBs have been shown to alter several neurochemical end-points and are implicated in the etiology of some neurological diseases. Recent in vivo studies from our laboratory indicated that developmental exposure to a commercial PCB mixture, Aroclor 1254, caused perturbations in cal...

  8. Adaptive Responses to Prochloraz Exposure That Alter Dose-Response and Time-Course Behaviors

    EPA Science Inventory

    Dose response and time-course (DRTC) are, along with exposure, the major determinants of health risk. Adaptive changes within exposed organisms in response to environmental stress are common, and alter DRTC behaviors to minimize the effects caused by stressors. In this project, ...

  9. GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE (EDS) ALTERS DEVELOPMENT OF THE MOUSE TESTIS

    EPA Science Inventory

    GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE (EDS) ALTERS DEVELOPMENT OF THE MOUSE TESTIS. D.K. Tarka*1,2, J.D. Suarez*2, N.L. Roberts*2, J.M. Rogers*1,2, M.P. Hardy3, and G.R. Klinefelter1,2. 1University of North Carolina, Curriculum in Toxicology, Chapel Hill, NC; 2USEPA,...

  10. Effects of perinatal bisphenol A exposure during early development on radial arm maze behavior in adult male and female rats

    PubMed Central

    Sadowski, Renee N.; Park, Pul; Neese, Steven L.; Ferguson, Duncan C.; Schantz, Susan L.; Juraska, Janice M.

    2014-01-01

    Previous work has shown that exposure to bisphenol A (BPA) can affect anxiety behavior. However, no studies have examined whether administration of this endocrine disruptor during the perinatal period has the potential to induce alterations in cognitive behavior in both adult males and females as assessed in an appetitive task. The goal of the current study was to determine whether exposure to different doses of BPA during early development alters performance on the 17-arm radial maze in adulthood in Long-Evans rats. Oral administration of corn oil (vehicle), 4 μg/kg, 40 μg/kg, or 400 μg/kg BPA to the dams occurred daily throughout pregnancy, and the pups received direct oral administration of BPA between postnatal days 1-9. Blood was collected from offspring at weaning age to determine levels of several hormones (thyroxine, thyroid stimulating hormone, follicle stimulating hormone, luteinizing hormone). One male and one female from each litter were evaluated on the 17-arm radial maze, a working/reference memory task, in adulthood. Results indicated that after exposure to BPA at both 4 and 400 μg/kg/day, rats of both sexes had decreased levels of FSH at weaning. There were no significant effects of BPA on performance on the radial arm maze in males or females. In conclusion, exposure to BPA during early development had modest effects on circulating hormones but did not affect a spatial learning and memory task. PMID:24440629

  11. Associations between Bisphenol A Exposure and Reproductive Hormones among Female Workers.

    PubMed

    Miao, Maohua; Yuan, Wei; Yang, Fen; Liang, Hong; Zhou, Zhijun; Li, Runsheng; Gao, Ersheng; Li, De-Kun

    2015-10-01

    The associations between Bisphenol-A (BPA) exposure and reproductive hormone levels among women are unclear. A cross-sectional study was conducted among female workers from BPA-exposed and unexposed factories in China. Women's blood samples were collected for assay of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17β-Estradiol (E2), prolactin (PRL), and progesterone (PROG). Their urine samples were collected for BPA measurement. In the exposed group, time weighted average exposure to BPA for an 8-h shift (TWA8), a measure incorporating historic exposure level, was generated based on personal air sampling. Multiple linear regression analyses were used to examine linear associations between urine BPA concentration and reproductive hormones after controlling for potential confounders. A total of 106 exposed and 250 unexposed female workers were included in this study. A significant positive association between increased urine BPA concentration and higher PRL and PROG levels were observed. Similar associations were observed after the analysis was carried out separately among the exposed and unexposed workers. In addition, a positive association between urine BPA and E2 was observed among exposed workers with borderline significance, while a statistically significant inverse association between urine BPA and FSH was observed among unexposed group. The results suggest that BPA exposure may lead to alterations in female reproductive hormone levels. PMID:26506366

  12. Effect of prenatal and neonatal exposure to lead on gonadotropin receptors and steroidogenesis in rat ovaries

    SciTech Connect

    Wiebe, J.P.; Barr, K.J.; Buckingham, K.D.

    1988-01-01

    Sprague-Dawley rats were treated with lead chloride (20 or 200 ppm) or sodium chloride (controls) in their drinking water, either prior to pregnancy or during pregnancy and lactation, and female offspring were examined at weaning (21 d) or at 150 d. Other female rats were treated from d 21 to 35. Tissue (blood, kidney, bone) lead levels, body, ovary, and uterus weights, ovarian steroidogenesis, and gonadotropin (luteinizing hormone and follicle-stimulating hormone) levels, and gonadotropin-receptor binding were determined. Prenatal and/or postnatal exposure to lead at these levels (20 and 200 ppm) did not affect tissue weights but did cause a significant decrease in gonadotropin-receptor binding in the prepubertal, pubertal and adult females. Conversion of progesterone to androstenedione and dihydrotestosterone was significantly decreased in 21-d-old rats; in 150-d-old females, the prenatal and/or postnatal exposure to lead resulted in significantly increased conversion to the 5-alpha-reduced steroid, normally high during puberty. The results demonstrate that lead exposure prior to mating may affect gonadotropin-receptor binding in the offspring and that lead exposure (in utero, via mother's milk, or post weaning) may significantly alter steroid production and gonadotropin binding in ovaries of the prepubertal, pubertal, and adult female.

  13. Associations between Bisphenol A Exposure and Reproductive Hormones among Female Workers

    PubMed Central

    Miao, Maohua; Yuan, Wei; Yang, Fen; Liang, Hong; Zhou, Zhijun; Li, Runsheng; Gao, Ersheng; Li, De-Kun

    2015-01-01

    The associations between Bisphenol-A (BPA) exposure and reproductive hormone levels among women are unclear. A cross-sectional study was conducted among female workers from BPA-exposed and unexposed factories in China. Women’s blood samples were collected for assay of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17β-Estradiol (E2), prolactin (PRL), and progesterone (PROG). Their urine samples were collected for BPA measurement. In the exposed group, time weighted average exposure to BPA for an 8-h shift (TWA8), a measure incorporating historic exposure level, was generated based on personal air sampling. Multiple linear regression analyses were used to examine linear associations between urine BPA concentration and reproductive hormones after controlling for potential confounders. A total of 106 exposed and 250 unexposed female workers were included in this study. A significant positive association between increased urine BPA concentration and higher PRL and PROG levels were observed. Similar associations were observed after the analysis was carried out separately among the exposed and unexposed workers. In addition, a positive association between urine BPA and E2 was observed among exposed workers with borderline significance, while a statistically significant inverse association between urine BPA and FSH was observed among unexposed group. The results suggest that BPA exposure may lead to alterations in female reproductive hormone levels. PMID:26506366

  14. Postnatal sulfur dioxide exposure reversibly alters parasympathetic regulation of heart rate.

    PubMed

    Woerman, Amanda L; Mendelowitz, David

    2013-08-01

    Perinatal sulfur dioxide exposure disrupts parasympathetic regulation of cardiovascular activity. Here, we examine the relative risks of prenatal versus postnatal exposure to the air pollutant and the reversibility of the cardiovascular effects. Two groups of animals were used for this study. For prenatal exposure, pregnant Sprague-Dawley dams were exposed to 5 parts per million sulfur dioxide for 1 hour daily throughout gestation and with their pups after birth to medical-grade air through 6 days postnatal. For postnatal exposure, dams were exposed to air, and after delivery along with their pups to 5 parts per million sulfur dioxide through postnatal day 6. ECGs were recorded from pups on postnatal day 5 to examine changes in heart rate. Whole-cell patch-clamp electrophysiology was used to examine changes in neurotransmission to cardiac vagal neurons in the nucleus ambiguus on sulfur dioxide exposure. Postnatal sulfur dioxide exposure diminished glutamatergic neurotransmission to cardiac vagal neurons by 40.9% and increased heart rate, whereas prenatal exposure altered neither of these properties. When postnatal exposure concluded on postnatal day 5, excitatory neurotransmission remained decreased through day 6 and returned to basal levels by day 7. ECGs showed that heart rate remained elevated through day 6 and recovered by day 7. On activation of the parasympathetic diving reflex, the response was significantly blunted by postnatal sulfur dioxide exposure through day 7 but recovered by day 8. Postnatal, but not prenatal, exposure to sulfur dioxide can disrupt parasympathetic regulation of cardiovascular activity. Neonates can recover from these effects within 2 to 3 days of discontinued exposure. PMID:23774227

  15. Postnatal Sulfur Dioxide Exposure Reversibly Alters Parasympathetic Regulation of Heart Rate

    PubMed Central

    Woerman, Amanda L.; Mendelowitz, David

    2014-01-01

    Perinatal sulfur dioxide exposure disrupts parasympathetic regulation of cardiovascular activity. Here, we examine the relative risks of prenatal versus postnatal exposure to the air pollutant, and the reversibility of the cardiovascular effects. Two groups of animals were used for this study. For prenatal exposure, pregnant Sprague-Dawley dams were exposed to 5 parts per million sulfur dioxide for 1 hour daily throughout gestation, and with their pups upon birth to medical-grade air through 6 days postnatal. For postnatal exposure, dams were exposed to air, and upon delivery along with their pups to 5 parts per million sulfur dioxide through postnatal day 6. Electrocardiograms were recorded from pups on postnatal day 5 to examine changes in heart rate. Whole-cell patch-clamp electrophysiology was used to examine changes in neurotransmission to cardiac vagal neurons upon sulfur dioxide exposure. Postnatal sulfur dioxide exposure diminished glutamatergic neurotransmission to cardiac vagal neurons by 40.9% and increased heart rate, whereas prenatal exposure altered neither of these properties. When postnatal exposure concluded on postnatal day 5, excitatory neurotransmission remained decreased through day 6, and returned to basal levels by day 7. Electrocardiograms showed that heart rate remained elevated through day 6 and recovered by day 7. Upon activation of the parasympathetic diving reflex, the response was significantly blunted by postnatal sulfur dioxide exposure through day 7 but recovered by day 8. Postnatal, but not prenatal, exposure to sulfur dioxide can disrupt parasympathetic regulation of cardiovascular activity. Neonates can recover from these effects within 2–3 days of discontinued exposure. PMID:23774227

  16. Ozone Exposure Alters Serotonin and Serotonin Receptor Expression in the Developing Lung

    PubMed Central

    Van Winkle, Laura S.

    2013-01-01

    Ozone, a pervasive environmental pollutant, adversely affects functional lung growth in children. Animal studies demonstrate that altered lung development is associated with modified signaling within the airway epithelial mesenchymal trophic unit, including mediators that can change nerve growth. We hypothesized that ozone exposure alters the normal pattern of serotonin, its transporter (5-HTT), and two key receptors (5-HT2A and 5-HT4), a pathway involved in postnatal airway neural, epithelial, and immune processes. We exposed monkeys to acute or episodic ozone during the first 2 or 6 months of life. There were three exposure groups/age: (1) filtered air, (2) acute ozone challenge, and (3) episodic ozone + acute ozone challenge. Lungs were prepared for compartment-specific qRT-PCR, immunohistochemistry, and stereology. Airway epithelial serotonin immunopositive staining increased in all exposure groups with the most prominent in 2-month midlevel and 6-month distal airways. Gene expression of 5-HTT, 5-HT2AR, and 5-HT4R increased in an age-dependent manner. Overall expression was greater in distal compared with midlevel airways. Ozone exposure disrupted both 5-HT2AR and 5-HT4R protein expression in airways and enhanced immunopositive staining for 5-HT2AR (2 months) and 5-HT4R (6 months) on smooth muscle. Ozone exposure increases serotonin in airway epithelium regardless of airway level, age, and exposure history and changes the spatial pattern of serotonin receptor protein (5-HT2A and 5-HT4) and 5-HTT gene expression depending on compartment, age, and exposure history. Understanding how serotonin modulates components of reversible airway obstruction exacerbated by ozone exposure sets the foundation for developing clinically relevant therapies for airway disease. PMID:23570994

  17. Preweaning cocaine exposure alters brain glucose metabolic rates following repeated amphetamine administration in the adult rat.

    PubMed

    Melnick, Susan M; Torres-Reveron, Annelyn; Dow-Edwards, Diana L

    2004-10-15

    Developmental cocaine exposure produces long-term alterations in function of many neuronal circuits. This study examined glucose metabolic rates following repeated amphetamine administration in adult male and female rats pretreated with cocaine during postnatal days (PND) 11-20. PND11-20 cocaine increased the response to amphetamine in many components of the motor system and the dorsal caudate-putamen, in particular, and decreased the metabolic response in the hypothalamus. While amphetamine alone produced widespread increases in metabolism, there were no cocaine-related effects in the mesolimbic, limbic or sensory structures. These data suggest that a brief cocaine exposure during development can alter ontogeny and result in abnormal neuronal responses to repeated psychostimulant administration in adulthood. PMID:15464226

  18. Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure.

    PubMed

    Klaren, W D; Gadupudi, G S; Wels, B; Simmons, D L; Olivier, A K; Robertson, L W

    2015-12-01

    Polychlorinated Biphenyls (PCBs) are industrial chemicals that have become a persistent threat to human health due to ongoing exposure. A subset of PCBs, known as dioxin-like PCBs, pose a special threat given their potent hepatic effects. Micronutrients, especially Cu, Zn and Se, homeostatic dysfunction is commonly seen after exposure to dioxin-like PCBs. This study investigates whether micronutrient alteration is the byproduct of the ongoing hepatotoxicity, marked by lipid accumulation, or a concurrent, yet independent event of hepatic damage. A time course study was carried out using male Sprague-Dawley rats with treatments of PCB126, the prototypical dioxin-like PCB, resulting in 6 different time points. Animals were fed a purified diet, based on AIN-93G, for three weeks to ensure micronutrient equilibration. A single IP injection of either tocopherol-stripped soy oil vehicle (5 mL/kg) or 5 μmol/kg PCB126 dose in vehicle was given at various time points resulting in exposures of 9h, 18 h, 36 h, 3 days, 6 days, and 12 days. Mild hepatic vacuolar change was seen as early as 36 h with drastic changes at the later time points, 6 and 12 days. Micronutrient alterations, specifically Cu, Zn, and Se, were not seen until after day 3 and only observed in the liver. No alterations were seen in the duodenum, suggesting that absorption and excretion may not be involved. Micronutrient alterations occur with ROS formation, lipid accumulation, and hepatomegaly. To probe the mechanistic underpinnings, alteration of gene expression of several copper chaperones was investigated; only metallothionein appeared elevated. These data suggest that the disruption in micronutrient status is a result of the hepatic injury elicited by PCB126 and is mediated in part by metallothionein. PMID:26410179

  19. CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FALLS TO ALTER SOMATOSENSORY EVOKED POTENTIALS, COMPOUND NERVE ACTION POTENTIALS, OR NERVE CONDUCTION VELOCITY IN RATS.

    EPA Science Inventory

    Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Cholinergic transmission is involved in sensory modulation in the cortex and cerebellum, and therefore may be altered following chlorpyrifos (CPF) exposure...

  20. Developmental alterations in olivary climbing fiber distribution following postnatal ethanol exposure in the rat.

    PubMed

    Pierce, D R; Hayar, A; Williams, D K; Light, K E

    2010-09-01

    Ethanol exposure during postnatal days (PN) 4-6 in rats alters cerebellar development resulting in significant loss of Purkinje cells. There is little knowledge, however, on what happens to the neurons that survive. In this study, rat pups were treated with a daily dose of ethanol (either 3.6 or 4.5 g/kg body weight) delivered by intragastric intubation on PN4, PN4-6, or PN7-9. Then the interactions between climbing fibers and Purkinje cells were examined on PN14 using confocal microscopy. Mid-vermal cerebellar sections were stained with antibodies to calbindin-D28k (to visualize Purkinje cells) and vesicular glutamate transporter 2 (VGluT2, to visualize climbing fibers). Confocal z-stack images were obtained from Lobule 1 and analyzed with Imaris software to quantify the staining of the two antibodies. The VGluT2 immunostaining was significantly reduced in the PN4 and PN4-6 ethanol groups for the 4.5 g/kg dose level, compared to controls, indicating that the cerebellar circuitry was significantly altered following developmental ethanol exposure. Not only were there fewer Purkinje cells following ethanol exposure, but the surviving neurons had significantly fewer VGluT2-labeled synapses. These alterations in the synaptic integrity were both dose dependent and temporally dependent. PMID:20542091

  1. Embryonic Atrazine Exposure Elicits Alterations in Genes Associated with Neuroendocrine Function in Adult Male Zebrafish.

    PubMed

    Wirbisky, Sara E; Sepúlveda, Maria S; Weber, Gregory J; Jannasch, Amber S; Horzmann, Katharine A; Freeman, Jennifer L

    2016-09-01

    The developmental origins of health and disease (DOHaD) hypothesis states that exposure to environmental stressors early in life can elicit genome and epigenome changes resulting in an increased susceptibility of a disease state during adulthood. Atrazine, a common agricultural herbicide used throughout the Midwestern United States, frequently contaminates potable water supplies and is a suspected endocrine disrupting chemical. In our previous studies, zebrafish was exposed to 0, 0.3, 3, or 30 parts per billion (μg/l) atrazine through embryogenesis, rinsed, and allowed to mature to adulthood. A decrease in spawning was observed with morphological alterations in offspring. In addition, adult females displayed an increase in ovarian progesterone and follicular atresia, alterations in levels of a serotonin metabolite and serotonin turnover in brain tissue, and transcriptome changes in brain and ovarian tissue supporting neuroendocrine alterations. As reproductive dysfunction is also influenced by males, this study assessed testes histology, hormone levels, and transcriptomic profiles of testes and brain tissue in the adult males. The embryonic atrazine exposure resulted in no alterations in body or testes weight, gonadosomatic index, testes histology, or levels of 11-ketotestosterone or testosterone. To further investigate potential alterations, transcriptomic profiles of adult male testes and brain tissue was completed. This analysis demonstrated alterations in genes associated with abnormal cell and neuronal growth and morphology; molecular transport, quantity, and production of steroid hormones; and neurotransmission with an emphasis on the hypothalamus-pituitary-adrenal and hypothalamus-pituitary-thyroid axes. Overall, this data indicate future studies should focus on additional neuroendocrine endpoints to determine potential functional impairments. PMID:27413107

  2. Cholinergic Synaptic Transmissions Were Altered after Single Sevoflurane Exposure in Drosophila Pupa

    PubMed Central

    Chen, Rongfa; Zhang, Tao; Kuang, Liting; Chen, Zhen; Ran, Dongzhi; Niu, Yang; Gu, Huaiyu

    2015-01-01

    Purpose. Sevoflurane, one of the most used general anesthetics, is widely used in clinical practice all over the world. Previous studies indicated that sevoflurane could induce neuron apoptosis and neural deficit causing query in the safety of anesthesia using sevoflurane. The present study was designed to investigate the effects of sevoflurane on electrophysiology in Drosophila pupa whose excitatory neurotransmitter is acetylcholine early after sevoflurane exposure using whole brain recording technique. Methods. Wide types of Drosophila (canton-s flies) were allocated to control and sevoflurane groups randomly. Sevoflurane groups (1% sevoflurane; 2% sevoflurane; 3% sevoflurane) were exposed to sevoflurane and the exposure lasted 5 hours, respectively. All flies were subjected to electrophysiology experiment using patch clamp 24 hours after exposure. Results. The results showed that, 24 hours after sevoflurane exposure, frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced (P < 0.05). Furthermore, we explored the underlying mechanism and found that calcium currents density, which partially regulated the frequency of mEPSCs, was significantly reduced after sevoflurane exposure (P < 0.05). Conclusions. All these suggested that sevoflurane could alter the mEPSCs that are related to synaptic plasticity partially through modulating calcium channel early after sevoflurane exposure. PMID:25705662

  3. Maternal mobile phone exposure alters intrinsic electrophysiological properties of CA1 pyramidal neurons in rat offspring.

    PubMed

    Razavinasab, Moazamehosadat; Moazzami, Kasra; Shabani, Mohammad

    2016-06-01

    Some studies have shown that exposure to electromagnetic field (EMF) may result in structural damage to neurons. In this study, we have elucidated the alteration in the hippocampal function of offspring Wistar rats (n = 8 rats in each group) that were chronically exposed to mobile phones during their gestational period by applying behavioral, histological, and electrophysiological tests. Rats in the EMF group were exposed to 900 MHz pulsed-EMF irradiation for 6 h/day. Whole cell recordings in hippocampal pyramidal cells in the mobile phone groups did show a decrease in neuronal excitability. Mobile phone exposure was mostly associated with a decrease in the number of action potentials fired in spontaneous activity and in response to current injection in both male and female groups. There was an increase in the amplitude of the afterhyperpolarization (AHP) in mobile phone rats compared with the control. The results of the passive avoidance and Morris water maze assessment of learning and memory performance showed that phone exposure significantly altered learning acquisition and memory retention in male and female rats compared with the control rats. Light microscopy study of brain sections of the control and mobile phone-exposed rats showed normal morphology.Our results suggest that exposure to mobile phones adversely affects the cognitive performance of both female and male offspring rats using behavioral and electrophysiological techniques. PMID:24604340

  4. Altered Hippocampal Lipid Profile Following Acute Postnatal Exposure to Di(2-Ethylhexyl) Phthalate in Rats

    PubMed Central

    Smith, Catherine A.; Farmer, Kyle; Lee, Hyunmin; Holahan, Matthew R.; Smith, Jeffrey C.

    2015-01-01

    Slight changes in the abundance of certain lipid species in the brain may drastically alter normal neurodevelopment via membrane stability, cell signalling, and cell survival. Previous findings have demonstrated that postnatal exposure to di (2-ethylhexyl) phthalate (DEHP) disrupts normal axonal and neural development in the hippocampus. The goal of the current study was to determine whether postnatal exposure to DEHP alters the lipid profile in the hippocampus during postnatal development. Systemic treatment with 10 mg/kg DEHP during postnatal development led to elevated levels of phosphatidylcholine and sphingomyelin in the hippocampus of female rats. There was no effect of DEHP exposure on the overall abundance of phosphatidylcholine or sphingomyelin in male rats or of lysophosphatidylcholine in male or female rats. Individual analyses of each identified lipid species revealed 10 phosphatidylcholine and six sphingomyelin lipids in DEHP-treated females and a single lysophosphatidylcholine in DEHP-treated males with a two-fold or higher increase in relative abundance. Our results are congruent with previous work that found that postnatal exposure to DEHP had a near-selective detrimental effect on hippocampal development in males but not females. Together, results suggest a neuroprotective effect of these elevated lipid species in females. PMID:26516880

  5. Environmentally Realistic Exposure to the Herbicide Atrazine Alters Some Sexually Selected Traits in Male Guppies

    PubMed Central

    Shenoy, Kausalya

    2012-01-01

    Male mating signals, including ornaments and courtship displays, and other sexually selected traits, like male-male aggression, are largely controlled by sex hormones. Environmental pollutants, notably endocrine disrupting compounds, can interfere with the proper functioning of hormones, thereby impacting the expression of hormonally regulated traits. Atrazine, one of the most widely used herbicides, can alter sex hormone levels in exposed animals. I tested the effects of environmentally relevant atrazine exposures on mating signals and behaviors in male guppies, a sexually dimorphic freshwater fish. Prolonged atrazine exposure reduced the expression of two honest signals: the area of orange spots (ornaments) and the number of courtship displays performed. Atrazine exposure also reduced aggression towards competing males in the context of mate competition. In the wild, exposure levels vary among individuals because of differential distribution of the pollutants across habitats; hence, differently impacted males often compete for the same mates. Disrupted mating signals can reduce reproductive success as females avoid mating with perceptibly suboptimal males. Less aggressive males are at a competitive disadvantage and lose access to females. This study highlights the effects of atrazine on ecologically relevant mating signals and behaviors in exposed wildlife. Altered reproductive traits have important implications for population dynamics, evolutionary patterns, and conservation of wildlife species. PMID:22312428

  6. Chronic alcohol exposure alters gene expression in HepG2 cells

    PubMed Central

    Pochareddy, Sirisha; Edenberg, Howard J.

    2011-01-01

    Background Liver is the primary site of alcohol metabolism and is highly vulnerable to injuries due to chronic alcohol abuse. Several molecular mechanisms, including oxidative stress and altered cellular metabolism, have been implicated in the development and progression of alcoholic liver disease. We sought to gain further insight into the molecular pathogenesis by studying the effects of ethanol exposure on global gene expression in HepG2 cells. Methods HepG2 cells were cultured in the presence or absence of 75 mM ethanol for nine days, with fresh media daily. Global gene expression changes were studied using Affymetrix GeneChip® Human Exon 1.0 ST Arrays. Gene expression differences were validated for thirteen genes by quantitative real-time RT-PCR. To identify biological pathways affected by ethanol treatment, differentially expressed genes were analyzed by Ingenuity Pathway Analysis software. Results Long term ethanol exposure altered the expression of 1093 genes (FDR ≤ 3%); many of these changes were modest. Long term ethanol exposure affected several pathways, including acute phase response, amino acid metabolism, carbohydrate metabolism and lipid metabolism. Conclusions Global measurements of gene expression show that a large number of genes are affected by chronic ethanol, although most show modest effect. These data provide insight into the molecular pathology resulting from extended alcohol exposure. PMID:22150570

  7. Altered Hippocampal Lipid Profile Following Acute Postnatal Exposure to Di(2-Ethylhexyl) Phthalate in Rats.

    PubMed

    Smith, Catherine A; Farmer, Kyle; Lee, Hyunmin; Holahan, Matthew R; Smith, Jeffrey C

    2015-10-01

    Slight changes in the abundance of certain lipid species in the brain may drastically alter normal neurodevelopment via membrane stability, cell signalling, and cell survival. Previous findings have demonstrated that postnatal exposure to di (2-ethylhexyl) phthalate (DEHP) disrupts normal axonal and neural development in the hippocampus. The goal of the current study was to determine whether postnatal exposure to DEHP alters the lipid profile in the hippocampus during postnatal development. Systemic treatment with 10 mg/kg DEHP during postnatal development led to elevated levels of phosphatidylcholine and sphingomyelin in the hippocampus of female rats. There was no effect of DEHP exposure on the overall abundance of phosphatidylcholine or sphingomyelin in male rats or of lysophosphatidylcholine in male or female rats. Individual analyses of each identified lipid species revealed 10 phosphatidylcholine and six sphingomyelin lipids in DEHP-treated females and a single lysophosphatidylcholine in DEHP-treated males with a two-fold or higher increase in relative abundance. Our results are congruent with previous work that found that postnatal exposure to DEHP had a near-selective detrimental effect on hippocampal development in males but not females. Together, results suggest a neuroprotective effect of these elevated lipid species in females. PMID:26516880

  8. Neonatal exposure to monosodium glutamate induces morphological alterations in suprachiasmatic nucleus of adult rat.

    PubMed

    Rojas-Castañeda, Julio César; Vigueras-Villaseñor, Rosa María; Chávez-Saldaña, Margarita; Rojas, Patricia; Gutiérrez-Pérez, Oscar; Rojas, Carolina; Arteaga-Silva, Marcela

    2016-02-01

    Neonatal exposure to monosodium glutamate (MSG) induces circadian disorders in several physiological and behavioural processes regulated by the suprachiasmatic nucleus (SCN). The objective of this study was to evaluate the effects of neonatal exposure to MSG on locomotor activity, and on morphology, cellular density and expression of proteins, as evaluated by optical density (OD), of vasopressin (VP)-, vasoactive intestinal polypeptide (VIP)- and glial fibrillary acidic protein (GFAP)-immunoreactive cells in the SCN. Male Wistar rats were used: the MSG group was subcutaneously treated from 3 to 10 days of age with 3.5 mg/g/day. Locomotor activity was evaluated at 90 days of age using 'open-field' test, and the brains were processed for immunohistochemical studies. MSG exposure induced a significant decrease in locomotor activity. VP- and VIP-immunoreactive neuronal densities showed a significant decrease, while the somatic OD showed an increase. Major axes and somatic area were significantly increased in VIP neurons. The cellular and optical densities of GFAP-immunoreactive sections of SCN were significantly increased. These results demonstrated that newborn exposure to MSG induced morphological alterations in SCN cells, an alteration that could be the basis for behavioural disorders observed in the animals. PMID:26799547

  9. Altered surfactant protein A gene expression and protein metabolism associated with repeat exposure to inhaled endotoxin.

    PubMed

    George, Caroline L S; White, Misty L; O'Neill, Marsha E; Thorne, Peter S; Schwartz, David A; Snyder, Jeanne M

    2003-12-01

    Chronically inhaled endotoxin, which is ubiquitous in many occupational and domestic environments, can adversely affect the respiratory system resulting in an inflammatory response and decreased lung function. Surfactant-associated protein A (SP-A) is part of the lung innate immune system and may attenuate the inflammatory response in various types of lung injury. Using a murine model to mimic occupational exposures to endotoxin, we hypothesized that SP-A gene expression and protein would be elevated in response to repeat exposure to inhaled grain dust and to purified lipopolysaccharide (LPS). Our results demonstrate that repeat exposure to inhaled endotoxin, either in the form of grain dust or purified LPS, results in increased whole lung SP-A gene expression and type II alveolar epithelial cell hyperplasia, whereas SP-A protein levels in lung lavage fluid are decreased. Furthermore, these alterations in SP-A gene activity and protein metabolism are dependent on an intact endotoxin signaling system. PMID:12922979

  10. Repeated exposures of the male Sprague Dawley rat reproductive tract to environmental toxicants: Do earlier exposures to di-(2-ethylhexyl)phthalate (DEHP) alter the effects of later exposures?

    PubMed

    Traore, Kassim; Martinez-Arguelles, Daniel B; Papadopoulos, Vassilios; Chen, Haolin; Zirkin, Barry R

    2016-06-01

    Although exposures to environmental toxicants occur throughout life, little attention has been paid to the possible effects of exposures early in life on later exposure effects. We asked whether DEHP administered in utero (GD14-parturition) affects how male rats respond to later exposures. Neither in utero nor juvenile (PND21-35) exposures to 100mg/kg/day DEHP affected testis weight or histology as assessed on PND35. However, after in utero DEHP, subsequent juvenile exposure resulted in significantly reduced testis weight and altered testicular histology. Both in utero and juvenile exposures resulted in significant reductions in serum testosterone, but there was no effect of earlier on later exposure. Whether or not there had been in utero DEHP exposure, juvenile DEHP exposure had no effect on body, kidney or liver weights. These observations indicate that in utero exposure can, but will not necessarily, alter later exposure effects, with outcomes dependent upon endpoints measured and dose. PMID:27040317

  11. Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development

    PubMed Central

    Caldwell, Katharine E.; Labrecque, Matthew T.; Solomon, Benjamin R.; Ali, Abdulmehdi; Allan, Andrea M.

    2015-01-01

    The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50 ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of

  12. Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development.

    PubMed

    Caldwell, Katharine E; Labrecque, Matthew T; Solomon, Benjamin R; Ali, Abdulmehdi; Allan, Andrea M

    2015-01-01

    The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of

  13. Low-Level Environmental Phthalate Exposure Associates with Urine Metabolome Alteration in a Chinese Male Cohort.

    PubMed

    Zhang, Jie; Liu, Liangpo; Wang, Xiaofei; Huang, Qingyu; Tian, Meiping; Shen, Heqing

    2016-06-01

    The general population is exposed to phthalates through various sources and routes. Integration of omics data and epidemiological data is a key step toward directly linking phthalate biomonitoring data with biological response. Urine metabolomics is a powerful tool to identify exposure biomarkers and delineate the modes of action of environmental stressors. The objectives of this study are to investigate the association between low-level environmental phthalate exposure and urine metabolome alteration in male population, and to unveil the metabolic pathways involved in the mechanisms of phthalate toxicity. In this retrospective cross-sectional study, we studied the urine metabolomic profiles of 364 male subjects exposed to low-level environmental phthalates. Di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) are the most widely used phthalates. ∑DEHP and MBP (the major metabolite of DBP) were associated with significant alteration of global urine metabolome in the male population. We observed significant increase in the levels of acetylneuraminic acid, carnitine C8:1, carnitine C18:0, cystine, phenylglycine, phenylpyruvic acid and glutamylphenylalanine; and meanwhile, decrease in the levels of carnitine C16:2, diacetylspermine, alanine, taurine, tryptophan, ornithine, methylglutaconic acid, hydroxyl-PEG2 and keto-PGE2 in high exposure group. The observations indicated that low-level environmental phthalate exposure associated with increased oxidative stress and fatty acid oxidation and decreased prostaglandin metabolism. Urea cycle, tryptophan and phenylalanine metabolism disruption was also observed. The urine metabolome disruption effects associated with ∑DEHP and MBP were similar, but not identical. The multibiomarker models presented AUC values of 0.845 and 0.834 for ∑DEHP and MBP, respectively. The predictive accuracy rates of established models were 81% for ΣDEHP and 73% for MBP. Our results suggest that low-level environmental phthalate

  14. Lead Exposure Disrupts Global DNA Methylation in Human Embryonic Stem Cells and Alters Their Neuronal Differentiation

    PubMed Central

    Senut, Marie-Claude; Sen, Arko; Cingolani, Pablo; Shaik, Asra; Land, Susan J.; Ruden, Douglas M.

    2014-01-01

    Exposure to lead (Pb) during childhood can result in learning disabilities and behavioral problems. Although described in animal models, whether Pb exposure also alters neuronal differentiation in the developing brains of exposed children is unknown. Here, we investigated the effects of physiologically relevant concentrations of Pb (from 0.4 to 1.9μM) on the capacity of human embryonic stem cells (hESCs) to progress to a neuronal fate. We found that neither acute nor chronic exposure to Pb prevented hESCs from generating neural progenitor cells (NPCs). NPCs derived from hESCs chronically exposed to 1.9μM Pb throughout the neural differentiation process generated 2.5 times more TUJ1-positive neurons than those derived from control hESCs. Pb exposure of hESCs during the stage of neural rosette formation resulted in a significant decrease in the expression levels of the neural marker genes PAX6 and MSI1. Furthermore, the resulting NPCs differentiated into neurons with shorter neurites and less branching than control neurons, as assessed by Sholl analysis. DNA methylation studies of control, acutely treated hESCs and NPCs derived from chronically exposed hESCs using the Illumina HumanMethylation450 BeadChip demonstrated that Pb exposure induced changes in the methylation status of genes involved in neurogenetic signaling pathways. In summary, our study shows that exposure to Pb subtly alters the neuronal differentiation of exposed hESCs and that these changes could be partly mediated by modifications in the DNA methylation status of genes crucial to brain development. PMID:24519525

  15. Lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation.

    PubMed

    Senut, Marie-Claude; Sen, Arko; Cingolani, Pablo; Shaik, Asra; Land, Susan J; Ruden, Douglas M

    2014-05-01

    Exposure to lead (Pb) during childhood can result in learning disabilities and behavioral problems. Although described in animal models, whether Pb exposure also alters neuronal differentiation in the developing brains of exposed children is unknown. Here, we investigated the effects of physiologically relevant concentrations of Pb (from 0.4 to 1.9μM) on the capacity of human embryonic stem cells (hESCs) to progress to a neuronal fate. We found that neither acute nor chronic exposure to Pb prevented hESCs from generating neural progenitor cells (NPCs). NPCs derived from hESCs chronically exposed to 1.9μM Pb throughout the neural differentiation process generated 2.5 times more TUJ1-positive neurons than those derived from control hESCs. Pb exposure of hESCs during the stage of neural rosette formation resulted in a significant decrease in the expression levels of the neural marker genes PAX6 and MSI1. Furthermore, the resulting NPCs differentiated into neurons with shorter neurites and less branching than control neurons, as assessed by Sholl analysis. DNA methylation studies of control, acutely treated hESCs and NPCs derived from chronically exposed hESCs using the Illumina HumanMethylation450 BeadChip demonstrated that Pb exposure induced changes in the methylation status of genes involved in neurogenetic signaling pathways. In summary, our study shows that exposure to Pb subtly alters the neuronal differentiation of exposed hESCs and that these changes could be partly mediated by modifications in the DNA methylation status of genes crucial to brain development. PMID:24519525

  16. Morning and Evening Blue-Enriched Light Exposure Alters Metabolic Function in Normal Weight Adults.

    PubMed

    Cheung, Ivy N; Zee, Phyllis C; Shalman, Dov; Malkani, Roneil G; Kang, Joseph; Reid, Kathryn J

    2016-01-01

    Increasing evidence points to associations between light-dark exposure patterns, feeding behavior, and metabolism. This study aimed to determine the acute effects of 3 hours of morning versus evening blue-enriched light exposure compared to dim light on hunger, metabolic function, and physiological arousal. Nineteen healthy adults completed this 4-day inpatient protocol under dim light conditions (<20lux). Participants were randomized to 3 hours of blue-enriched light exposure on Day 3 starting either 0.5 hours after wake (n = 9; morning group) or 10.5 hours after wake (n = 10; evening group). All participants remained in dim light on Day 2 to serve as their baseline. Subjective hunger and sleepiness scales were collected hourly. Blood was sampled at 30-minute intervals for 4 hours in association with the light exposure period for glucose, insulin, cortisol, leptin, and ghrelin. Homeostatic model assessment of insulin resistance (HOMA-IR) and area under the curve (AUC) for insulin, glucose, HOMA-IR and cortisol were calculated. Comparisons relative to baseline were done using t-tests and repeated measures ANOVAs. In both the morning and evening groups, insulin total area, HOMA-IR, and HOMA-IR AUC were increased and subjective sleepiness was reduced with blue-enriched light compared to dim light. The evening group, but not the morning group, had significantly higher glucose peak value during blue-enriched light exposure compared to dim light. There were no other significant differences between the morning or the evening groups in response to blue-enriched light exposure. Blue-enriched light exposure acutely alters glucose metabolism and sleepiness, however the mechanisms behind this relationship and its impacts on hunger and appetite regulation remain unclear. These results provide further support for a role of environmental light exposure in the regulation of metabolism. PMID:27191727

  17. Morning and Evening Blue-Enriched Light Exposure Alters Metabolic Function in Normal Weight Adults

    PubMed Central

    Cheung, Ivy N.; Zee, Phyllis C.; Shalman, Dov; Malkani, Roneil G.; Kang, Joseph; Reid, Kathryn J.

    2016-01-01

    Increasing evidence points to associations between light-dark exposure patterns, feeding behavior, and metabolism. This study aimed to determine the acute effects of 3 hours of morning versus evening blue-enriched light exposure compared to dim light on hunger, metabolic function, and physiological arousal. Nineteen healthy adults completed this 4-day inpatient protocol under dim light conditions (<20lux). Participants were randomized to 3 hours of blue-enriched light exposure on Day 3 starting either 0.5 hours after wake (n = 9; morning group) or 10.5 hours after wake (n = 10; evening group). All participants remained in dim light on Day 2 to serve as their baseline. Subjective hunger and sleepiness scales were collected hourly. Blood was sampled at 30-minute intervals for 4 hours in association with the light exposure period for glucose, insulin, cortisol, leptin, and ghrelin. Homeostatic model assessment of insulin resistance (HOMA-IR) and area under the curve (AUC) for insulin, glucose, HOMA-IR and cortisol were calculated. Comparisons relative to baseline were done using t-tests and repeated measures ANOVAs. In both the morning and evening groups, insulin total area, HOMA-IR, and HOMA-IR AUC were increased and subjective sleepiness was reduced with blue-enriched light compared to dim light. The evening group, but not the morning group, had significantly higher glucose peak value during blue-enriched light exposure compared to dim light. There were no other significant differences between the morning or the evening groups in response to blue-enriched light exposure. Blue-enriched light exposure acutely alters glucose metabolism and sleepiness, however the mechanisms behind this relationship and its impacts on hunger and appetite regulation remain unclear. These results provide further support for a role of environmental light exposure in the regulation of metabolism. PMID:27191727

  18. Altered Proteome of Burkholderia pseudomallei Colony Variants Induced by Exposure to Human Lung Epithelial Cells

    PubMed Central

    Al-Maleki, Anis Rageh; Mariappan, Vanitha; Vellasamy, Kumutha Malar; Tay, Sun Tee; Vadivelu, Jamuna

    2015-01-01

    Burkholderia pseudomallei primary diagnostic cultures demonstrate colony morphology variation associated with expression of virulence and adaptation proteins. This study aims to examine the ability of B. pseudomallei colony variants (wild type [WT] and small colony variant [SCV]) to survive and replicate intracellularly in A549 cells and to identify the alterations in the protein expression of these variants, post-exposure to the A549 cells. Intracellular survival and cytotoxicity assays were performed followed by proteomics analysis using two-dimensional gel electrophoresis. B. pseudomallei SCV survive longer than the WT. During post-exposure, among 259 and 260 protein spots of SCV and WT, respectively, 19 were differentially expressed. Among SCV post-exposure up-regulated proteins, glyceraldehyde 3-phosphate dehydrogenase, fructose-bisphosphate aldolase (CbbA) and betaine aldehyde dehydrogenase were associated with adhesion and virulence. Among the down-regulated proteins, enolase (Eno) is implicated in adhesion and virulence. Additionally, post-exposure expression profiles of both variants were compared with pre-exposure. In WT pre- vs post-exposure, 36 proteins were differentially expressed. Of the up-regulated proteins, translocator protein, Eno, nucleoside diphosphate kinase (Ndk), ferritin Dps-family DNA binding protein and peptidyl-prolyl cis-trans isomerase B were implicated in invasion and virulence. In SCV pre- vs post-exposure, 27 proteins were differentially expressed. Among the up-regulated proteins, flagellin, Eno, CbbA, Ndk and phenylacetate-coenzyme A ligase have similarly been implicated in adhesion, invasion. Protein profiles differences post-exposure provide insights into association between morphotypic and phenotypic characteristics of colony variants, strengthening the role of B. pseudomallei morphotypes in pathogenesis of melioidosis. PMID:25996927

  19. Functional Alterations in the Dorsal Raphe Nucleus Following Acute and Chronic Ethanol Exposure

    PubMed Central

    Lowery-Gionta, Emily G; Marcinkiewcz, Catherine A; Kash, Thomas L

    2015-01-01

    Alcoholism is a pervasive disorder perpetuated in part to relieve negative mood states like anxiety experienced during alcohol withdrawal. Emerging evidence demonstrates a role for the serotonin-rich dorsal raphe (DR) in anxiety following ethanol withdrawal. The current study examined the effects of chronic ethanol vapor exposure on the DR using slice electrophysiology in male DBA2/J mice. We found that chronic ethanol exposure resulted in deficits in social approach indicative of increased anxiety-like behavior at both 24 h and 7 days post-ethanol exposure. At 24 h post-ethanol exposure, we observed increased excitability and decreased spontaneous inhibitory transmission (inhibitory postsynaptic currents, IPSCs) in the DR. At 7 days post-ethanol exposure, we observed increased spontaneous and miniature excitatory transmission (excitatory postsynaptic currents, EPSCs). Because acute ethanol alters GABA transmission in other brain regions, we assessed the effects of ex vivo ethanol (50 mM) on miniature IPSCs (mIPSCs) in the DR 24-h post-ethanol exposure. Bath application of ethanol enhanced the amplitude of mIPSCs in cells from ethanol-naive and chronic intermittent ethanol-exposed (CIE) mice, but significantly enhanced the frequency of mIPSCs only in cells from CIE mice, suggesting that DR neurons are more sensitive to the inhibitory effects of acute ethanol following CIE. On the basis of these findings, we hypothesize that net excitation of DR neurons following chronic ethanol exposure contributes to enhanced anxiety during ethanol withdrawal, and that increased sensitivity of DR neurons to subsequent ethanol exposure may mediate acute ethanol's ability to relieve anxiety during ethanol withdrawal. PMID:25120075

  20. Olivary climbing fiber alterations in PN40 rat cerebellum following postnatal ethanol exposure.

    PubMed

    Pierce, Dwight R; Hayar, Abdallah; Williams, D Keith; Light, Kim Edward

    2011-03-10

    Developmental ethanol exposure in rats during postnatal days (PN) 4-6 is known to cause significant loss of the cerebellar Purkinje cells. It is not known what happens to the surviving neurons as they continue to develop. This study was designed to quantify the interactions between the olivary climbing fibers and the Purkinje cells when the cerebellar circuits have matured. Rat pups were treated with a daily dose of ethanol (4.5g/kg body weight) delivered by intragastric intubation on PN4, PN4-6, or PN7-9. The interactions between the climbing fibers and the Purkinje cells were examined on PN40 using confocal microscopy. Mid-vermal cerebellar sections were stained with antibodies to calbindin-D28k (to visualize Purkinje cells) and vesicular glutamate transporter 2 (VGluT2, to visualize climbing fibers). Confocal z-stack images were obtained from Lobule 1 and analyzed with Imaris software to quantify the staining of the two antibodies. The VGluT2 immunostaining was significantly reduced and this was associated with alterations in the synaptic integrity, and synaptic number per Purkinje cell with only a single exposure on PN4 enough to cause the alterations. Previously, we demonstrated similar deficits in climbing fiber innervation when analyzed on PN14 (Pierce, Hayar, Williams, and Light, 2010). The present study confirms that these alterations are sustained and further identifies the decreased synaptic density as well as alterations to the general morphology of the molecular layer of the cerebellar cortex that are the result of the binge ethanol exposure. PMID:21241681

  1. Genistein exposure inhibits growth and alters steroidogenesis in adult mouse antral follicles.

    PubMed

    Patel, Shreya; Peretz, Jackye; Pan, Yuan-Xiang; Helferich, William G; Flaws, Jodi A

    2016-02-15

    Genistein is a naturally occurring isoflavone phytoestrogen commonly found in plant products such as soybeans, lentils, and chickpeas. Genistein, like other phytoestrogens, has the potential to mimic, enhance, or impair the estradiol biosynthesis pathway, thereby potentially altering ovarian follicle growth. Previous studies have inconsistently indicated that genistein exposure may alter granulosa cell proliferation and hormone production, but no studies have examined the effects of genistein on intact antral follicles. Thus, this study was designed to test the hypothesis that genistein exposure inhibits follicle growth and steroidogenesis in intact antral follicles. To test this hypothesis, antral follicles isolated from CD-1 mice were cultured with vehicle (dimethyl sulfoxide; DMSO) or genistein (6.0 and 36μM) for 18-96h. Every 24h, follicle diameters were measured to assess growth. At the end of each culture period, the media were pooled to measure hormone levels, and the cultured follicles were collected to measure expression of cell cycle regulators and steroidogenic enzymes. The results indicate that genistein (36μM) inhibits growth of mouse antral follicles. Additionally, genistein (6.0 and 36μM) increases progesterone, testosterone, and dehydroepiandrosterone (DHEA) levels, but decreases estrone and estradiol levels. The results also indicate that genistein alters the expression of steroidogenic enzymes at 24, 72 and 96h, and the expression of cell cycle regulators at 18h. These data indicate that genistein exposure inhibits antral follicle growth by inhibiting the cell cycle, alters sex steroid hormone levels, and dysregulates steroidogenic enzymes in cultured mouse antral follicles. PMID:26792615

  2. Early life exposure to allergen and ozone results in altered development in adolescent rhesus macaque lungs

    SciTech Connect

    Herring, M.J.; Putney, L.F.; St George, J.A.; Avdalovic, M.V.; Schelegle, E.S.; Miller, L.A.; Hyde, D.M.

    2015-02-15

    In rhesus macaques, previous studies have shown that episodic exposure to allergen alone or combined with ozone inhalation during the first 6 months of life results in a condition with many of the hallmarks of asthma. This exposure regimen results in altered development of the distal airways and parenchyma (Avdalovic et al., 2012). We hypothesized that the observed alterations in the lung parenchyma would be permanent following a long-term recovery in filtered air (FA) housing. Forty-eight infant rhesus macaques (30 days old) sensitized to house dust mite (HDM) were treated with two week cycles of FA, house dust mite allergen (HDMA), ozone (O{sub 3}) or HDMA/ozone (HDMA + O{sub 3}) for five months. At the end of the five months, six animals from each group were necropsied. The other six animals in each group were allowed to recover in FA for 30 more months at which time they were necropsied. Design-based stereology was used to estimate volumes of lung components, number of alveoli, size of alveoli, distribution of alveolar volumes, interalveolar capillary density. After 30 months of recovery, monkeys exposed to HDMA, in either group, had significantly more alveoli than filtered air. These alveoli also had higher capillary densities as compared with FA controls. These results indicate that early life exposure to HDMA alone or HDMA + O{sub 3} alters the development process in the lung alveoli. - Highlights: • Abnormal lung development after postnatal exposure to ozone and allergen • This remodeling is shown as smaller, more numerous alveoli and narrower airways. • Allergen appears to have more of an effect than ozone during recovery. • These animals also have continued airway hyperresponsiveness (Moore et al. 2014)

  3. Alcohol exposure during late ovine gestation alters fetal liver iron homeostasis without apparent dysmorphology.

    PubMed

    Sozo, Foula; Dick, Anna M; Bensley, Jonathan G; Kenna, Kelly; Brien, James F; Harding, Richard; De Matteo, Robert

    2013-06-15

    High levels of alcohol (ethanol) exposure during fetal life can affect liver development and can increase susceptibility to infection after birth. Our aim was to determine the effects of a moderate level of ethanol exposure in late gestation on the morphology, iron status, and inflammatory status of the ovine fetal liver. Pregnant ewes were chronically catheterized at 91 days of gestation (DG; term ~145 DG) for daily intravenous infusion of ethanol (0.75 g/kg maternal body wt; n = 8) or saline (n = 7) over 1 h from 95 to 133 DG. At necropsy (134 DG), fetal livers were collected for analysis. Liver weight, general liver morphology, hepatic cell proliferation and apoptosis, perivascular collagen deposition, and interleukin (IL)-1β, IL-6, or IL-8 mRNA levels were not different between groups. However, ethanol exposure led to significant decreases in hepatic content of ferric iron and gene expression of the iron-regulating hormone hepcidin and tumor necrosis factor (TNF)-α (all P < 0.05). In the placenta, there was no difference in transferrin receptor, divalent metal transporter 1, and ferritin mRNA levels; however, ferroportin mRNA levels were increased in ethanol-exposed animals (P < 0.05), and ferroportin protein tended to be increased (P = 0.054). Plasma iron concentration was not different between control and ethanol-exposed groups; control fetuses had significantly higher iron concentrations than their mothers, whereas maternal and fetal iron concentrations were similar in ethanol-exposed animals. We conclude that daily ethanol exposure during the third-trimester-equivalent in sheep does not alter fetal liver morphology; however, decreased fetal liver ferric iron content and altered hepcidin and ferroportin gene expression indicate that iron homeostasis is altered. PMID:23594612

  4. Acute exposure to 2,4-dinitrophenol alters zebrafish swimming performance and whole body triglyceride levels.

    PubMed

    Marit, Jordan S; Weber, Lynn P

    2011-06-01

    While swimming endurance (critical swimming speed or U(crit)) and lipid stores have both been reported to acutely decrease after exposure to a variety of toxicants, the relationship between these endpoints has not been clearly established. In order to examine these relationships, adult zebrafish (Danio rerio) were aqueously exposed to solvent control (ethanol) or two nominal concentrations of 2,4-dinitrophenol (DNP), a mitochondrial electron transport chain uncoupler, for a 24-h period. Following exposure, fish were placed in a swim tunnel in clean water for swimming testing or euthanized immediately without testing, followed by analysis of whole body triglyceride levels. U(crit) decreased in both the 6 mg/L and 12 mg/L DNP groups, with 12 mg/L approaching the LC₅₀. A decrease in tail beat frequency was observed without a significant change in tail beat amplitude. In contrast, triglyceride levels were elevated in a concentration-dependent manner in the DNP exposure groups, but only in fish subjected to swimming tests. This increase in triglyceride stores may be due to a direct interference of DNP on lipid catabolism as well as increased triglyceride production when zebrafish were subjected to the co-stressors of swimming and toxicant exposure. Future studies should be directed at determining how acute DNP exposure combines with swimming to cause alterations in triglyceride accumulation. PMID:21406246

  5. Growth Retardation and Altered Isotope Composition As Delayed Effects of PCB Exposure in Daphnia magna.

    PubMed

    Ek, Caroline; Gerdes, Zandra; Garbaras, Andrius; Adolfsson-Erici, Margaretha; Gorokhova, Elena

    2016-08-01

    Trophic magnification factor (TMF) analysis employs stable isotope signatures to derive biomagnification potential for environmental contaminants. This approach relies on species δ(15)N values aligning with their trophic position (TP). This, however, may not always be true, because toxic exposure can alter growth and isotope allocation patterns. Here, effects of PCB exposure (mixture of PCB18, PCB40, PCB128, and PCB209) on δ(15)N and δ(13)C as well as processes driving these effects were explored using the cladoceran Daphnia magna. A two-part experiment assessed effects of toxic exposure during and after exposure; juvenile daphnids were exposed during 3 days (accumulation phase) and then allowed to depurate for 4 days (depuration phase). No effects on survival, growth, carbon and nitrogen content, and stable isotope composition were observed after the accumulation phase, whereas significant changes were detected in adults after the depuration phase. In particular, a significantly lower nitrogen content and a growth inhibition were observed, with a concomitant increase in δ(15)N (+0.1 ‰) and decrease in δ(13)C (-0.1 ‰). Although of low magnitude, these changes followed the predicted direction indicating that sublethal effects of contaminant exposure can lead to overestimation of TP and hence underestimated TMF. PMID:27367056

  6. A Complex Interaction Between Reduced Reelin Expression and Prenatal Organophosphate Exposure Alters Neuronal Cell Morphology

    PubMed Central

    Mullen, Brian R.; Ross, Brennan; Chou, Joan Wang; Khankan, Rana; Khialeeva, Elvira; Bui, Kimberly

    2016-01-01

    Genetic and environmental factors are both likely to contribute to neurodevelopmental disorders including schizophrenia, autism spectrum disorders, and major depressive disorders. Prior studies from our laboratory and others have demonstrated that the combinatorial effect of two factors—reduced expression of reelin protein and prenatal exposure to the organophosphate pesticide chlorpyrifos oxon—gives rise to acute biochemical effects and to morphological and behavioral phenotypes in adolescent and young adult mice. In the current study, we examine the consequences of these factors on reelin protein expression and neuronal cell morphology in adult mice. While the cell populations that express reelin in the adult brain appear unchanged in location and distribution, the levels of full length and cleaved reelin protein show persistent reductions following prenatal exposure to chlorpyrifos oxon. Cell positioning and organization in the hippocampus and cerebellum are largely normal in animals with either reduced reelin expression or prenatal exposure to chlorpyrifos oxon, but cellular complexity and dendritic spine organization is altered, with a skewed distribution of immature dendritic spines in adult animals. Paradoxically, combinatorial exposure to both factors appears to generate a rescue of the dendritic spine phenotypes, similar to the mitigation of behavioral and morphological changes observed in our prior study. Together, our observations support an interaction between reelin expression and chlorpyrifos oxon exposure that is not simply additive, suggesting a complex interplay between genetic and environmental factors in regulating brain morphology. PMID:27364165

  7. CHRONIC ZEBRAFISH PFOS EXPOSURE ALTERS SEX RATIO AND MATERNAL RELATED EFFECTS IN F1 OFFSPRING

    PubMed Central

    Wang, Mingyong; Chen, Jiangfei; Lin, Kuanfei; Chen, Yuanhong; Hu, Wei; Tanguay, Robert L.; Huang, Changjiang; Dong, Qiaoxiang

    2012-01-01

    Perfluorooctanesulfonic acid (PFOS) is an organic contaminant ubiquitous in the environment, wildlife, and humans. Few studies have assessed its chronic toxicity on aquatic organisms. The present study defined the effects of long-term exposure to PFOS on zebrafish development and reproduction. Specifically, zebrafish at 8 h postfertilization (hpf) were exposed to PFOS at 0, 5, 50, and 250 μg/L for five months. Growth suppression was observed in the 250 μg/L PFOS-treated group. The sex ratio was altered, with a significant female dominance in the high-dose PFOS group. Male gonad development was also impaired in a dose-dependent manner by PFOS exposure. Although female fecundity was not impacted, the F1 embryos derived from high-dose exposed females paired with males without PFOS exposure developed severe deformity at early development stages and resulted in 100% larval mortality at 7 d postfertilization (dpf). Perfluorooctanesulfonic acid quantification in embryos indicated that decreased larval survival in F1 offspring was directly correlated to the PFOS body burden, and larval lethality was attributable to maternal transfer of PFOS to the eggs. Lower-dose parental PFOS exposure did not result in decreased F1 survival; however, the offspring displayed hyperactivity of basal swimming speed in a light-to-dark behavior assessment test. These findings demonstrate that chronic exposure to PFOS adversely impacts embryonic growth, reproduction, and subsequent offspring development. Environ. PMID:21671259

  8. Polychlorinated biphenyl 126 exposure in L6 myotubes alters glucose metabolism: a pilot study.

    PubMed

    Mauger, Jean-François; Nadeau, Lucien; Caron, Audrey; Chapados, Natalie Ann; Aguer, Céline

    2016-04-01

    Polychlorinated biphenyls (PCBs) are increasingly recognized as metabolic disruptors. Due to its mass, skeletal muscle is the major site of glucose disposal. While muscle mitochondrial dysfunction and oxidative stress have been shown to play a central role in metabolic disease development, no studies to date have investigated the effect of PCB exposure on muscle energy metabolism and oxidative stress. In this pilot study, we tested the effect of exposure to PCB126 in L6 myotubes (from 1 to 2500 nM for 24 h) on mitochondrial function, glucose metabolism, and oxidative stress. Exposure to PCB126 had no apparent effect on resting, maximal, and proton leak-dependent oxygen consumption rate in intact L6 myotubes. However, basal glucose uptake and glycolysis were inhibited by 20-30 % in L6 myotubes exposed to PCB126. Exposure to PCB126 did not appear to alter skeletal muscle anti-oxidant defense or oxidative stress. In conclusion, our study shows for the first time that exposure to a dioxin-like PCB adversely affects skeletal muscle glucose metabolism. Given the importance of skeletal muscle in the maintenance of glucose homeostasis, PCB126 could play an important role in the development of metabolic disorders. PMID:26936477

  9. A Complex Interaction Between Reduced Reelin Expression and Prenatal Organophosphate Exposure Alters Neuronal Cell Morphology.

    PubMed

    Mullen, Brian R; Ross, Brennan; Chou, Joan Wang; Khankan, Rana; Khialeeva, Elvira; Bui, Kimberly; Carpenter, Ellen M

    2016-06-01

    Genetic and environmental factors are both likely to contribute to neurodevelopmental disorders including schizophrenia, autism spectrum disorders, and major depressive disorders. Prior studies from our laboratory and others have demonstrated that the combinatorial effect of two factors-reduced expression of reelin protein and prenatal exposure to the organophosphate pesticide chlorpyrifos oxon-gives rise to acute biochemical effects and to morphological and behavioral phenotypes in adolescent and young adult mice. In the current study, we examine the consequences of these factors on reelin protein expression and neuronal cell morphology in adult mice. While the cell populations that express reelin in the adult brain appear unchanged in location and distribution, the levels of full length and cleaved reelin protein show persistent reductions following prenatal exposure to chlorpyrifos oxon. Cell positioning and organization in the hippocampus and cerebellum are largely normal in animals with either reduced reelin expression or prenatal exposure to chlorpyrifos oxon, but cellular complexity and dendritic spine organization is altered, with a skewed distribution of immature dendritic spines in adult animals. Paradoxically, combinatorial exposure to both factors appears to generate a rescue of the dendritic spine phenotypes, similar to the mitigation of behavioral and morphological changes observed in our prior study. Together, our observations support an interaction between reelin expression and chlorpyrifos oxon exposure that is not simply additive, suggesting a complex interplay between genetic and environmental factors in regulating brain morphology. PMID:27364165

  10. Perinatal exposure to diethylstilbestrol alters the functional differentiation of the adult rat uterus.

    PubMed

    Bosquiazzo, Verónica L; Vigezzi, Lucía; Muñoz-de-Toro, Mónica; Luque, Enrique H

    2013-11-01

    The exposure to endocrine disrupters and female reproductive tract disorders has not been totally clarified. The present study assessed the long-term effect of perinatal (gestation+lactation) exposure to diethylstilbestrol (DES) on the rat uterus and the effect of estrogen replacement therapy. DES (5μg/kg bw/day) was administered in the drinking water from gestational day 9 until weaning and we studied the uterus of young adult (PND90) and adult (PND360) females. To investigate whether perinatal exposure to DES modified the uterine response to a long-lasting estrogen treatment, 12-month-old rats exposed to DES were ovariectomized and treated with 17β-estradiol for 3 months (PND460). In young adult rats (PND90), the DES treatment decreased both the proliferation of glandular epithelial cells and the percentage of glandular perimeter occupied by α-smooth muscle actin-positive cells. The other tissue compartments remained unchanged. Cell apoptosis was not altered in DES-exposed females. In control adult rats (PND360), there were some morphologically abnormal uterine glands. In adult rats exposed to DES, the incidence of glands with cellular anomalies increased. In response to estrogens (PND460), the incidence of cystic glands increased in the DES group. We observed glands with daughter glands and conglomerates of glands only on PND460 and in response to estrogen replacement therapy, independently of DES exposure. The p63 isoforms were expressed without changes on PND460. Estrogen receptors α and β showed no changes, while the progesterone receptor decreased in the subepithelial stroma of DES-exposed animals with estrogen treatment. The long-lasting effects of perinatal exposure to DES included the induction of abnormalities in uterine tissues of aged female rats and an altered response of the adult uterus to estradiol. PMID:23454116

  11. Exposure to the Endocrine Disruptor Bisphenol A Alters Susceptibility for Mammary Cancer

    PubMed Central

    Lamartiniere, Coral A.; Jenkins, Sarah; Betancourt, Angela M.; Wang, Jun; Russo, Jose

    2011-01-01

    Bisphenol A (BPA) is a synthetically made chemical used in the production of polycarbonate plastics and epoxy resins. Recent studies have shown over ninety percent of humans investigated have detectable BPA concentrations. Yet, the biggest concern for BPA is exposure during early development because BPA has been shown to bind to the estrogen receptors (ER) and cause developmental and reproductive toxicity. We have investigated the potential of perinatal BPA to alter susceptibility for chemically-induced mammary cancer in rats. We demonstrate that prepubertal exposure to low concentrations of orally administered BPA given to lactating dams resulted in a significantly decreased tumor latency and increased tumor multiplicity in the dimethylbenz[a]anthracene (DMBA) model of rodent mammary carcinogenesis. Our data suggested that the mechanism of action behind this carcinogenic response was mediated through increased cell proliferation, decreased apoptosis, and centered on an up-regulation of steroid receptor coactivators (SRCs) 1–3, erbB3, and increased Akt signaling in the mammary gland. Also, we demonstrate that prenatal exposure to BPA shifts the time of susceptibility from 50 days to 100 days for chemically-induced mammary carcinogenesis. Proteomic data suggest that prenatal BPA exposure alters the expression of several proteins involved in regulating protein metabolism, signal transduction, developmental processes, and cell cycle and proliferation. Increases in ER-alpha, SRCs 1–3, Bcl-2, epidermal growth factor–receptor (EGFR), phospho-IGF-1R, phospho-c-Raf, phospho-ERKs 1/2, phospho-ErbB2 and phospho-Akt are accompanied by increase in cell proliferation. We conclude that exposure to low concentrations of BPA during the prenatal and early postnatal periods of life can predispose for chemically-induced mammary cancer. PMID:21687816

  12. Prenatal endotoxin exposure alters behavioural pain responses to lipopolysaccharide in adult offspring.

    PubMed

    Hodyl, Nicolette A; Walker, F Rohan; Krivanek, Klara M; Clifton, Vicki L; Hodgson, Deborah M

    2010-05-11

    Evidence suggests that exposure to bacterial endotoxin in early life can alter the production of pro-inflammatory cytokines in later life. This phenomenon may have significant consequences for pain and pain related behaviours as pro-inflammatory cytokines heighten pain sensitivity. This association has yet to be examined. As such, the aim of the present study was to characterize pain behaviours in adult rat offspring following prenatal endotoxin (PE) exposure. Pregnant F344 rats received endotoxin (200microg/kg, s.c.) or saline on gestational days 16, 18 and 20. Pain thresholds were assessed in the adult PE offspring (n=23) and control offspring (n=24) prior to and 4h following administration of lipopolysaccharide (LPS; 100microg/kg, s.c.). Three assays of pain were employed - the hot plate, tail immersion and von Frey tests. Results demonstrated sex-specific effects of prenatal endotoxin on the offspring, with PE males displaying unaltered pain thresholds on the von Frey test post-LPS administration (p<0.01), while male control offspring (n=24) displayed the expected hyperalgesia. Male PE offspring also displayed increased pain thresholds on the tail immersion test (p<0.01), while no change in pain sensitivity was observed in control males following LPS exposure. No difference in response was observed between the female PE and control offspring on the von Frey test, however PE female offspring displayed increased thresholds on the tail immersion test compared to baseline - an effect not observed in the control female offspring. Pain sensitivity on the hot plate test was unaffected by prenatal exposure to endotoxin. These data suggest that prenatal exposure to products associated with bacterial infection have the capacity to alter pain responses, which are evident in the adult offspring. PMID:20184906

  13. Alterations in the striatal dopamine system during intravenous methamphetamine exposure: effects of contingent and noncontingent administration.

    PubMed

    Laćan, Goran; Hadamitzky, Martin; Kuczenski, Ronald; Melega, William P

    2013-08-01

    The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long-term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a "humanized" plasma METH half life or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7 and 1.5 µM. Animals were sacrificed during their last METH administration for autoradiography assessment using [³H]ligands and D2 agonist-induced [³⁵S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15-20%) and [³⁵S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal's total intake was similar within and across three 24-h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans. PMID:23417852

  14. Alterations in the Striatal Dopamine System During Intravenous Methamphetamine Exposure: Effects of Contingent and Noncontingent Administration

    PubMed Central

    Laćan, Goran; Hadamitzky, Martin; Kuczenski, Ronald; Melega, William P.

    2014-01-01

    The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a ‘humanized’ plasma METH half life, or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7–1.5 μM. Animals were sacrificed during their last METH administration for autoradiography assessment using [3H]ligands and D2 agonist-induced [35S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15–20%) and [35S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal’s total intake was similar within and across three 24 h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans. PMID:23417852

  15. In Vitro Exposure of Harbor Seal Immune Cells to Aroclor 1260 Alters Phocine Distemper Virus Replication.

    PubMed

    Bogomolni, Andrea; Frasca, Salvatore; Levin, Milton; Matassa, Keith; Nielsen, Ole; Waring, Gordon; De Guise, Sylvain

    2016-01-01

    In the last 30 years, several large-scale marine mammal mortality events have occurred, often in close association with highly polluted regions, leading to suspicions that contaminant-induced immunosuppression contributed to these epizootics. Some of these recent events also identified morbillivirus as a cause of or contributor to death. The role of contaminant exposures regarding morbillivirus mortality is still unclear. The results of this study aimed to address the potential for a mixture of polychlorinated biphenyls (PCBs), specifically Aroclor 1260, to alter harbor seal T-lymphocyte proliferation and to assess if exposure resulted in increased likelihood of phocine distemper virus (PDV USA 2006) to infect susceptible seals in an in vitro system. Exposure of peripheral blood mononuclear cells to Aroclor 1260 did not significantly alter lymphocyte proliferation (1, 5, 10, and 20 ppm). However, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), lymphocytes exposed to 20 ppm Aroclor 1260 exhibited a significant decrease in PDV replication at day 7 and a significant increase at day 11 compared with unexposed control cells. Similar and significant differences were apparent on exposure to Aroclor 1260 in monocytes and supernatant. The results here indicate that in harbor seals, Aroclor 1260 exposure results in a decrease in virus early during infection and an increase during late infection. The consequences of this contaminant-induced infection pattern in a highly susceptible host could result in a greater potential for systemic infection with greater viral load, which could explain the correlative findings seen in wild populations exposed to a range of persistent contaminants that suffer from morbillivirus epizootics. PMID:26142119

  16. Chronic exposure to pentachlorophenol alters thyroid hormones and thyroid hormone pathway mRNAs in zebrafish.

    PubMed

    Yu, Li-Qin; Zhao, Gao-Feng; Feng, Min; Wen, Wu; Li, Kun; Zhang, Pan-Wei; Peng, Xi; Huo, Wei-Jie; Zhou, Huai-Dong

    2014-01-01

    Pentachlorophenol (PCP) is frequently detected in the aquatic environment and has been implicated as an endocrine disruptor in fish. In the present study, 4-month-old zebrafish (Danio rerio) were exposed to 1 of 4 concentrations of PCP (0.1, 1, 9, and 27 µg/L) for 70 d. The effects of PCP exposure on plasma thyroid hormone levels, and the expression levels of selected genes, were measured in the brain and liver. The PCP exposure at 27 µg/L resulted in elevated plasma thyroxine concentrations in male and female zebrafish and depressed 3, 5, 3'-triiodothyronine concentrations in males only. In both sexes, PCP exposure resulted in decreased messenger RNA (mRNA) expression levels of thyroid-stimulating hormone β-subunit (tshβ) and thyroid hormone receptor β (trβ) in the brain, as well as increased liver levels of uridine diphosphoglucuronosyl transferase (ugt1ab) and decreased deiodinase 1 (dio1). The authors also identified several sex-specific effects of PCP exposure, including changes in mRNA levels for deiodinase 2 (dio2), cytosolic sulfotransferase (sult1 st5), and transthyretin (ttr) genes in the liver. Environmental PCP exposure also caused an increased malformation rate in offspring that received maternal exposure to PCP. The present study demonstrates that chronic exposure to environmental levels of PCP alters plasma thyroid hormone levels, as well as the expression of genes associated with thyroid hormone signaling and metabolism in the hypothalamic-pituitary-thyroid (HPT) axis and liver, resulting in abnormal zebrafish development. PMID:24123209

  17. Elevated bulk-silica exposures and evidence for multiple aqueous alteration episodes in Nili Fossae, Mars

    NASA Astrophysics Data System (ADS)

    Amador, Elena S.; Bandfield, Joshua L.

    2016-09-01

    The Nili Fossae region of Mars contains some of the most mineralogically diverse bedrock on the planet. Previous studies have established three main stratigraphic units in the region: a phyllosilicate-bearing basement rock, a variably altered olivine-rich basalt, and a capping rock. Here, we present evidence for the localized alteration of the northeast Nili Fossae capping unit, previously considered to be unaltered. Both near-infrared and thermal-infrared spectral datasets were analyzed, including the application of a method for determining the relative abundance of bulk-silica (SiO2) over surfaces using thermal emission imaging system (THEMIS) images. Elevated bulk-silica exposures are present on surfaces previously defined as unaltered capping rock. Given the lack of spectral evidence for phyllosilicate, hydrated silica, or quartz phases coincident with the newly detected exposures-the elevated bulk-silica may have formed under a number of aqueous scenarios, including as a product of the carbonation of the underlying olivine-rich basalt under moderate water: rock scenarios and temperatures. Regardless of formation mechanism, the detection of elevated bulk-silica exposures in the Nili Fossae capping unit extends the history of aqueous activity in the region to include all three of the main stratigraphic units.

  18. Alterations induced by chronic lead exposure on the cells of circadian pacemaker of developing rats

    PubMed Central

    Rojas-Castañeda, Julio César; Vigueras-Villaseñor, Rosa María; Rojas, Patricia; Chávez-Saldaña, Margarita; Pérez, Oscar Gutiérrez; Montes, Sergio; Ríos, Camilo

    2011-01-01

    Lead (Pb) exposure alters the temporal organization of several physiological and behavioural processes in which the suprachiasmatic nucleus (SCN) of the hypothalamus plays a fundamental role. In this study, we evaluated the effects of chronic early Pb exposure (CePbe) on the morphology, cellular density and relative optical density (OD) in the cells of the SCN of male rats. Female Wistar rats were exposed during gestation and lactation to a Pb solution containing 320 ppm of Pb acetate through drinking water. After weaning, the pups were maintained with the same drinking water until sacrificed at 90 days of age. Pb levels in the blood, hypothalamus, hippocampus and prefrontal cortex were significantly increased in the experimental group. Chronic early Pb exposure induced a significant increase in the minor and major axes and somatic area of vasoactive intestinal polypeptide (VIP)- and vasopressin (VP)-immunoreactive neurons. The density of VIP-, VP- and glial fibrillary acidic protein (GFAP)-immunoreactive cells showed a significant decrease in the experimental group. OD analysis showed a significant increase in VIP neurons of the experimental group. The results showed that CePbe induced alterations in the cells of the SCN, as evidenced by modifications in soma morphology, cellular density and OD in circadian pacemaker cells. These findings provide a morphological and cellular basis for deficits in circadian rhythms documented in Pb-exposed animals. PMID:21324006

  19. Alterations in Cell Signaling Pathways in Breast Cancer Cells after Environmental Exposure

    SciTech Connect

    Kulp, K; McCutcheon-Maloney, S M; Bennett, L M

    2003-02-01

    Recent human epidemiological studies suggest that up to 75% of human cancers can be attributed to environmental exposures. Understanding the biologic impact of being exposed to a lifetime of complex environmental mixtures that may not be fully characterized is currently a major challenge. Functional endpoints may be used to assess the gross health consequences of complex mixture exposures from groundwater contamination, superfund sites, biologic releases, or nutritional sources. Such endpoints include the stimulation of cell growth or the induction of a response in an animal model. An environmental exposure that upsets normal cell growth regulation may have important ramifications for cancer development. Stimulating cell growth may alter an individual's cancer risk by changing the expression of genes and proteins that have a role in growth regulatory pathways within cells. Modulating the regulation of these genes and their products may contribute to the initiation, promotion or progression of disease in response to environmental exposure. We are investigating diet-related compounds that induce cell proliferation in breast cancer cell lines. These compounds, PhIP, Flor-Essence{reg_sign} and Essiac{reg_sign}, may be part of an everyday diet. PhIP is a naturally occurring mutagen that is formed in well-cooked muscle meats. PhIP consistently causes dose-dependent breast tumor formation in rats and consumption of well-done meat has been linked to increased risk of breast cancer in women. Flor-Essence{reg_sign} and Essiac{reg_sign} herbal tonics are complementary and alternative medicines used by women who have been diagnosed with breast cancer as an alternative therapy for disease treatment and prevention. The long-term goal of this work is to identify those cellular pathways that are altered by a chemical or biologic environmental exposure and understand how those changes correlate with and or predict changes in human health risk. This project addressed this goal by

  20. Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs

    PubMed Central

    Schuster, Andrew; Skinner, Michael K.; Yan, Wei

    2016-01-01

    Exposure to the agricultural fungicide vinclozolin during gestation promotes a higher incidence of various diseases in the subsequent unexposed F3 and F4 generations. This phenomenon is termed epigenetic transgenerational inheritance and has been shown to in part involve alterations in DNA methylation, but the role of other epigenetic mechanisms remains unknown. The current study investigated the alterations in small noncoding RNA (sncRNA) in the sperm from F3 generation control and vinclozolin lineage rats. Over 200 differentially expressed sncRNAs were identified and the tRNA-derived sncRNAs, namely 5′ halves of mature tRNAs (5′ halves), displayed the most dramatic changes. Gene targets of the altered miRNAs and tRNA 5′ halves revealed associations between the altered sncRNAs and differentially DNA methylated regions. Dysregulated sncRNAs appear to correlate with mRNA profiles associated with the previously observed vinclozolin-induced disease phenotypes. Data suggest potential connections between sperm-borne RNAs and the vinclozolin-induced epigenetic transgenerational inheritance phenomenon. PMID:27390623

  1. In vitro exposure of Ulva lactuca Linnaeus (Chlorophyta) to gasoline - Biochemical and morphological alterations.

    PubMed

    Pilatti, Fernanda Kokowicz; Ramlov, Fernanda; Schmidt, Eder Carlos; Kreusch, Marianne; Pereira, Débora Tomazi; Costa, Christopher; de Oliveira, Eva Regina; Bauer, Cláudia M; Rocha, Miguel; Bouzon, Zenilda Laurita; Maraschin, Marcelo

    2016-08-01

    Refined fuels have considerable share of pollution of marine ecosystems. Gasoline is one of the most consumed fuel worldwide, but its effects on marine benthic primary producers are poorly investigated. In this study, Ulva lactuca was chosen as a biological model due to its cosmopolitan nature and tolerance to high levels and wide range of xenobiotics and our goal was to evaluate the effects of gasoline on ultrastructure and metabolism of that seaweed. The experimental design consisted of in vitro exposure of U. lactuca to four concentrations of gasoline (0.001%, 0.01%, 0.1%, and 1.0%, v/v) over 30 min, 1 h, 12 h, and 24 h, followed by cytochemical, SEM, and biochemical analysis. Increase in the number of cytoplasmic granules, loss of cell turgor, cytoplasmic shrinkage, and alterations in the mucilage were some of the ultrastructural alterations observed in thalli exposed to gasoline. Decrease in carotenoid and polyphenol contents, as well as increase of soluble sugars and starch contents were associated with the time of exposure to the xenobiotic. In combination, the results revealed important morphological and biochemical alterations in the phenotype of U. lactuca upon acute exposure to gasoline. This seaweed contain certain metabolites assigned as candidates to biomarkers of the environmental stress investigated and it is thought to be a promise species for usage in coastal ecosystems perturbation monitoring system. In addition, the findings suggest that U. lactuca is able to metabolize gasoline hydrocarbons and use them as energy source, acting as bioremediator of marine waters contaminated by petroleum derivatives. PMID:27192480

  2. Adolescent Alcohol Exposure Alters GABAA Receptor Subunit Expression in Adult Hippocampus

    PubMed Central

    Centanni, Samuel W.; Teppen, Tara; Risher, Mary-Louise; Fleming, Rebekah L.; Moss, Julia L.; Acheson, Shawn K.; Mulholland, Patrick J.; Pandey, Subhash C.; Chandler, L. Judson; Swartzwelder, H. Scott

    2014-01-01

    Background The long-term consequences of adolescent alcohol abuse that persist into adulthood are poorly understood and have not been widely investigated. We have shown that intermittent exposure to alcohol during adolescence decreased the amplitude of GABAA receptor-mediated tonic currents in hippocampal dentate granule cells in adulthood. The aim of the present study was to investigate the enduring effects of chronic intermittent alcohol exposure during adolescence or adulthood on the expression of hippocampal GABAA receptors (GABAARs). Methods We used a previously characterized tissue fractionation method to isolate detergent resistant membranes and soluble fractions, followed by western blots to measure GABAAR protein expression. We also measured mRNA levels of GABAAR subunits using quantitative real-time PCR. Results Although the protein levels of α1-, α4- and δ-GABAAR subunits remained stable between postnatal day (PD) 30 (early adolescence) and PD71 (adulthood), the α5-GABAAR subunit was reduced across that period. In rats that were subjected to adolescent intermittent ethanol (AIE) exposure between PD30–46, there was a significant reduction in the protein levels of the δ-GABAAR, in the absence of any changes in mRNA levels, at 48 hours and 26 days after the last ethanol exposure. Protein levels of the α4-GABAAR subunit were significantly reduced, but mRNA levels were increased, 26 days (but not 48 hours) after the last AIE exposure. Protein levels of α5-GABAAR were not changed by AIE, but mRNA levels were reduced at 48hrs but normalized 26 days after AIE. In contrast to the effects of AIE, chronic intermittent exposure to ethanol during adulthood (CIE) had no effect on expression of any of the GABAAR subunits examined. Conclusions AIE produced both short- and long-term alterations of GABAAR subunits mRNA and protein expression in the hippocampus, whereas CIE produced no long lasting effects on those measures. The observed reduction of protein

  3. Intermittent prenatal MDMA exposure alters physiological but not mood related parameters in adult rat offspring.

    PubMed

    Adori, Csaba; Zelena, Dóra; Tímár, Júlia; Gyarmati, Zsuzsa; Domokos, Agnes; Sobor, Melinda; Fürst, Zsuzsanna; Makara, Gábor; Bagdy, György

    2010-01-20

    The recreational party drug "ecstasy" (3,4-methylenedioxymethamphetamine MDMA) is particularly popular among young adults who are in the childbearing age and thus there is a substantial risk of prenatal MDMA exposure. We applied an intermittent treatment protocol with an early first injection on pregnant Wistar rats (15 mg/kg MDMA s.c. on the E4, E11 and E18 days of gestation) to examine the potential physiological, endocrine and behavioral effects on adult male and female offspring. Prenatal MDMA-treatment provoked reduced body weight of offspring from the birth as far as the adulthood. Adult MDMA-offspring had a reduced blood-glucose concentration and hematocrit, altered relative spleen and thymus weight, had lower performance on wire suspension test and on the first trial of rotarod test. In contrast, no alteration in the locomotor activity was found. Anxiety and depression related behavioral parameters in elevated plus maze, sucrose preference or forced swimming tests were normal. MDMA-offspring had elevated concentration of the ACTH-precursor proopiomelanocortin and male MDMA-offspring exhibited elevated blood corticosterone concentration. No significant alteration was detected in the serotonergic marker tryptophan-hydroxylase and the catcholaminergic marker tyrosine-hydroxylase immunoreactive fiber densities in MDMA-offspring. The mothers exhibited reduced densities of serotonergic but not catecholaminergic fibers after the MDMA treatment. Our findings suggest that an intermittent prenatal MDMA exposure with an early first injection and a relatively low cumulative dose provokes mild but significant alterations in physical-physiological parameters and reduces motor skill learning in adulthood. In contrast, these adult offspring do not produce anxiety or depression like behavior. PMID:19782105

  4. Alterations in cytochrome P-450 levels in adult rats following neonatal exposure to xenobiotics

    SciTech Connect

    Zangar, R.C. Pacific Northwest Laboratories, Richland, WA ); Springer, D.L. ); Buhler, D.R. )

    1993-01-01

    Neonatal exposure to certain xenobiotics has been shown to alter hepatic metabolism in adult rats in a manner that indicates long-term changes in enzyme regulation. Previously, the authors have observed changes in adult testosterone metabolism and in cytochrome P-450 (P-450) mRNA levels in animals neonatally exposed to phenobarbital (PB) or diethylstilbestrol (DES). In order to test for other enzyme alterations, they used Western blot procedures for specific P-450s to analyze hepatic microsomes from adult rats (24 wk old) that had been exposed neonatally to DES, PB, 7,12-dimethylbenz[a]anthracene (DMBA), or pregnenolone 16[alpha]-carbonitrile (PCN). The most striking effects were observed in the DES-treated males: P-4502C6 and an immunologically similar protein were increased 60 and 90%, respectively, relative to control values, but P-4503A2 was decreased by 44%. No changes were observed in the DES-treated males in levels of P-4502E1, P-4502B, or the male-specific P-4502C13. Adult males neonatally treated with PB had 150% increase in levels of anti-P4502B-reactive protein without significant changes in the other enzymes. The DES- and DMBA-treated females had increased levels of the female-specific P-4502C12 of 38 and 48%, respectively, but no other observed alterations. The results confirm that neonatal exposure to DES or PB can cause alterations in adult hepatic cytochrome P-450 levels but show that these chemicals act on different enzymes. Neonatal DMBA resulted in changes in adult females similar to those produced by the synthetic estrogen DES, but did so at about two-thirds lower dose. 37 refs., 5 figs.

  5. Chronic ultraviolet exposure-induced p53 gene alterations in sencar mouse skin carcinogenesis model

    SciTech Connect

    Tong, Ying; Smith, M.A.; Tucker, S.B.

    1997-06-27

    Alterations of the tumor suppressor gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10137 (27%) of SCCs and 12124 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C {r_arrow} A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C {r_arrow} T, two C {r_arrow} A, one C {r_arrow} G, and one A {r_arrow} T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin. 40 refs., 5 figs., 1 tab.

  6. Formaldehyde exposure alters miRNA expression profiles in the olfactory bulb.

    PubMed

    Li, Guifa; Yang, Jing; Ling, Shucai

    2015-01-01

    It has been reported that inhaling formaldehyde (FA) causes damage to the central nervous system. However, it is unclear whether FA can disturb the function of the olfactory bulb. Using a microarray, we found that FA inhalation altered the miRNA expression profile. Functional enrichment analysis of the predicted targets of the changed miRNA showed that the enrichment canonical pathways and networks associated with cancer and transcriptional regulation. FA exposure disrupts miRNA expression profiles within the olfactory bulb. PMID:26161908

  7. Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome

    PubMed Central

    2014-01-01

    Background Environmental factors during perinatal development may influence developmental plasticity and disease susceptibility via alterations to the epigenome. Developmental exposure to the endocrine active compound, bisphenol A (BPA), has previously been associated with altered methylation at candidate gene loci. Here, we undertake the first genome-wide characterization of DNA methylation profiles in the liver of murine offspring exposed perinatally to multiple doses of BPA through the maternal diet. Results Using a tiered focusing approach, our strategy proceeds from unbiased broad DNA methylation analysis using methylation-based next generation sequencing technology to in-depth quantitative site-specific CpG methylation determination using the Sequenom EpiTYPER MassARRAY platform to profile liver DNA methylation patterns in offspring maternally exposed to BPA during gestation and lactation to doses ranging from 0 BPA/kg (Ctr), 50 μg BPA/kg (UG), or 50 mg BPA/kg (MG) diet (N = 4 per group). Genome-wide analyses indicate non-monotonic effects of DNA methylation patterns following perinatal exposure to BPA, corroborating previous studies using multiple doses of BPA with non-monotonic outcomes. We observed enrichment of regions of altered methylation (RAMs) within CpG island (CGI) shores, but little evidence of RAM enrichment in CGIs. An analysis of promoter regions identified several hundred novel BPA-associated methylation events, and methylation alterations in the Myh7b and Slc22a12 gene promoters were validated. Using the Comparative Toxicogenomics Database, a number of candidate genes that have previously been associated with BPA-related gene expression changes were identified, and gene set enrichment testing identified epigenetically dysregulated pathways involved in metabolism and stimulus response. Conclusions In this study, non-monotonic dose dependent alterations in DNA methylation among BPA-exposed mouse liver samples and their relevant pathways

  8. Pituitary self-priming actions of gonadotropin-releasing hormone. Kinetics of estradiol's potentiating effects on gonadotropin-releasing hormone-facilitated luteinizing hormone and follicle-stimulating hormone release in healthy postmenopausal women.

    PubMed

    Veldhuis, J D; Evans, W S; Rogol, A D; Kolp, L; Thorner, M O; Stumpf, P

    1986-06-01

    We examined the kinetically distinct characteristics of estradiol's effects upon pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in response to pulses of exogenous gonadotropin-releasing hormone (GnRH) in healthy postmenopausal individuals. The putative self-priming actions of GnRH on LH and FSH release were tested by intravenous injections of equal paired doses of GnRH (10 micrograms) before and after 1, 5, 10, and 30 d of pure estradiol-17 beta delivery via an intravaginal silastic ring. Self-priming actions of GnRH, as defined by heightened gonadotropin release in response to the second pulse of GnRH compared with the first, were completely absent in the hypoestrogenemic state. However, estradiol administration unmasked GnRH self-priming in a time-dependent fashion, with maximal expression after 5 and 10 d of steroid replacement, followed by attenuation by 30 d. Since estradiol's modulation of GnRH action was expressed differentially on LH and FSH release, we suggest that such facilitation of GnRH-stimulated pituitary LH and FSH release may provide an additional mechanism for dissociated secretion of gonadotropic hormones in health or disease. PMID:3086382

  9. Common behaviors alterations after extremely low-frequency electromagnetic field exposure in rat animal model.

    PubMed

    Mahdavi, Seyed Mohammad; Sahraei, Hedayat; Rezaei-Tavirani, Mostafa; Najafi Abedi, Akram

    2016-01-01

    Naturally, the presence of electromagnetic waves in our living environment affects all components of organisms, particularly humans and animals, as the large part of their body consists of water. In the present study, we tried to investigate the relation between exposure to the extremely low-frequency electromagnetic field (ELF-EMF) and common behaviors such as body weight, food and water intake, anorexia (poor appetite), plasma glucose concentration, movement, rearing and sniffing in rats. For this purpose, rats were exposed to 40  Hz ELF-EMF once a day for 21 days, then at days 1, 3, 7, 14 and 21 after exposure, any changes in the above-mentioned items were assessed in the exposed rats and compared to the non-exposed group as control. Body weight of irradiated rats significantly increased only a week after exposure and decreased after that. No significant change was observed in food and water intake of irradiated rats compared to the control, and the anorexia parameter in the group exposed to ELF-EMF was significantly decreased at one and two weeks after irradiation. A week after exposure, the level of glucose was significantly increased but at other days these changes were not significant. Movements, rearing and sniffing of rats at day 1 after exposure were significantly decreased and other days these changes did not follow any particular pattern. However, the result of this study demonstrated that exposure to ELF-EMF can alter the normal condition of animals and may represent a harmful impact on behavior. PMID:26182237

  10. Developmental exposure to terbutaline alters cell signaling in mature rat brain regions and augments the effects of subsequent neonatal exposure to the organophosphorus insecticide chlorpyrifos

    SciTech Connect

    Meyer, Armando; Seidler, Frederic J.; Aldridge, Justin E.; Slotkin, Theodore A. . E-mail: t.slotkin@duke.edu

    2005-03-01

    Exposure to apparently unrelated neurotoxicants can nevertheless converge on common neurodevelopmental events. We examined the long-term effects of developmental exposure of rats to terbutaline, a {beta}-adrenoceptor agonist used to arrest preterm labor, and the organophosphorus insecticide chlorpyrifos (CPF) separately and together. Treatments mimicked the appropriate neurodevelopmental stages for human exposures: terbutaline on postnatal days (PN) 2-5 and CPF on PN11-14, with assessments conducted on PN45. Although neither treatment affected growth or viability, each elicited alterations in CNS cell signaling mediated by adenylyl cyclase (AC), a transduction pathway shared by numerous neuronal and hormonal signals. Terbutaline altered signaling in the brainstem and cerebellum, with gender differences particularly notable in the cerebellum (enhanced AC in males, suppressed in females). By itself, CPF exposure elicited deficits in AC signaling in the midbrain, brainstem, and striatum. However, sequential exposure to terbutaline followed by CPF produced larger alterations and involved a wider spectrum of brain regions than were obtained with either agent alone. In the cerebral cortex, adverse effects of the combined treatment intensified between PN45 and PN60, suggesting that exposures alter the long-term program for development of synaptic communication, leading to alterations in AC signaling that emerge even after adolescence. These findings indicate that terbutaline, like CPF, is a developmental neurotoxicant, and reinforce the idea that its use in preterm labor may create a subpopulation that is sensitized to long-term CNS effects of organophosphorus insecticides.

  11. Adaptations of the vestibular system to short and long-term exposures to altered gravity

    NASA Astrophysics Data System (ADS)

    Bruce, L. L.

    2003-10-01

    Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival of a given organism. The development and maintenance of vestibular connections are controlled by environmental gravitational stimulation as well as genetically controlled molecular interactions. This paper describes the effects of hypergravity on axonal growth and dendritic morphology, respectively. Two aspects of this vestibular adaptation are examined: (1) How does long-term exposure to hypergravity affect the development of vestibular axons? (2) How does short-term exposure to extremely rapid changes in gravity, such as those that occur during shuttle launch and landing, affect dendrites of the vestibulocerebellar system? To study the effects of longterm exposures to altered gravity, embryonic rats that developed in hypergravity were compared to microgravity-exposed and control rats. Examination of the vestibular projections from epithelia devoted to linear and angular acceleration revealed that the terminal fields segregate differently in rat embryos that gestated in each of the gravitational environments.To study the effects of short-term exposures to altered gravity, mice were exposed briefly to strong vestibular stimuli and the vestibulocerebellum was examined for any resulting morphological changes. My data show that these stimuli cause intense vestibular excitation of cerebellar Purkinje cells, which induce up-regulation of clathrin-mediated endocytosis and other morphological changes that are comparable to those seen in long-term depression. This system provides a basis for studying how the vestibular environment can modify cerebellar function, allowing animals to adapt to new environments.

  12. Exposure of rainbow trout milt to mercury and cadmium alters sperm motility parameters and reproductive success.

    PubMed

    Dietrich, Grzegorz J; Dietrich, Mariola; Kowalski, R K; Dobosz, Stefan; Karol, Halina; Demianowicz, Wiesław; Glogowski, Jan

    2010-05-10

    In the current work, seminal plasma was used for the first time as an incubation medium for monitoring short-time exposure effects of sublethal concentrations of mercury and cadmium ions on rainbow trout sperm. Sperm motility parameters (CASA) and hatching rates were used as gamete quality markers. Additionally live/dead sperm viability test and comet assay of DNA fragmentation were performed. We demonstrated that computer-assisted sperm motility analysis (CASA) may serve as a predictor of reproductive success, when milt contaminated with heavy metals is used. Results presented in this study demonstrate that mercury ions altered sperm motility characteristics at 1-10 mg Hg2+/l and 10 mg Cd2+/l and hatching rates at 10 mg Hg2+/l and 10 mg Cd2+/l after 4h of exposure. Although mercury ions affected sperm motility parameters immediately after dilution with milt as well as at 4h of exposure, no differences in sperm motility parameters were found between intact and mercury-treated milt after 24h of exposure. Our results suggest that rainbow trout seminal plasma has a protective role against the toxic effects of mercury ions of rainbow trout sperm motility. PMID:20044150

  13. Prenatal androgen exposure alters girls' responses to information indicating gender-appropriate behaviour.

    PubMed

    Hines, Melissa; Pasterski, Vickie; Spencer, Debra; Neufeld, Sharon; Patalay, Praveetha; Hindmarsh, Peter C; Hughes, Ieuan A; Acerini, Carlo L

    2016-02-19

    Individual variability in human gender-related behaviour is influenced by many factors, including androgen exposure prenatally, as well as self-socialization and socialization by others postnatally. Many studies have looked at these types of influences in isolation, but little is known about how they work together. Here, we report that girls exposed to high concentrations of androgens prenatally, because they have the genetic condition congenital adrenal hyperplasia, show changes in processes related to self-socialization of gender-related behaviour. Specifically, they are less responsive than other girls to information that particular objects are for girls and they show reduced imitation of female models choosing particular objects. These findings suggest that prenatal androgen exposure may influence subsequent gender-related behaviours, including object (toy) choices, in part by changing processes involved in the self-socialization of gendered behaviour, rather than only by inducing permanent changes in the brain during early development. In addition, the findings suggest that some of the behavioural effects of prenatal androgen exposure might be subject to alteration by postnatal socialization processes. The findings also suggest a previously unknown influence of early androgen exposure on later processes involved in self-socialization of gender-related behaviour, and thus expand understanding of the developmental systems regulating human gender development. PMID:26833843

  14. Short-term cigarette smoke exposure leads to metabolic alterations in lung alveolar cells.

    PubMed

    Agarwal, Amit R; Yin, Fei; Cadenas, Enrique

    2014-08-01

    Cigarette smoke (CS)-induced alveolar destruction and energy metabolism changes are known contributors to the pathophysiology of chronic obstructive pulmonary disease (COPD). This study examines the effect of CS exposure on metabolism in alveolar type II cells. Male A/J mice (8 wk old) were exposed to CS generated from a smoking machine for 4 or 8 weeks, and a recovery group was exposed to CS for 8 weeks and allowed to recover for 2 weeks. Alveolar type II cells were isolated from air- or CS- exposed mice. Acute CS exposure led to a reversible airspace enlargement in A/J mice as measured by the increase in mean linear intercept, indicative of alveolar destruction. The effect of CS exposure on cellular respiration was studied using the XF Extracellular Flux Analyzer. A decrease in respiration while metabolizing glucose was observed in the CS-exposed group, indicating altered glycolysis that was compensated by an increase in palmitate utilization; palmitate utilization was accompanied by an increase in the expression of CD36 and carnitine-palmitoyl transferase 1 in type II alveolar cells for the transport of palmitate into the cells and into mitochondria, respectively. The increase in palmitate use for energy production likely affects the surfactant biosynthesis pathway, as evidenced by the decrease in phosphatidylcholine levels and the increase in phospholipase A2 activity after CS exposure. These findings help our understanding of the mechanism underlying the surfactant deficiency observed in smokers and provide a target to delay the onset of COPD. PMID:24625219

  15. Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure.

    PubMed

    Manning, Elizabeth E; van den Buuse, Maarten

    2016-05-15

    Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia. PMID:26965573

  16. Effects of radiation exposure on glass alteration in a steam environment

    SciTech Connect

    Wronkiewicz, D.J.; Bates, J.K.; Tani, B.S.; Wang, L.M.

    1992-12-31

    Several Savannah River Plant (SRL) glass compositions were reacted in steam at temperatures of 150 to 200{degrees}C. Half of the tests utilized actinide-doped monoliths and were exposed to an external ionizing gamma source, while the remainder were doped only with U and reacted without gamma exposure. All glass samples readily reacted to form secondary mineral phases within the first week of testing. An in situ layer of smectite initially developed on nonirradiated SRL 202 glass test samples. After 21 days, a thin layer of illite was precipitated from solution onto the smectite layer. A number of alteration products including zeolite, Casilicate, and alkali or alkaline earth uranyl silicate phases were also distributed over most sample surfaces. In the irradiated SRL 202 glass tests, up to three layers enveloped rounded, and sometimes fractured, glass cores. After 35 to 56 days these remnant cores were replaced by a mottled or banded Fe- and Si-rich material. The formation of some secondary mineral phases also has been accelerated in the irradiated tests, and in some instances, the irradiated environment may have led to the precipitation of a different suite of minerals. The alteration layer(s) developed at rates of 2.3 and 32 {mu}m/day for the nonirradiated and irradiated SRL 202 glasses, respectively, indicating that layer development is accelerated by a factor of {approximately} 10 to 15X due to radiation exposure under the test conditions.

  17. Alcohol Exposure Alters Mouse Lung Inflammation in Response to Inhaled Dust

    PubMed Central

    McCaskill, Michael L.; Romberger, Debra J.; DeVasure, Jane; Boten, Jessica; Sisson, Joseph H.; Bailey, Kristina L.; Poole, Jill A.; Wyatt, Todd A.

    2012-01-01

    Alcohol exposure is associated with increased lung infections and decreased mucociliary clearance. Occupational workers exposed to dusts from concentrated animal feeding operations (CAFOs) are at risk for developing chronic inflammatory lung diseases. Agricultural worker co-exposure to alcohol and organic dust has been established, although little research has been conducted on the combination effects of alcohol and organic dusts on the lung. Previously, we have shown in a mouse model that exposure to hog dust extract (HDE) collected from a CAFO results in the activation of protein kinase C (PKC), elevated lavage fluid cytokines/chemokines including interleukin-6 (IL-6), and the development of significant lung pathology. Because alcohol blocks airway epithelial cell release of IL-6 in vitro, we hypothesized that alcohol exposure would alter mouse lung inflammatory responses to HDE. To test this hypothesis, C57BL/6 mice were fed 20% alcohol or water ad libitum for 6 weeks and treated with 12.5% HDE by intranasal inhalation method daily during the final three weeks. Bronchoalveolar lavage fluid (BALF), tracheas and lungs were collected. HDE stimulated a 2–4 fold increase in lung and tracheal PKCε (epsilon) activity in mice, but no such increase in PKCε activity was observed in dust-exposed mice fed alcohol. Similarly, alcohol-fed mice demonstrated significantly less IL-6 in lung lavage in response to dust than that observed in control mice instilled with HDE. TNFα levels were also inhibited in the alcohol and HDE-exposed mouse lung tissue as compared to the HDE only exposed group. HDE-induced lung inflammatory aggregates clearly present in the tissue from HDE only exposed animals were not visually detectable in the HDE/alcohol co-exposure group. Statistically significant weight reductions and 20% mortality were also observed in the mice co-exposed to HDE and alcohol. These data suggest that alcohol exposure depresses the ability of the lung to activate PKCε

  18. Alcohol exposure alters mouse lung inflammation in response to inhaled dust.

    PubMed

    McCaskill, Michael L; Romberger, Debra J; DeVasure, Jane; Boten, Jessica; Sisson, Joseph H; Bailey, Kristina L; Poole, Jill A; Wyatt, Todd A

    2012-07-01

    Alcohol exposure is associated with increased lung infections and decreased mucociliary clearance. Occupational workers exposed to dusts from concentrated animal feeding operations (CAFOs) are at risk for developing chronic inflammatory lung diseases. Agricultural worker co-exposure to alcohol and organic dust has been established, although little research has been conducted on the combination effects of alcohol and organic dusts on the lung. Previously, we have shown in a mouse model that exposure to hog dust extract (HDE) collected from a CAFO results in the activation of protein kinase C (PKC), elevated lavage fluid cytokines/chemokines including interleukin-6 (IL-6), and the development of significant lung pathology. Because alcohol blocks airway epithelial cell release of IL-6 in vitro, we hypothesized that alcohol exposure would alter mouse lung inflammatory responses to HDE. To test this hypothesis, C57BL/6 mice were fed 20% alcohol or water ad libitum for 6 weeks and treated with 12.5% HDE by intranasal inhalation method daily during the final three weeks. Bronchoalveolar lavage fluid (BALF), tracheas and lungs were collected. HDE stimulated a 2-4 fold increase in lung and tracheal PKCε (epsilon) activity in mice, but no such increase in PKCε activity was observed in dust-exposed mice fed alcohol. Similarly, alcohol-fed mice demonstrated significantly less IL-6 in lung lavage in response to dust than that observed in control mice instilled with HDE. TNFα levels were also inhibited in the alcohol and HDE-exposed mouse lung tissue as compared to the HDE only exposed group. HDE-induced lung inflammatory aggregates clearly present in the tissue from HDE only exposed animals were not visually detectable in the HDE/alcohol co-exposure group. Statistically significant weight reductions and 20% mortality were also observed in the mice co-exposed to HDE and alcohol. These data suggest that alcohol exposure depresses the ability of the lung to activate PKCε

  19. Developmental exposure to endocrine disrupting chemicals alters the epigenome: Identification of reprogrammed targets

    PubMed Central

    Prusinski, Lauren; Al-Hendy, Ayman; Yang, Qiwei

    2016-01-01

    Endocrine disruptions induced by environmental toxicants have placed an immense burden on society to properly diagnose, treat and attempt to alleviate symptoms and disease. Environmental exposures during critical periods of development can permanently reprogram normal physiological responses, thereby increasing susceptibility to disease later in life - a process known as developmental reprogramming. During development, organogenesis and tissue differentiation occur through a continuous series of tightly-regulated and precisely-timed molecular, biochemical and cellular events. Humans may encounter endocrine disrupting chemicals (EDCs) daily and during all stages of life, from conception and fetal development through adulthood and senescence. Though puberty and perimenopausal periods may be affected by endocrine disruption due to hormonal effects, prenatal and early postnatal windows are most critical for proper development due to rapid changes in system growth. Developmental reprogramming is shown to be caused by alterations in the epigenome. Development is the time when epigenetic programs are ‘installed’ on the genome by ‘writers’, such as histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs), which add methyl groups to lysine and arginine residues on histone tails and to CpG sites in DNA, respectively. A number of environmental compounds, referred to as estrogenic endocrine disruptors (EEDs), are able to bind to estrogen receptors (ERs) and interfere with the normal cellular development in target tissues including the prostate and uterus. These EEDs, including diethylstilbestrol (DES), bisphenol A (BPA), and genistein (a phytoestrogen derived from soybeans), have been implicated in the malformation of reproductive organs and later development of disease. Due to the lack of fully understanding the underlying mechanisms of how environmental toxicants and their level of exposure affect the human genome, it can be challenging to create clear

  20. Developmental Exposure to Estrogen Alters Differentiation and Epigenetic Programming in a Human Fetal Prostate Xenograft Model

    PubMed Central

    Saffarini, Camelia M.; McDonnell-Clark, Elizabeth V.; Amin, Ali; Huse, Susan M.; Boekelheide, Kim

    2015-01-01

    Prostate cancer is the most frequent non-cutaneous malignancy in men. There is strong evidence in rodents that neonatal estrogen exposure plays a role in the development of this disease. However, there is little information regarding the effects of estrogen in human fetal prostate tissue. This study explored early life estrogen exposure, with and without a secondary estrogen and testosterone treatment in a human fetal prostate xenograft model. Histopathological lesions, proliferation, and serum hormone levels were evaluated at 7, 30, 90, and 200-day time-points after xenografting. The expression of 40 key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors and tumor suppressors was evaluated using a custom PCR array. Epigenome-wide analysis of DNA methylation was performed on whole tissue, and laser capture-microdissection (LCM) isolated epithelial and stromal compartments of 200-day prostate xenografts. Combined initial plus secondary estrogenic exposures had the most severe tissue changes as revealed by the presence of hyperplastic glands at day 200. Gene expression changes corresponded with the cellular events in the KEGG prostate cancer pathway, indicating that initial plus secondary exposure to estrogen altered the PI3K-Akt signaling pathway, ultimately resulting in apoptosis inhibition and an increase in cell cycle progression. DNA methylation revealed that differentially methylated CpG sites significantly predominate in the stromal compartment as a result of estrogen-treatment, thereby providing new targets for future investigation. By using human fetal prostate tissue and eliminating the need for species extrapolation, this study provides novel insights into the gene expression and epigenetic effects related to prostate carcinogenesis following early life estrogen exposure. PMID:25799167

  1. Prenatal cocaine exposure alters progenitor cell markers in the subventricular zone of the adult rat brain

    PubMed Central

    Patel, Dhyanesh Arvind; Booze, Rosemarie M.; Mactutus, Charles F.

    2013-01-01

    Long-term consequences of early developmental exposure to drugs of abuse may have deleterious effects on the proliferative plasticity of the brain. The purpose of this study was to examine the long-term effects of prenatal exposure to cocaine, using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, on the proliferative cell types of the subventricular zones (SVZ) in the adult (180 days-old) rat brain. Employing immunocytochemistry, the expression of GFAP+ (type B cells) and nestin+(GFAP−) (Type C and A cells) staining was quantified in the subcallosal area of the SVZ. GFAP+ expression was significantly different between the prenatal cocaine treated group and the vehicle (saline) control group. The prenatal cocaine treated group possessed significantly lower GFAP+ expression relative to the vehicle control group, suggesting that prenatal cocaine exposure significantly reduced the expression of type B neural stem cells of the SVZ. In addition, there was a significant sex difference in nestin+ expression with females showing approximately 8–13% higher nestin+ expression compared to the males. More importantly, a significant prenatal treatment condition (prenatal cocaine, control) by sex interaction in nestin+ expression was confirmed, indicating different effects of cocaine based on sex of the animal. Specifically, prenatal cocaine exposure eliminated the basal difference between the sexes. Collectively, the present findings suggest that prenatal exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, can selectively alter the major proliferative cell types in the subcallosal area of the SVZ in an adult rat brain, and does so differently for males and females. PMID:22119286

  2. Untargeted Metabolomics Reveals Predominant Alterations in Lipid Metabolism Following Light Exposure in Broccoli Sprouts

    PubMed Central

    Maldini, Mariateresa; Natella, Fausta; Baima, Simona; Morelli, Giorgio; Scaccini, Cristina; Langridge, James; Astarita, Giuseppe

    2015-01-01

    The consumption of vegetables belonging to the family Brassicaceae (e.g., broccoli and cauliflower) is linked to a reduced incidence of cancer and cardiovascular diseases. The molecular composition of such plants is strongly affected by growing conditions. Here we developed an unbiased metabolomics approach to investigate the effect of light and dark exposure on the metabolome of broccoli sprouts and we applied such an approach to provide a bird’s-eye view of the overall metabolic response after light exposure. Broccoli seeds were germinated and grown hydroponically for five days in total darkness or with a light/dark photoperiod (16 h light/8 h dark cycle). We used an ultra-performance liquid-chromatography system coupled to an ion-mobility, time-of-flight mass spectrometer to profile the large array of metabolites present in the sprouts. Differences at the metabolite level between groups were analyzed using multivariate statistical analyses, including principal component analysis and correlation analysis. Altered metabolites were identified by searching publicly available and in-house databases. Metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that may have gone unnoticed with conventional approaches. Besides the chlorophyll pathway, light exposure activated the biosynthesis and metabolism of sterol lipids, prenol lipids, and polyunsaturated lipids, which are essential for the photosynthetic machinery. Our results also revealed that light exposure increased the levels of polyketides, including flavonoids, and oxylipins, which play essential roles in the plant’s developmental processes and defense mechanism against herbivores. This study highlights the significant contribution of light exposure to the ultimate metabolic phenotype, which might affect the cellular physiology and nutritional value of broccoli sprouts. Furthermore, this study highlights the potential of an

  3. Hypertension Does Not Alter the Increase in Cardiac Baroreflex Sensitivity Caused by Moderate Cold Exposure.

    PubMed

    Hintsala, Heidi E; Kiviniemi, Antti M; Tulppo, Mikko P; Helakari, Heta; Rintamäki, Hannu; Mäntysaari, Matti; Herzig, Karl-Heinz; Keinänen-Kiukaanniemi, Sirkka; Jaakkola, Jouni J K; Ikäheimo, Tiina M

    2016-01-01

    Exposure to cold increases blood pressure and may contribute to higher wintertime cardiovascular morbidity and mortality in hypertensive people, but the mechanisms are not well-established. While hypertension does not alter responses of vagally-mediated heart rate variability to cold, it is not known how hypertension modifies baroreflex sensitivity (BRS) and blood pressure variability during cold exposure. Our study assessed this among untreated hypertensive men during short-term exposure comparable to habitual winter time circumstances in subarctic areas. We conducted a population-based recruitment of 24 untreated hypertensive and 17 men without hypertension (age 55-65 years) who underwent a whole-body cold exposure (-10°C, wind 3 m/s, winter clothes, 15 min, standing). Electrocardiogram and continuous blood pressure were measured to compute spectral powers of systolic blood pressure and heart rate variability at low (0.04-0.15 Hz) and high frequency (0.15-0.4 Hz) and spontaneous BRS at low frequency (LF). Comparable increases in BRS were detected in hypertensive men, from 2.6 (2.0, 4.2) to 3.8 (2.5, 5.1) ms/mmHg [median (interquartile range)], and in control group, from 4.3 (2.7, 5.0) to 4.4 (3.1, 7.1) ms/mmHg. Instead, larger increase (p < 0.05) in LF blood pressure variability was observed in control group; response as median (interquartile range): 8 (2, 14) mmHg(2), compared with hypertensive group [0 (-13, 20) mmHg(2)]. Untreated hypertension does not disturb cardiovascular protective mechanisms during moderate cold exposure commonly occurring in everyday life. Blunted response of the estimate of peripheral sympathetic modulation may indicate higher tonic sympathetic activity and decreased sympathetic responsiveness to cold in hypertension. PMID:27313543

  4. Hypertension Does Not Alter the Increase in Cardiac Baroreflex Sensitivity Caused by Moderate Cold Exposure

    PubMed Central

    Hintsala, Heidi E.; Kiviniemi, Antti M.; Tulppo, Mikko P.; Helakari, Heta; Rintamäki, Hannu; Mäntysaari, Matti; Herzig, Karl-Heinz; Keinänen-Kiukaanniemi, Sirkka; Jaakkola, Jouni J. K.; Ikäheimo, Tiina M.

    2016-01-01

    Exposure to cold increases blood pressure and may contribute to higher wintertime cardiovascular morbidity and mortality in hypertensive people, but the mechanisms are not well-established. While hypertension does not alter responses of vagally-mediated heart rate variability to cold, it is not known how hypertension modifies baroreflex sensitivity (BRS) and blood pressure variability during cold exposure. Our study assessed this among untreated hypertensive men during short-term exposure comparable to habitual winter time circumstances in subarctic areas. We conducted a population-based recruitment of 24 untreated hypertensive and 17 men without hypertension (age 55–65 years) who underwent a whole-body cold exposure (−10°C, wind 3 m/s, winter clothes, 15 min, standing). Electrocardiogram and continuous blood pressure were measured to compute spectral powers of systolic blood pressure and heart rate variability at low (0.04–0.15 Hz) and high frequency (0.15–0.4 Hz) and spontaneous BRS at low frequency (LF). Comparable increases in BRS were detected in hypertensive men, from 2.6 (2.0, 4.2) to 3.8 (2.5, 5.1) ms/mmHg [median (interquartile range)], and in control group, from 4.3 (2.7, 5.0) to 4.4 (3.1, 7.1) ms/mmHg. Instead, larger increase (p < 0.05) in LF blood pressure variability was observed in control group; response as median (interquartile range): 8 (2, 14) mmHg2, compared with hypertensive group [0 (−13, 20) mmHg2]. Untreated hypertension does not disturb cardiovascular protective mechanisms during moderate cold exposure commonly occurring in everyday life. Blunted response of the estimate of peripheral sympathetic modulation may indicate higher tonic sympathetic activity and decreased sympathetic responsiveness to cold in hypertension. PMID:27313543

  5. Untargeted Metabolomics Reveals Predominant Alterations in Lipid Metabolism Following Light Exposure in Broccoli Sprouts.

    PubMed

    Maldini, Mariateresa; Natella, Fausta; Baima, Simona; Morelli, Giorgio; Scaccini, Cristina; Langridge, James; Astarita, Giuseppe

    2015-01-01

    The consumption of vegetables belonging to the family Brassicaceae (e.g., broccoli and cauliflower) is linked to a reduced incidence of cancer and cardiovascular diseases. The molecular composition of such plants is strongly affected by growing conditions. Here we developed an unbiased metabolomics approach to investigate the effect of light and dark exposure on the metabolome of broccoli sprouts and we applied such an approach to provide a bird's-eye view of the overall metabolic response after light exposure. Broccoli seeds were germinated and grown hydroponically for five days in total darkness or with a light/dark photoperiod (16 h light/8 h dark cycle). We used an ultra-performance liquid-chromatography system coupled to an ion-mobility, time-of-flight mass spectrometer to profile the large array of metabolites present in the sprouts. Differences at the metabolite level between groups were analyzed using multivariate statistical analyses, including principal component analysis and correlation analysis. Altered metabolites were identified by searching publicly available and in-house databases. Metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that may have gone unnoticed with conventional approaches. Besides the chlorophyll pathway, light exposure activated the biosynthesis and metabolism of sterol lipids, prenol lipids, and polyunsaturated lipids, which are essential for the photosynthetic machinery. Our results also revealed that light exposure increased the levels of polyketides, including flavonoids, and oxylipins, which play essential roles in the plant's developmental processes and defense mechanism against herbivores. This study highlights the significant contribution of light exposure to the ultimate metabolic phenotype, which might affect the cellular physiology and nutritional value of broccoli sprouts. Furthermore, this study highlights the potential of an

  6. Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice.

    PubMed

    Martella, G; Madeo, G; Maltese, M; Vanni, V; Puglisi, F; Ferraro, E; Schirinzi, T; Valente, E M; Bonanni, L; Shen, J; Mandolesi, G; Mercuri, N B; Bonsi, P; Pisani, A

    2016-07-01

    Heterozygous mutations in the PINK1 gene are considered a susceptibility factor to develop early-onset Parkinson's disease (PD), as supported by dopamine hypometabolism in asymptomatic mutation carriers and subtle alterations of dopamine-dependent striatal synaptic plasticity in heterozygous PINK1 knockout (PINK1(+/-)) mice. The aim of the present study was to investigate whether exposure to low-dose rotenone of heterozygous PINK1(+/-) mice, compared to their wild-type PINK1(+/+) littermates, could impact on dopamine-dependent striatal synaptic plasticity, in the absence of apparent structural alterations. Mice were exposed to a range of concentrations of rotenone (0.01-1mg/kg). Chronic treatment with concentrations of rotenone up to 0.8mg/kg did not cause manifest neuronal loss or changes in ATP levels both in the striatum or substantia nigra of PINK1(+/-) and PINK1(+/+) mice. Moreover, rotenone (up to 0.8mg/kg) treatment did not induce mislocalization of the mitochondrial membrane protein Tom20 and release of cytochrome c in PINK1(+/-) striata. Accordingly, basic electrophysiological properties of nigral dopaminergic and striatal medium spiny neurons (MSNs) were normal. Despite the lack of gross alterations in neuronal viability in chronically-treated PINK1(+/-), a complete loss of both long-term depression (LTD) and long-term potentiation (LTP) was recorded in MSNs from PINK1(+/-) mice treated with a low rotenone (0.1mg/kg) concentration. Even lower concentrations (0.01mg/kg) blocked LTP induction in heterozygous PINK1(+/-) MSNs compared to PINK1(+/+) mice. Of interest, chronic pretreatment with the antioxidants alpha-tocopherol and Trolox, a water-soluble analog of vitamin E and powerful antioxidant, rescued synaptic plasticity impairment, confirming that, at the doses we utilized, rotenone did not induce irreversible alterations. In this model, chronic exposure to low-doses of rotenone was not sufficient to alter mitochondrial integrity and ATP production, but

  7. Bisphenol A Exposure Leads to Specific MicroRNA Alterations in Placental Cells

    PubMed Central

    Avissar-Whiting, Michele; Veiga, Keila; Uhl, Kristen; Maccani, Matthew; Gagne, Luc; Moen, Erika; Marsit, Carmen J.

    2010-01-01

    Exposure to bisphenol-A (BPA) has been observed to alter developmental pathways and cell processes, at least in part, through epigenetic mechanisms. This study sought to investigate the effect of BPA on microRNAs (miRNAs) in human placental cells. miRNA microarray was performed following BPA treatment in three immortalized cytotrophoblast cell lines and the results validated using quantitative real-time PCR. For functional analysis, overexpression constructs were stably transfected into cells that were then assayed for changes in proliferation and response to toxicants. Microarray analysis revealed several miRNAs to be significantly altered in response to BPA treatment in two cell lines. Real-time PCR results confirmed that miR-146a was particularly strongly induced and its overexpression in cells led to slower proliferation as well as higher sensitivity to the DNA damaging agent, bleomycin. Overall, these results suggest that BPA can alter miRNA expression in placental cells, a potentially novel mode of BPA toxicity. PMID:20417706

  8. Prenatal Cigarette Smoke Exposure Causes Hyperactivity and Agressive Behavior: Role of Altered Catcholamines and BDNF

    PubMed Central

    Yochum, Carrie; Doherty-Lyon, Shannon; Hoffman, Carol; Hossain, Muhammad M.; Zellikoff, Judith T.; Richardson, Jason R.

    2014-01-01

    Smoking during pregnancy is associated with a variety of untoward effects on the offspring. However, recent epidemiological studies have brought into question whether the association between neurobehavioral deficits and maternal smoking is causal. We utilized an animal model of maternal smoking to determine the effects of prenatal cigarette smoke (CS) exposure on neurobehavioral development. Pregnant mice were exposed to either filtered air or mainstream CS from gestation day (GD) 4 to parturition for 4 hr/d and 5 d/wk, with each exposure producing maternal plasma concentration of cotinine equivalent to smoking <1 pack of cigarettes per day (25 ng/ml plasma cotinine level). Pups were weaned at postnatal day (PND) 21 and behavior assessed on at 4 weeks of age and again at 4–6 months of age. Male, but not female, offspring of CS-exposed dams demonstrated a significant increase in locomotor activity during adolescence and adulthood that was ameliorated by methylphenidate treatment. Additionally, male offspring exhibited increased aggression, as evidenced by decreased latency to attack and number of attacks in a resident intruder task. These behavioral abnormalities were accompanied by a significant decrease in striatal and cortical dopamine and serotonin and a significant reduction in brain-derived neurotrophic factor (BDNF) mRNA and protein. Taken in concert, these data demonstrate that prenatal exposure to CS produces behavioral alterations in mice that are similar to those observed in epidemiological studies linking maternal smoking to neurodevelopmental disorders and suggest a role for monoaminergic and BDNF alterations in these effects. PMID:24486851

  9. Prenatal cigarette smoke exposure causes hyperactivity and aggressive behavior: role of altered catecholamines and BDNF.

    PubMed

    Yochum, Carrie; Doherty-Lyon, Shannon; Hoffman, Carol; Hossain, Muhammad M; Zelikoff, Judith T; Richardson, Jason R

    2014-04-01

    Smoking during pregnancy is associated with a variety of untoward effects on the offspring. However, recent epidemiological studies have brought into question whether the association between neurobehavioral deficits and maternal smoking is causal. We utilized an animal model of maternal smoking to determine the effects of prenatal cigarette smoke (CS) exposure on neurobehavioral development. Pregnant mice were exposed to either filtered air or mainstream CS from gestation day (GD) 4 to parturition for 4h/d and 5d/wk, with each exposure producing maternal plasma concentration of cotinine equivalent to smoking <1 pack of cigarettes per day (25ng/ml plasma cotinine level). Pups were weaned at postnatal day (PND) 21 and behavior was assessed at 4weeks of age and again at 4-6months of age. Male, but not female, offspring of CS-exposed dams demonstrated a significant increase in locomotor activity during adolescence and adulthood that was ameliorated by methylphenidate treatment. Additionally, male offspring exhibited increased aggression, as evidenced by decreased latency to attack and number of attacks in a resident-intruder task. These behavioral abnormalities were accompanied by a significant decrease in striatal and cortical dopamine and serotonin and a significant reduction in brain-derived neurotrophic factor (BDNF) mRNA and protein. Taken in concert, these data demonstrate that prenatal exposure to CS produces behavioral alterations in mice that are similar to those observed in epidemiological studies linking maternal smoking to neurodevelopmental disorders. Further, these data also suggest a role for monaminergic and BDNF alterations in these effects. PMID:24486851

  10. Prenatal Ethanol Exposure Alters Core Body Temperature and Corticosterone Rhythms in Adult Male Rats

    PubMed Central

    Handa, Robert J.; Zuloaga, Damian G.; McGivern, Robert F.

    2008-01-01

    Ethanol’s effects on the developing brain include alterations in morphological and biochemistry of the hypothalamus. In order to examine the potential functional consequences of ethanol’s interference with hypothalamic differentiation, we studied the long-term effects of prenatal ethanol exposure on basal circadian rhythms of core body temperature (CBT) and heart rate (HR). We also examined the late afternoon surge in corticosterone (CORT). CBT and HR rhythms were studied in separate groups of animals at 4 months, 8 months and 20 months of age. The normal late-afternoon rise in plasma corticosterone was examined in freely-moving male rats at 6 months of age via an indwelling right-atrial cannula. Results showed that the CBT circadian rhythm exhibited an earlier rise following the nadir of the rhythm in fetal alcohol exposed (FAE) males at all ages compared to controls. At 8 months of age, the amplitude of the CBT circadian rhythm in FAE males was significantly reduced to the level observed in controls at 20 months. No significant effects of prenatal ethanol exposure were observed on basal HR rhythm at any age. The diurnal rise in corticosterone secretion was blunted and prolonged in 6-month-old FAE males compared to controls. Both control groups exhibited a robust surge in corticosterone secretion around the onset of the dark phase of the light cycle, which peaked at 1930 hours. Instead, FAE males exhibited a linear rise beginning in mid afternoon, which peaked at 2130 hours. These results indicate that exposure to ethanol during the period of hypothalamic development can alter the long-term regulation of circadian rhythms in specific physiological systems. PMID:18047910

  11. Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats.

    PubMed

    McDougall, Sanders A; Mohd-Yusof, Alena; Kaplan, Graham J; Abdulla, Zuhair I; Lee, Ryan J; Crawford, Cynthia A

    2013-04-15

    Administering manganese chloride (Mn) to rats on postnatal day (PD) 1-21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as a persistent increase in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1-21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., "autoreceptor" doses) of apomorphine (0.06 and 0.12 mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired. PMID:23458069

  12. Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats

    PubMed Central

    McDougall, Sanders A.; Mohd-Yusof, Alena; Kaplan, Graham J.; Abdulla, Zuhair I.; Lee, Ryan J.; Crawford, Cynthia A.

    2013-01-01

    Administering manganese chloride (Mn) to rats on postnatal day (PD) 1–21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as persistent increases in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1–21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., “autoreceptor” doses) of apomorphine (0.06 and 0.12 mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired. PMID:23458069

  13. Association between mitochondrial C-tract alteration and tobacco exposure in oral precancer cases

    PubMed Central

    Pandey, Rahul; Mehrotra, Divya; Mahdi, Abbas Ali; Sarin, Rajiv; Kowtal, Pradnya; Maurya, Shailendra S.; Parmar, Devendra

    2013-01-01

    Introduction: Tobacco exposure is a known risk factor for oral cancer. India is home to oral cancer epidemic chiefly due to the prevalent use of both smoke and smokeless tobacco. To reduce the related morbidity early detection is required. The key to this is detailing molecular events during early precancer stage. Mitochondrion is an important cellular organelle involved in cell metabolism and apoptosis. Mitochondrial dysfunction is thought to be the key event in oncogenesis. Last decade has seen a spurt of reports implicating mitochondrial mutations in oral carcinogenesis. However, there are few reports that study mitochondrial deoxyribonucleic acid (mtDNA) changes in oral precancer. This study aims to understand and link effect of tobacco exposure on mtDNA in oral precancer cases. Subjects and Methods: A total of 100 oral precancer cases of which 50 oral leukoplakia and 50 oral submucous fibrosis were recruited in the study and a detailed questionnaire were filled about the tobacco habits. Their tissue and blood samples were collected. Total genomic DNA was isolated from both sources. Mitochondrial C-tract was amplified and bidirectional sequencing was carried out. Mutations were scored over matched blood DNA. Results: There was a significant association between the presence of mitochondrial C-tract alteration and duration of tobacco exposure. The probability increased with increasing duration of tobacco consumption. The risk of having this alteration was more in chewers than in smokers. Conclusions: Tobacco in both form, chewable and smoke, is oncogenic and causes early changes in mitochondrial genome and chances increases with increasing duration of tobacco consumption. PMID:24665180

  14. Sustained alterations in neuroimmune gene expression after daily, but not intermittent, alcohol exposure.

    PubMed

    Gano, Anny; Doremus-Fitzwater, Tamara L; Deak, Terrence

    2016-09-01

    Acute ethanol intoxication is associated with Rapid Alterations in Neuroimmune Gene Expression (RANGE), including increased Interleukin (IL)-6 and Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), and suppressed IL-1β and Tumor necrosis factor (TNF) α, yet little is known about adaptations in cytokines across the first few ethanol exposures. Thus, the present studies examined central cytokines during intoxication (3h post-ethanol) following 2, 4 or 6 intragastric ethanol challenges (4g/kg) delivered either daily or every-other-day (EOD). Subsequent analyses of blood ethanol concentrations (BECs) and corticosterone were performed to determine whether the schedule of ethanol delivery would alter the pharmacokinetics of, or general sensitivity to, subacute ethanol exposure. As expected, ethanol led to robust increases in IL-6 and IκBα gene expression in hippocampus, amygdala and bed nucleus of the stria terminalis (BNST), whereas IL-1β and TNFα were suppressed, thereby replicating our prior work. Ethanol-dependent increases in IL-6 and IκBα remained significant in all structures - even after 6 days of ethanol. When these doses were administered EOD, modest IL-6 increases in BNST were observed, with TNFα and IL-1β suppressed exclusively in the hippocampus. Analysis of BECs revealed a small but significant reduction in ethanol after 4 EOD exposures - an effect which was not observed when ethanol was delivered after 6 daily intubations. These findings suggest that ethanol-induced RANGE effects are not simply a function of ethanol load per se, and underscore the critical role that ethanol dosing interval plays in determining the neuroimmune consequences of alcohol. PMID:27208497

  15. Acute exposure to methamphetamine alters TLR9-mediated cytokine expression in human macrophage.

    PubMed

    Burns, Ariel; Ciborowski, Pawel

    2016-02-01

    Recent studies show that methamphetamine (Meth) use leads to higher susceptibility to and progression of infections, which suggests impairment of the immune system. The first line of defense against infections is the innate immune system and the macrophage is a key player in preventing and fighting infections. So we profiled cytokines over time in Meth treated THP-1 cells, as a human macrophage model, at a relevant concentration using high throughput screening to find a signaling target. We showed that after a single exposure, the effect of Meth on macrophage cytokine production was rapid and time dependent and shifted the balance of expression of cytokines to pro-inflammatory. Our results were analogous to previous reports in that Meth up-regulates TNF-α and IL-8 after two hours of exposure. However, global screening led to the novel identification of CXCL16, CXCL1 and many other up-regulated cytokines. We also showed CCL7 as the most down-regulated chemokine due to Meth exposure, which led us to hypothesize that Meth dysregulates the MyD88-dependent Toll-like receptor 9 (TLR9) signaling pathway. In conclusion, altered cytokine expression in macrophages suggests it could lead to a suppressed innate immunity in people who use Meth. PMID:26387832

  16. Neuroplastic alterations in the limbic system following cocaine or alcohol exposure.

    PubMed

    Stuber, Garret D; Hopf, F Woodward; Tye, Kay M; Chen, Billy T; Bonci, Antonello

    2010-01-01

    Neuroplastic changes in the CNS are thought to be a fundamental component of learning and memory. While pioneering studies in the hippocampus and cerebellum have detailed many of the basic mechanisms that can lead to alterations in synaptic transmission based on previous activity, only more recently has synaptic plasticity been monitored after behavioral manipulation or drug exposure. In this chapter, we review evidence that drugs of abuse are powerful modulators of synaptic plasticity. Both the dopaminergic neurons of the ventral tegmental area as well medium spiny neurons in nucleus accumbens show enhanced excitatory synaptic strength following passive or active exposure to drugs such as cocaine and alcohol. In the VTA, both the enhancement of excitatory synaptic strength and the acquisition of drug-related behaviors depend on signaling through the N-methyl-D: -aspartate receptors (NMDARs) which are mechanistically thought to lead to increased synaptic insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Synaptic insertion of AMPARs by drugs of abuse can be long lasting, depending on the route of administration, number of drug exposures, or whether the drugs are received passively or self-administered. PMID:21161748

  17. Metabolic and histopathological alterations in the marine bivalve Mytilus galloprovincialis induced by chronic exposure to acrylamide.

    PubMed

    Larguinho, Miguel; Cordeiro, Ana; Diniz, Mário S; Costa, Pedro M; Baptista, Pedro V

    2014-11-01

    Although the neurotoxic and genotoxic potential of acrylamide has been established in freshwater fish, the full breadth of the toxicological consequences induced by this xenobiotic has not yet been disclosed, particularly in aquatic invertebrates. To assess the effects of acrylamide on a bivalve model, the Mediterranean mussel (Mytilus galloprovincialis), two different setups were accomplished: 1) acute exposure to several concentrations of waterborne acrylamide to determine lethality thresholds of the substance and 2) chronic exposure to more reduced acrylamide concentrations to survey phases I and II metabolic endpoints and to perform a whole-body screening for histopathological alterations. Acute toxicity was low (LC50≈400mg/L). However, mussels were responsive to prolonged exposure to chronic concentrations of waterborne acrylamide (1-10mg/L), yielding a significant increase in lipid peroxidation plus EROD and GST activities. Still, total anti-oxidant capacity was not exceeded. In addition, no neurotoxic effects could be determined through acetylcholine esterase (AChE) activity. The findings suggest aryl-hydrocarbon receptor (Ahr)-dependent responses in mussels exposed to acrylamide, although reduced comparatively to vertebrates. No significant histological damage was found in digestive gland or gills but female gonads endured severe necrosis and oocyte atresia. Altogether, the results indicate that acrylamide may induce gonadotoxicity in mussels, although the subject should benefit from further research. Altogether, the findings suggest that the risk of acrylamide to aquatic animals, especially molluscs, may be underestimated. PMID:25262075

  18. Neonatal exposure to amphetamine alters social affiliation and central dopamine activity in adult male prairie voles.

    PubMed

    Fukushiro, D F; Olivera, A; Liu, Y; Wang, Z

    2015-10-29

    The prairie vole (Microtus ochrogaster) is a socially monogamous rodent species that forms pair bonds after mating. Recent data have shown that amphetamine (AMPH) is rewarding to prairie voles as it induces conditioned place preferences. Further, repeated treatment with AMPH impairs social bonding in adult prairie voles through a central dopamine (DA)-dependent mechanism. The present study examined the effects of neonatal exposure to AMPH on behavior and central DA activity in adult male prairie voles. Our data show that neonatal exposure to AMPH makes voles less social in an affiliation test during adulthood, but does not affect animals' locomotor activity and anxiety-like behavior. Neonatal exposure to AMPH also increases the levels of tyrosine hydroxylase (TH) and DA transporter (DAT) mRNA expression in the ventral tegmental area (VTA) in the brain, indicating an increase in central DA activity. As DA has been implicated in AMPH effects on behavioral and cognitive functions, altered DA activity in the vole brain may contribute to the observed changes in social behavior. PMID:26321240

  19. Expression of E-Cadherin and N-Cadherin in Perinatal Hamster Ovary: Possible Involvement in Primordial Follicle Formation and Regulation by Follicle-Stimulating Hormone

    PubMed Central

    Wang, Cheng; Roy, Shyamal K.

    2010-01-01

    We examined the expression and hormonal regulation of E-cadherin (CDH1) and N-cadherin (CDH2) with respect to primordial follicle formation. Hamster Cdh1 and Cdh2 cDNA and amino acid sequences were more than 90% similar to those of the mouse, rat, and human. Although CDH1 expression remained exclusively in the oocytes during neonatal ovary development, CDH2 expression shifted from the oocytes to granulosa cells of primordial follicles on postnatal day (P)8. Subsequently, strong CDH2 expression was restricted to granulosa cells of growing follicles. Cdh2 mRNA levels in the ovary decreased from embryonic d 13 through P10 with a transient increase on P7, which was the day before the appearance of primordial follicles. Cdh1 mRNA levels decreased from embryonic d 13 through P3 and then showed a transient increase on P8, coinciding with the formation of primordial follicles. CDH1 and CDH2 expression were consistent with that of mRNA. Neutralization of FSH in utero impaired primordial follicle formation with an associated decrease in Cdh2 mRNA and CDH2, but an increase in Cdh1 mRNA and CDH1 expression. The altered expression was reversed by equine chorionic gonadotropin treatment on P1. Whereas a CDH2 antibody significantly reduced the formation of primordial and primary follicles in vitro, a CDH1 antibody had the opposite effect. This is the first evidence to suggest that primordial follicle formation requires a differential spatiotemporal expression and action of CDH1 and CDH2. Further, FSH regulation of primordial follicle formation may involve the action of CDH1 and CDH2. PMID:20219978

  20. Polychlorinated biphenyl exposure alters the expression profile of microRNAs associated with vascular diseases.

    PubMed

    Wahlang, Banrida; Petriello, Michael C; Perkins, Jordan T; Shen, Shu; Hennig, Bernhard

    2016-09-01

    Exposure to persistent organic pollutants, including polychlorinated biphenyls (PCBs) is correlated with multiple vascular complications including endothelial cell dysfunction and atherosclerosis. PCB-induced activation of the vasculature subsequently leads to oxidative stress and induction of pro-inflammatory cytokines and adhesion proteins. Gene expression of these cytokines/proteins is known to be regulated by small, endogenous oligonucleotides known as microRNAs that interact with messenger RNA. MicroRNAs are an acknowledged component of the epigenome, but the role of environmentally-driven epigenetic changes such as toxicant-induced changes in microRNA profiles is currently understudied. The objective of this study was to determine the effects of PCB exposure on microRNA expression profile in primary human endothelial cells using the commercial PCB mixture Aroclor 1260. Samples were analyzed using Affymetrix GeneChip® miRNA 4.0 arrays for high throughput detection and selected microRNA gene expression was validated (RT-PCR). Microarray analysis identified 557 out of 6658 microRNAs that were changed with PCB exposure (p<0.05). In-silico analysis using MetaCore database identified 21 of these microRNAs to be associated with vascular diseases. Further validation showed that Aroclor 1260 increased miR-21, miR-31, miR-126, miR-221 and miR-222 expression levels. Upregulated miR-21 has been reported in cardiac injury while miR-126 and miR-31 modulate inflammation. Our results demonstrated evidence of altered microRNA expression with PCB exposure, thus providing novel insights into mechanisms of PCB toxicity. PMID:27288564

  1. Early Phthalates Exposure in Pregnant Women Is Associated with Alteration of Thyroid Hormones

    PubMed Central

    Tsai, Chih-Hsin; Liang, Wei-Yen; Li, Sih-Syuan; Huang, Han-Bin

    2016-01-01

    Introduction Previous studies revealed that phthalate exposure could alter thyroid hormones during the last trimester of pregnancy. However, thyroid hormones are crucial for fetal development during the first trimester. We aimed to clarify the effect of phthalate exposure on thyroid hormones during early pregnancy. Method We recruited 97 pregnant women who were offered an amniocentesis during the early trimester from an obstetrics clinic in southern Taiwan from 2013 to 2014. After signing an informed consent form, we collected amniotic fluid and urine samples from pregnant women to analyze 11 metabolites, including mono-ethyl phthalate (MEP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethylhexyl) phthalate (MEHP), mono-butyl phthalate (MnBP), of 9 phthalates using liquid chromatography/ tandem mass spectrometry. We collected blood samples from each subject to analyze serum thyroid hormones including thyroxine (T4), free T4, and thyroid-binding globulin (TBG). Results Three phthalate metabolites were discovered to be >80% in the urine samples of the pregnant women: MEP (88%), MnBP (81%) and MECPP (86%). Median MnBP and MECPP levels in pregnant Taiwanese women were 21.5 and 17.6 μg/g-creatinine, respectively, that decreased after the 2011 Taiwan DEHP scandal. Results of principal component analysis suggested two major sources (DEHP and other phthalates) of phthalates exposure in pregnant women. After adjusting for age, gestational age, TBG, urinary creatinine, and other phthalate metabolites, we found a significantly negative association between urinary MnBP levels and serum T4 (β = –5.41; p-value = 0.012; n = 97) in pregnant women using Bonferroni correction. Conclusion We observed a potential change in the thyroid hormones of pregnant women during early pregnancy after DnBP exposure. Additional study is necessitated to clarify these associations. PMID:27455052

  2. Asthmatics Exhibit Altered Oxylipin Profiles Compared to Healthy Individuals after Subway Air Exposure

    PubMed Central

    Nording, Malin; Klepczynska-Nyström, Anna; Sköld, Magnus; Haeggström, Jesper Z.; Grunewald, Johan; Svartengren, Magnus; Hammock, Bruce D.; Larsson, Britt-Marie; Eklund, Anders; Wheelock, Åsa M.; Wheelock, Craig E.

    2011-01-01

    Background Asthma is a chronic inflammatory lung disease that causes significant morbidity and mortality worldwide. Air pollutants such as particulate matter (PM) and oxidants are important factors in causing exacerbations in asthmatics, and the source and composition of pollutants greatly affects pathological implications. Objectives This randomized crossover study investigated responses of the respiratory system to Stockholm subway air in asthmatics and healthy individuals. Eicosanoids and other oxylipins were quantified in the distal lung to provide a measure of shifts in lipid mediators in association with exposure to subway air relative to ambient air. Methods Sixty-four oxylipins representing the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) metabolic pathways were screened using liquid chromatography-tandem mass spectrometry (LC-MS/MS) of bronchoalveolar lavage (BAL)-fluid. Validations through immunocytochemistry staining of BAL-cells were performed for 15-LOX-1, COX-1, COX-2 and peroxisome proliferator-activated receptor gamma (PPARγ). Multivariate statistics were employed to interrogate acquired oxylipin and immunocytochemistry data in combination with patient clinical information. Results Asthmatics and healthy individuals exhibited divergent oxylipin profiles following exposure to ambient and subway air. Significant changes were observed in 8 metabolites of linoleic- and α-linolenic acid synthesized via the 15-LOX pathway, and of the COX product prostaglandin E2 (PGE2). Oxylipin levels were increased in healthy individuals following exposure to subway air, whereas asthmatics evidenced decreases or no change. Conclusions Several of the altered oxylipins have known or suspected bronchoprotective or anti-inflammatory effects, suggesting a possible reduced anti-inflammatory response in asthmatics following exposure to subway air. These observations may have ramifications for sensitive subpopulations in urban areas. PMID:21897859

  3. Perinatal Exposure to Oestradiol and Bisphenol A Alters the Prostate Epigenome and Increases Susceptibility to Carcinogenesis

    PubMed Central

    Prins, Gail S.; Tang, Wan-Yee; Belmonte, Jessica; Ho, Shuk-Mei

    2010-01-01

    An important and controversial health concern is whether low-dose exposures to hormonally active environmental oestrogens such as bisphenol A can promote human diseases including prostate cancer. Our studies in rats have shown that pharmacological doses of oestradiol administered during the critical window of prostate development result in marked prostate pathology in adulthood that progress to neoplastic lesions with ageing. Our recent studies have also demonstrated that transient developmental exposure of rats to low, environmentally relevant doses of bisphenol A or oestradiol increases prostate gland susceptibility to adult-onset precancerous lesions and hormonal carcinogenesis. These findings indicate that a wide range of oestrogenic exposures during development can predispose to prostatic neoplasia that suggests a potential developmental basis for this adult disease. To identify a molecular basis for oestrogen imprinting, we screened for DNA methylation changes over time in the exposed prostate glands. We found permanent alterations in DNA methylation patterns of multiple cell signalling genes suggesting an epigenetic mechanism of action. For phosphodiesterase type 4 variant 4 (PDE4D4), an enzyme responsible for intracellular cyclic adenosine monophosphate breakdown, a specific methylation cluster was identified in the 5′-flanking CpG island that was gradually hypermethylated with ageing in normal prostates resulting in loss of gene expression. However, in prostates exposed to neonatal oestradiol or bisphenol A, this region became hypomethylated with ageing resulting in persistent and elevated PDE4D4 expression. In total, these findings indicate that low-dose exposures to ubiquitous environmental oestrogens impact the prostate epigenome during development and in so doing, promote prostate disease with ageing. PMID:18226066

  4. PRENATAL ALCOHOL EXPOSURE ALTERS STEADY-STATE AND ACTIVATED GENE EXPRESSION IN THE ADULT RAT BRAIN

    PubMed Central

    Stepien, Katarzyna A.; Lussier, Alexandre A.; Neumann, Sarah M.; Pavlidis, Paul; Kobor, Michael S.; Weinberg, Joanne

    2016-01-01

    Background Prenatal alcohol exposure (PAE) is associated with alterations in numerous physiological systems, including the stress and immune systems . We have previously shown that PAE increases the course and severity of arthritis in an adjuvant-induced arthritis (AA) model. While the molecular mechanisms underlying these effects are not fully known, changes in neural gene expression are emerging as important factors in the etiology of PAE effects. As the prefrontal cortex (PFC) and hippocampus (HPC) play key roles in neuroimmune function, PAE-induced alterations to their transcriptome may underlie abnormal steady-state functions and responses to immune challenge. The current study examined brains from adult PAE and control females from our recent AA study to determine whether PAE causes long-term alterations in gene expression and whether these mediate the altered severity and course of arthritis in PAE females Methods Adult females from PAE, pair-fed [PF], and ad libitum-fed control [C]) groups were injected with either saline or complete Freund’s adjuvant. Animals were terminated at the peak of inflammation or during resolution (days 16 and 39 post-injection, respectively); cohorts of saline-injected PAE, PF and C females were terminated in parallel. Gene expression was analyzed in the PFC and HPC using whole genome mRNA expression microarrays. Results Significant changes in gene expression in both the PFC and HPC were found in PAE compared to controls in response to ethanol exposure alone (saline-injected females), including genes involved in neurodevelopment, apoptosis, and energy metabolism. Moreover, in response to inflammation (adjuvant-injected females), PAE animals showed unique expression patterns, while failing to exhibit the activation of genes and regulators involved in the immune response observed in control and pair-fed animals. Conclusions These results support the hypothesis that PAE affects neuroimmune function at the level of gene expression

  5. Neuropsychological evaluation for detecting alterations in the central nervous system after chemical exposure.

    PubMed

    Bolla, K I

    1996-08-01

    Individuals with multiple chemical sensitivity (MCS) report decreased attention/concentration, memory loss, disorientation, confusion, fatigue, depression, irritability, decreased libido, sleep disturbances, headaches, and weakness. These neurobehavioral symptoms represent possible alterations in the central nervous system (CNS). The evaluation of neurobehavioral functioning using neuropsychological techniques provides an indirect method for determining the integrity of the CNS. However, caution must be used in interpreting neuropsychological test results, since this technique is extremely sensitive but is not specific. Clinically significant aberrant test performance may be noted after chemical exposure as well as with other diseases of the CNS. In addition, neuropsychiatric conditions such as anxiety and depression are often manifested as cognitive difficulties that are similar in pattern to the cognitive dysfunction caused by toxic chemicals. Herein, limitations and cautions in the interpretations of neuropsychological test results are discussed. PMID:8921555

  6. Does ozone exposure alter growth and carbon allocation of mycorrhizal plants

    SciTech Connect

    Yoshida, L.C.; Gamon, J.A. ); Andersen, C.P. )

    1994-06-01

    Ozone is known to adversely affect plant growth. However, it is less clear how ozone affects belowground processes. This study tests the hypothesis that ozone alters growth and carbon allocation of vesicular arbuscular mycorrhizal (VAM) plants. Two ecotypes of Elymus glaucus (blue wild rye) were exposed to mycorrhizal inoculation and episodic ozone exposures simulating atmospheric conditions in the Los Angeles Basin. Preliminary results show that effects of ozone on growth were subtle. In both ecotypes, growth of aboveground biomass was not affected by ozone while root growth was decreased. In most treatments, mycorrhizal inoculation decreased growth of leaves and stems, but had no significant effect on root growth. Three-way ANOVA tests indicated interactive effects between ecotype, mycorrhiza and ozone. Further experimental work is needed to reveal the biological processes governing these responses.

  7. Nicotine exposure during adolescence alters the rules for prefrontal cortical synaptic plasticity during adulthood

    PubMed Central

    Goriounova, Natalia A.; Mansvelder, Huibert D.

    2012-01-01

    The majority of adolescents report to have smoked a cigarette at least once. Adolescence is a critical period of brain development during which maturation of areas involved in cognitive functioning, such as the medial prefrontal cortex (mPFC), is still ongoing. Tobacco smoking during this age may compromise the normal course of prefrontal development and lead to cognitive impairments in later life. In addition, adolescent smokers suffer from attention deficits, which progress with the years of smoking. Recent studies in rodents reveal the molecular changes induced by adolescent nicotine exposure that alter the functioning of synapses in the PFC and underlie the lasting effects on cognitive function. In particular, the expression and function of metabotropic glutamate receptors (mGluRs) are changed and this has an impact on short- and long-term plasticity of glutamatergic synapses in the PFC and ultimately on the attention performance. Here, we review and discuss these recent findings. PMID:22876231

  8. Altered behavioral development in Nrf2 knockout mice following early postnatal exposure to valproic acid

    PubMed Central

    Furnari, Melody A.; Saw, Constance Lay-Lay; Kong, Ah-Ng; Wagner, George C

    2015-01-01

    Early exposure to valproic acid results in autism-like neural and behavioral deficits in humans and other animals through oxidative stress-induced neural damage. In the present study, valproic acid was administered to genetically altered mice lacking the Nrf2 (nuclear factor-erythroid 2 related factor 2) gene on postnatal day 14 (P14). Nrf2 is a transcription factor that induces genes that protect against oxidative stress. It was found that valproic acid-treated Nrf2 knockout mice were less active in open field activity chambers, less successful on the rotorod, and had deficits in learning and memory in the Morris water maze compared to the valproic acid-treated wild type mice. Given these results, it appears that Nrf2 knockout mice were more sensitive to the neural damage caused by valproic acid administered during early development. PMID:25454122

  9. Economic evaluation of highly purified human menopausal gonadotropin versus recombinant human follicle-stimulating hormone in fresh and frozen in vitro fertilization/intracytoplasmic sperm-injection cycles in Sweden

    PubMed Central

    Wex, Jaro; Abou-Setta, Ahmed M

    2013-01-01

    Gonadotropin-releasing hormone-analog type, fertilization method, and number of embryos available for cryopreservation should be incorporated into economic evaluations of highly purified human menopausal gonadotropin (HP-hMG) and recombinant human follicle-stimulating hormone (r-hFSH), as they may affect treatment costs. We searched for randomized trials and meta-analyses comparing HP-hMG and r-hFSH. Meta-analysis showed no significant difference in live births (odds ratio 0.82, 95% confidence interval [CI] 0.66–1.01), but a greater number of oocytes with r-hFSH (mean difference [MD] 1.96, 95% CI 1.02–2.90). Using a cost-minimization model for Sweden, accounting for embryo availability, survival following thawing, and patient dropout, we simulated patients individually for up to three cycles. R-hFSH was found to be cost-saving, at 2,767 kr (95% CI 1,580–4,057) per patient (€315 or $411); baseline savings were 6.43% of the total HP-hMG cost. In fresh cycles only, the savings for r-hFSH were 1,752 kr (95% CI 48–3,658) per patient (€200 or $260). In univariate sensitivity analyses, savings were obtained until the price of r-hFSH increased by 30% or the dosage of HP-hMG decreased by 38%–62% of baseline value. In probabilistic sensitivity analysis, r-hFSH was cost-saving in 100% of the simulated cohort per patient and in 85% per live birth; the respective percentages for fresh cycles only were 97.3% and 73.1%. In conclusion, a greater number of oocytes with r-hFSH allows for more frozen embryo transfers, thereby reducing overall treatment cost. PMID:23966798

  10. Oocyte and cumulus cell transcripts from cultured mouse follicles are induced to deviate from normal in vivo conditions by combinations of insulin, follicle-stimulating hormone, and human chorionic gonadotropin.

    PubMed

    Sánchez, Flor; Romero, Sergio; Smitz, Johan

    2011-09-01

    Gonadotropins and insulin are major regulators of cell proliferation, differentiation, and survival in cultured mouse ovarian follicles. Applications of variable doses of insulin in combination with follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were studied at the gene expression level in oocytes and cumulus cells. Early preantral follicles grown over 9 days were sequentially exposed to combinations of doses of insulin, FSH, and human chorionic gonadotropin (hCG). From culture Day 1 to 6 (preantral stage), two insulin concentrations (5 ng/ml and 5 μg/ml) were combined with 10 mIU/ml FSH. From Days 6 to 9 (antral stage), the three variable gonadotropin treatments set under each insulin condition were 10 mIU/ml FSH, 25 mIU/ml FSH, and 25 mIU/ml FSH plus 3 mIU/ml hCG. The Gdf9, Bmp15, Fgf8, Dazl, Pou5f1, and Pik3ca mRNA transcripts were quantified in oocytes, and the Amh, Lhcgr, Hsd3b1, Vegfa, and Insig1 mRNA transcripts were quantified in cumulus cells. In vivo controls were unprimed and eCG (equine chorionic gonadotropin)-primed prepubertal female mice. During the preantral stage, none except the Amh transcripts was regulated by insulin. Oocyte transcripts were not affected by the variable gonadotropin treatments on the last culture day but were upregulated in the combination of high insulin plus 25 mIU/ml FSH. Under low insulin conditions, high FSH levels increased levels of Lhcgr and Vegfa expression, and hCG abated this effect. However, under high insulin conditions, hCG upregulated levels of Lhcgr, Vegfa, and Insig1 mRNA. High insulin concentrations upregulated Hsd3b1 transcripts. These results demonstrate that in an in vitro follicle culture, a near physiological insulin background yields oocyte and cumulus cell transcript levels that are more similar to those in vivo. PMID:21565993

  11. Functional and inflammatory alterations in the lung following exposure of rats to nitrogen mustard

    SciTech Connect

    Sunil, Vasanthi R.; Patel, Kinal J.; Shen, Jianliang; Reimer, David; Gow, Andrew J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2011-01-01

    Nitrogen mustard is a vesicant that causes damage to the respiratory tract. In these studies, we characterized the acute effects of nitrogen mustard on lung structure, inflammatory mediator expression, and pulmonary function, with the goal of identifying mediators potentially involved in toxicity. Treatment of rats (male Wistar, 200-225 g) with nitrogen mustard (mechlorethamine hydrochloride, i.t., 0.25 mg/kg) resulted in marked histological changes in the respiratory tract, including necrotizing bronchiolitis, thickening of alveolar septa, and inflammation which was evident within 24 h. This was associated with increases in bronchoalveolar lavage protein and cells, confirming injury to alveolar epithelial regions of the lung. Nitrogen mustard administration also resulted in increased expression of inducible nitric oxide synthase and cyclooxygenase-2, pro-inflammatory proteins implicated in lung injury, in alveolar macrophages and alveolar and bronchial epithelial cells. Expression of connective tissue growth factor and matrix metalloproteinase-9, mediators regulating extracellular matrix turnover was also increased, suggesting that pathways leading to chronic lung disease are initiated early in the pathogenic process. Following nitrogen mustard exposure, alterations in lung mechanics and function were also observed. These included decreases in baseline static compliance, end-tidal volume and airway resistance, and a pronounced loss of methacholine responsiveness in resistance, tissue damping and elastance. Taken together, these data demonstrate that nitrogen mustard induces rapid structural and inflammatory changes in the lung which are associated with altered lung functioning. Understanding the nature of the injury induced by nitrogen mustard and related analogs may aid in the development of efficacious therapies for treatment of pulmonary injury resulting from exposure to vesicants.

  12. Sulfite exposure-induced hepatocyte death is not associated with alterations in p53 protein expression.

    PubMed

    Bai, Jianying; Lei, Peiyu; Zhang, Jidong; Zhao, Chunyan; Liang, Ruifeng

    2013-10-01

    Although sulfite (SO3(2-)) is commonly used as an antimicrobial agent and preservative in foods, medicines and wine, it has also been listed as an important risk factor for the initiation and progression of liver diseases due to oxidative damage. In general, apoptosis that is induced by oxidative stress is triggered by increases in p53 and alterations in Mdm2 and Bcl-2. However, the level of involvement of the p53 signaling pathway, which has been shown to be upregulated in some animal studies, in hepatocyte death remains unclear. To examine the response of the p53 signaling pathway to stimulation with different concentrations of sulfite, a time course study of p53, Mdm2, and Bcl-2 expression was conducted in an immortalized hepatic cell line, HL-7702. When the HL-7702 cells were cultured in the presence of Na2SO3, the cell viability was significantly decreased after 24h compared to that of the control group (0mmol/L) (p<0.05). Meanwhile, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the supernatants of HL-7702 cells were significantly increased following Na2SO3 administration. Interestingly, the expression of p53 and p-p53 (Ser15) remained unchanged. In addition, no obvious alterations in Mdm2 and Bcl-2 expression were observed in HL-7702 cells that had been stimulated with various concentrations of sulfite. To further investigate the detailed mechanism underlying sulfite toxicity, caspase-3, PCNA and RIP1 expression in HL-7702 cells was studied. The expression levels of caspase-3 and PCNA were unchanged, but RIP1 expression was increased significantly after 24h of exposure. In light of this evidence, we propose that sulfite is cytotoxic to hepatocytes, but this cytotoxicity is not achieved by direct interruption of the p53 signaling pathway. In addition, we propose that an alternative necrotic process underlies hepatocellular death following sulfite exposure. PMID:23973939

  13. Altered lung function at mid-adulthood in mice following neonatal exposure to hyperoxia.

    PubMed

    Sozo, Foula; Horvat, Jay C; Essilfie, Ama-Tawiah; O'Reilly, Megan; Hansbro, Philip M; Harding, Richard

    2015-11-01

    Infants born very preterm are usually exposed to high oxygen concentrations but this may impair lung function in survivors in later life. However, the precise changes involved are poorly understood. We determined how neonatal hyperoxia alters lung function at mid-adulthood in mice. Neonatal C57BL/6J mice inhaled 65% oxygen (HE group) from birth for 7 days. They then breathed room air until 11 months of age (P11mo); these mice experienced growth restriction. Controls breathed only room air. To exclude the effects of growth restriction, a group of dams was rotated between hyperoxia and normoxia during the exposure period (HE+DR group). Lung function was measured at P11mo. HE mice had increased inspiratory capacity, work of breathing and tissue damping. HE+DR mice had further increases in inspiratory capacity and work of breathing, and reduced FEV100/FVC. Total lung capacity was increased in HE+DR males. HE males had elevated responses to methacholine. Neonatal hyperoxia alters lung function at mid-adulthood, especially in males. PMID:26197245

  14. Maternal caffeine exposure alters neuromotor development and hippocampus acetylcholinesterase activity in rat offspring.

    PubMed

    Souza, Ana Claudia; Souza, Andressa; Medeiros, Liciane Fernandes; De Oliveira, Carla; Scarabelot, Vanessa Leal; Da Silva, Rosane Souza; Bogo, Mauricio Reis; Capiotti, Katiucia Marques; Kist, Luiza Wilges; Bonan, Carla D; Caumo, Wolnei; Torres, Iraci L S

    2015-01-21

    The objective of this study was to evaluate the effects of maternal caffeine intake on the neuromotor development of rat offspring and on acetylcholine degradation and acetylcholinesterase (AChE) expression in the hippocampus of 14-day-old infant rats. Rat dams were treated with caffeine (0.3g/L) throughout gestation and lactation until the pups were 14 days old. The pups were divided into three groups: (1) control, (2) caffeine, and (3) washout caffeine. The washout group received a caffeine solution until the seventh postnatal day (P7). Righting reflex (RR) and negative geotaxis (NG) were assessed to evaluate postural parameters as an index of neuromotor reflexes. An open-field (OF) test was conducted to assess locomotor and exploratory activities as well as anxiety-like behaviors. Caffeine treatment increased both RR and NG latency times. In the OF test, the caffeine group had fewer outer crossings and reduced locomotion compared to control, while the washout group showed increased inner crossings in relation to the other groups and fewer rearings only in comparison to the control group. We found decreased AChE activity in the caffeine group compared to the other groups, with no alteration in AChE transcriptional regulation. Chronic maternal exposure to caffeine promotes important alterations in neuromotor development. These results highlight the ability of maternal caffeine intake to interfere with cholinergic neurotransmission during brain development. PMID:25451122

  15. In utero exposure to chloroquine alters sexual development in the male fetal rat

    SciTech Connect

    Clewell, Rebecca A. Pluta, Linda; Thomas, Russell S.; Andersen, Melvin E.

    2009-06-15

    Chloroquine (CQ), a drug that has been used extensively for the prevention and treatment of malaria, is currently considered safe for use during pregnancy. However, CQ has been shown to disrupt steroid homeostasis in adult rats and similar compounds, such as quinacrine, inhibit steroid production in the Leydig cell in vitro. To explore the effect of in utero CQ exposure on fetal male sexual development, pregnant Sprague-Dawley rats were given a daily dose of either water or chloroquine diphosphate from GD 16-18 by oral gavage. Chloroquine was administered as 200 mg/kg CQ base on GD 16, followed by two maintenance doses of 100 mg/kg CQ base on GD 16 and 18. Three days of CQ treatment resulted in reduced maternal and fetal weight on GD 19 and increased necrosis and steatosis in the maternal liver. Fetal livers also displayed mild lipid accumulation. Maternal serum progesterone was increased after CQ administration. Fetal testes testosterone, however, was significantly decreased. Examination of the fetal testes revealed significant alterations in vascularization and seminiferous tubule development after short-term CQ treatment. Anogenital distance was not altered. Microarray and RT-PCR showed down-regulation of several genes associated with cholesterol transport and steroid synthesis in the fetal testes. This study indicates that CQ inhibits testosterone synthesis and normal testis development in the rat fetus at human relevant doses.

  16. Lactational Exposure to Di (2-ethylhexyl) Phthalate Impairs the Ovarian and Uterine Function of Adult Offspring Rat.

    PubMed

    Somasundaram, Dinesh Babu; Selvanesan, Benson Chellakkan; Ramachandran, Ilangovan; Bhaskaran, Ravi Sankar

    2016-04-01

    Phthalates, a class of chemicals used as plasticizers, are economically important due to several industrial applications. Di-(2-ethylhexyl) phthalate (DEHP) is the most commonly used phthalate plasticizer, and it has been described as a potent antiandrogen in males. In this study, lactating dams were exposed via oral gavage to corn oil (vehicle) and DEHP (1, 10, and 100 mg/kg body weight) from postnatal day 1 to 21, and the effects were evaluated in the ovary and uterus of F1 progeny. DEHP exposure significantly decreased the body weight and organ weight in a dose-dependent manner. Serum levels of estradiol, testosterone, and progesterone were decreased but anogenital distance was unaffected. The mRNA expressions of luteinizing hormone receptor, follicle-stimulating hormone receptor, androgen receptor, estrogen receptor (ERα and ERβ), progesterone receptor, peroxisome proliferator-activated receptor γ, 3β hydroxysteroid dehydrogenase, aromatase, and steroidogenic acute regulatory protein were altered in the ovary of F1 progeny rats. Our finding suggest that lactational exposure to DEHP has transgenerational effect on female reproductive system. PMID:26482208

  17. RNA-Seq identifies key reproductive gene expression alterations in response to cadmium exposure.

    PubMed

    Hu, Hanyang; Lu, Xing; Cen, Xiang; Chen, Xiaohua; Li, Feng; Zhong, Shan

    2014-01-01

    Cadmium is a common toxicant that is detrimental to many tissues. Although a number of transcriptional signatures have been revealed in different tissues after cadmium treatment, the genes involved in the cadmium caused male reproductive toxicity, and the underlying molecular mechanism remains unclear. Here we observed that the mice treated with different amount of cadmium in their rodent chow for six months exhibited reduced serum testosterone. We then performed RNA-seq to comprehensively investigate the mice testicular transcriptome to further elucidate the mechanism. Our results showed that hundreds of genes expression altered significantly in response to cadmium treatment. In particular, we found several transcriptional signatures closely related to the biological processes of regulation of hormone, gamete generation, and sexual reproduction, respectively. The expression of several testosterone synthetic key enzyme genes, such as Star, Cyp11a1, and Cyp17a1, were inhibited by the cadmium exposure. For better understanding of the cadmium-mediated transcriptional regulatory mechanism of the genes, we computationally analyzed the transcription factors binding sites and the mircoRNAs targets of the differentially expressed genes. Our findings suggest that the reproductive toxicity by cadmium exposure is implicated in multiple layers of deregulation of several biological processes and transcriptional regulation in mice. PMID:24982889

  18. RNA-Seq Identifies Key Reproductive Gene Expression Alterations in Response to Cadmium Exposure

    PubMed Central

    Hu, Hanyang; Lu, Xing; Cen, Xiang; Chen, Xiaohua; Li, Feng; Zhong, Shan

    2014-01-01

    Cadmium is a common toxicant that is detrimental to many tissues. Although a number of transcriptional signatures have been revealed in different tissues after cadmium treatment, the genes involved in the cadmium caused male reproductive toxicity, and the underlying molecular mechanism remains unclear. Here we observed that the mice treated with different amount of cadmium in their rodent chow for six months exhibited reduced serum testosterone. We then performed RNA-seq to comprehensively investigate the mice testicular transcriptome to further elucidate the mechanism. Our results showed that hundreds of genes expression altered significantly in response to cadmium treatment. In particular, we found several transcriptional signatures closely related to the biological processes of regulation of hormone, gamete generation, and sexual reproduction, respectively. The expression of several testosterone synthetic key enzyme genes, such as Star, Cyp11a1, and Cyp17a1, were inhibited by the cadmium exposure. For better understanding of the cadmium-mediated transcriptional regulatory mechanism of the genes, we computationally analyzed the transcription factors binding sites and the mircoRNAs targets of the differentially expressed genes. Our findings suggest that the reproductive toxicity by cadmium exposure is implicated in multiple layers of deregulation of several biological processes and transcriptional regulation in mice. PMID:24982889

  19. Alteration of transcriptional networks in the entorhinal cortex after maternal immune activation and adolescent cannabinoid exposure.

    PubMed

    Hollins, Sharon L; Zavitsanou, Katerina; Walker, Frederick Rohan; Cairns, Murray J

    2016-08-01

    Maternal immune activation (MIA) and adolescent cannabinoid exposure (ACE) have both been identified as major environmental risk factors for schizophrenia. We examined the effects of these two risk factors alone, and in combination, on gene expression during late adolescence. Pregnant rats were exposed to the viral infection mimic polyriboinosinic-polyribocytidylic acid (poly I:C) on gestational day (GD) 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14days starting on postnatal day (PND) 35. Gene expression was examined in the left entorhinal cortex (EC) using mRNA microarrays. We found prenatal treatment with poly I:C alone, or HU210 alone, produced relatively minor changes in gene expression. However, following combined treatments, offspring displayed significant changes in transcription. This dramatic and persistent alteration of transcriptional networks enriched with genes involved in neurotransmission, cellular signalling and schizophrenia, was associated with a corresponding perturbation in the expression of small non-coding microRNA (miRNA). These results suggest that a combination of environmental exposures during development leads to significant genomic remodeling that disrupts maturation of the EC and its associated circuitry with important implications as the potential antecedents of memory and learning deficits in schizophrenia and other neuropsychiatric disorders. PMID:26923065

  20. Repeated Stimulus Exposure Alters the Way Sound Is Encoded in the Human Brain

    PubMed Central

    Tremblay, Kelly L.; Inoue, Kayo; McClannahan, Katrina; Ross, Bernhard

    2010-01-01

    Auditory training programs are being developed to remediate various types of communication disorders. Biological changes have been shown to coincide with improved perception following auditory training so there is interest in determining if these changes represent biologic markers of auditory learning. Here we examine the role of stimulus exposure and listening tasks, in the absence of training, on the modulation of evoked brain activity. Twenty adults were divided into two groups and exposed to two similar sounding speech syllables during four electrophysiological recording sessions (24 hours, one week, and up to one year later). In between each session, members of one group were asked to identify each stimulus. Both groups showed enhanced neural activity from session-to-session, in the same P2 latency range previously identified as being responsive to auditory training. The enhancement effect was most pronounced over temporal-occipital scalp regions and largest for the group who participated in the identification task. The effects were rapid and long-lasting with enhanced synchronous activity persisting months after the last auditory experience. Physiological changes did not coincide with perceptual changes so results are interpreted to mean stimulus exposure, with and without being paired with an identification task, alters the way sound is processed in the brain. The cumulative effect likely involves auditory memory; however, in the absence of training, the observed physiological changes are insufficient to result in changes in learned behavior. PMID:20421969

  1. Ethanol exposure during gastrulation alters neuronal morphology and behavior in zebrafish.

    PubMed

    Shan, Shubham D; Boutin, Savanna; Ferdous, Jannatul; Ali, Declan W

    2015-01-01

    Ethanol (EtOH) exposure during development has been shown to lead to deficits in fine and gross motor control. In this study we used zebrafish embryos to determine the effects of EtOH treatment during gastrulation. We treated embryos in the gastrulation stage (5.25 hours post fertilization (hpf) to 10.75 hpf) with 10 mM, 50 mM or 100 mM EtOH and examined the effects on general animal morphology, the c-start reflex behavior, Mauthner cell (M-cell) morphology and motor neuron morphology. EtOH treated fish exhibited a minor but significant increase in gross morphological deformities compared with untreated fish. Behavioral studies showed that EtOH treatment resulted in an increase in the peak speed of the tail during the escape response. Furthermore, there was a marked increase in abnormally directed c-starts, with treated fish showing greater incidences of c-starts in inappropriate directions. Immunolabeling of the M-cells, which are born during gastrulation, revealed that they were significantly smaller in fish treated with 100 mM EtOH compared with controls. Immunolabeling of primary motor neurons using anti-znp1, showed no significant effect on axonal branching, whereas secondary motor axons had a greater number of branches in ethanol treated fish compared with controls. Together these findings indicate that ethanol exposure during gastrulation can lead to alterations in behavior, neuronal morphology and possibly function. PMID:25599605

  2. Prior exposure to extreme pain alters neural response to pain in others.

    PubMed

    Eidelman-Rothman, Moranne; Goldstein, Abraham; Weisman, Omri; Schneiderman, Inna; Zagoory-Sharon, Orna; Decety, Jean; Feldman, Ruth

    2016-08-01

    In the extant literature examining the brain mechanisms implicated in pain perception, researchers have theorized that the overlapping responses to pain in the self and in others mark the human capacity for empathy. Here we investigated how prior exposure to extreme pain affects pain perception, by assessing the dynamics of pain processing in veterans who were previously exposed to severe injury. Forty-three participants (28 pain-exposed and 15 controls) underwent whole-head magnetoencephalography (MEG) while viewing photographs of limbs in painful and nonpainful (neutral) conditions. Among controls, an early (0-220 ms) "pain effect" in the posterior cingulate and sensorimotor cortices, and a later (760-900 ms) "pain effect" in the posterior cingulate cortex, superior temporal gyrus/insula, and fusiform gyrus were found, indicated by enhanced alpha suppression to the pain versus nonpain conditions. Importantly, pain-exposed participants exhibited an atypical pain response in the posterior cingulate cortex, indicated by a normative response to pain, but no pain-to-no-pain differentiation. This may suggest that individuals exposed to extreme pain may perceive neutral stimuli as potentially threatening. Our findings demonstrate alterations in pain perception following extreme pain exposure, chart the sequence from automatic to evaluative pain processing, and emphasize the importance of considering past experiences in studying the neural response to others' states. PMID:27032959

  3. Levonorgestrel exposure to fathead minnows (Pimephales promelas) alters survival, growth, steroidogenic gene expression and hormone production.

    PubMed

    Overturf, Matthew D; Overturf, Carmen L; Carty, Dennis R; Hala, David; Huggett, Duane B

    2014-03-01

    Human pharmaceuticals are commonly detected in the environment. Concern over these compounds in the environment center around the potential for pharmaceuticals to interfere with the endocrine system of aquatic organisms. The main focus of endocrine disruption research has centered on how estrogenic and androgenic compounds interact with the endocrine system to elicit reproductive effects. Other classes of compounds, such as progestins, have been overlooked. Recently, studies have investigated the potential for synthetic progestins to impair reproduction and growth in aquatic organisms. The present study utilizes the OECD 210 Early-life Stage (ELS) study to investigate the impacts levonorgestrel (LNG), a synthetic progestin, on fathead minnow (FHM) survival and growth. After 28 days post-hatch, survival of larval FHM was impacted at 462 ng/L, while growth was significantly reduced at 86.9 ng/L. Further analysis was conducted by measuring specific endocrine related mRNA transcript profiles in FHM larvae following the 28 day ELS exposure to LNG. Transcripts of 3β-HSD, 20β-HSD, CYP17, AR, ERα, and FSH were significantly down-regulated following 28d exposure to 16.3 ng/L LNG, while exposure to 86.9 ng/L significantly down-regulated 3β-HSD, 20β-HSD, CYP19A, and FSH. At 2,392 ng/L of LNG, a significant down-regulation occurred with CYP19A and ERβ transcripts, while mPRα and mPRβ profiles were significantly induced. No significant changes occurred in 11β-HSD, CYP11A, StAR, LHβ, and VTG mRNA expression following LNG exposure. An ex vivo steroidogenesis assay was conducted with sexually mature female FHM following a 7 day exposure 100 ng/L LNG with significant reductions observed in pregnenolone, 17α,20β-dihydroxy-4-pregnen-3-one (17,20-DHP), testosterone, and 11-ketotestosterone. Together these data suggest LNG can negatively impact FHM larval survival and growth, with significant alterations in endocrine related responses. PMID:24503577

  4. Alterations in DNA methylation corresponding with lung inflammation and as a biomarker for disease development after MWCNT exposure.

    PubMed

    Brown, Traci A; Lee, Joong Won; Holian, Andrij; Porter, Virginia; Fredriksen, Harley; Kim, Minju; Cho, Yoon Hee

    2016-05-01

    Use of multi-walled carbon nanotubes (MWCNT) is growing which increases occupational exposures to these materials. Their toxic potential makes it important to have an in-depth understanding of the inflammation and disease that develops due to exposure. Epigenetics is one area of interest that has been quickly developing to assess disease processes due to its ability to change gene expression and thus the lung environment after exposure. In this study, promoter methylation of inflammatory genes (IFN-γ and TNF-α) was measured after MWCNT exposure using the pyrosequencing assay and found to correlate with initial cytokine production. In addition, methylation of a gene involved in tissue fibrosis (Thy-1) was also altered in a way that matched collagen deposition. In addition to using epigenetics to better understand disease processes, it has also been used as a biomarker of exposure and disease. In this study, global methylation was determined in the lung to ascertain whether MWCNT alter global methylation at the site of exposure and if those alterations coincide with disease development. Then, global methylation levels were determined in the blood to ascertain whether global methylation could be used as a biomarker of exposure in a more easily accessible tissue. Using the LuUminometric Methylation Assay (LUMA) and 5-Methylcytosine (5-mC) Quantification assay, we found that MWCNT lead to DNA hypomethylation in the lung and blood, which coincided with disease development. This study provides initial data showing that alterations in gene-specific methylation correspond with an inflammatory response to MWCNT exposure. In addition, global DNA methylation in the lung and blood coincides with MWCNT-induced disease development, suggesting its potential as a biomarker of both exposure and disease development. PMID:26375518

  5. Exposure to Acetylcholinesterase Inhibitors Alters the Physiology and Motor Function of Honeybees

    PubMed Central

    Williamson, Sally M.; Moffat, Christopher; Gomersall, Martha A. E.; Saranzewa, Nastja; Connolly, Christopher N.; Wright, Geraldine A.

    2013-01-01

    Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24 h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15 min. At a 10 nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1 μM concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival. PMID:23386834

  6. Alteration of the aPA ELISA by UV exposure of polystyrene microtiter plates.

    PubMed

    Goldberg, J S; Wagenknecht, D R; McIntyre, J A

    1996-01-01

    Interlaboratory inconsistencies in antiphospholipid antibody (aPA) solid phase assays have prompted controversy in clinical laboratory testing for aPA. We found that the aPA ELISA can be influenced by the type of microtiter plate utilized and by the conditions in which the plates are stored. By exposing 96-well, flat-bottom polystyrene microtiter plates to short wave UV light (254 nm), the aPA ELISA signal decreased in a UV dose-dependent manner. No effect was seen with long wave UV light (366 nm). These results were independent of the antibody isotype under study or the phospholipid (PL) antigen used: anionic phosphatidylserine (PS) and cardiolipin (CL), or zwitterionic phosphatidylethanolamine (PE). Purified human beta 2-glycoprotein I (beta 2 GPI), a known cofactor for anionic PL, and rabbit anti-beta 2 GPI antisera were used to demonstrate that beta 2 GPI bound equally to UV treated and untreated microtiter plates. In contrast, recognition of beta 2 GPI on an anionic PL surface was decreased on UV treated plates, suggesting that UV exposure alters the lipid binding properties of the microliter plate. To determine whether UV exposure inhibited PL binding directly or caused a change in the way the PL was bound, the amount of PL bound to UV treated and untreated plates was measured by using fluorescent labeled PS and a fluorimeter. PS binding was decreased by 53% in UV treated wells as compared to untreated wells. These data show that short wave UV exposure reduces PL binding to polystyrene microtiter plates, thereby reducing the amount of beta 2 GPI bound to PL coated ELISA plates. Thus by using UV exposed microtiter plates, decreased or false-negative a PA ELISA results may be obtained for aPA positive plasmas. PMID:8887002

  7. Follicle-stimulating hormone (FSH) blood test

    MedlinePlus

    ... the test done on certain days of your menstrual cycle. ... In women, FSH helps manage the menstrual cycle and stimulates the ovaries to produce eggs. The test is used to help diagnose or evaluate: Menopause Women who have polycystic ovary ...

  8. Follicle-stimulating hormone (FSH) blood test

    MedlinePlus

    ... Parts of the brain (the pituitary gland or hypothalamus ) not producing normal amounts of some or all ... parts of the brain (the pituitary gland or hypothalamus) do not produce normal amounts of some or ...

  9. FSH (Follicle-Stimulating Hormone) Test

    MedlinePlus

    ... FSH and LH may be ordered when a boy or girl does not appear to be entering puberty at ... hair Growth of the testicles and penis in boys Beginning of menstruation in girls ^ Back to top What does the test result ...

  10. Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain.

    PubMed

    Ngai, Ying Fai; Sulistyoningrum, Dian C; O'Neill, Ryan; Innis, Sheila M; Weinberg, Joanne; Devlin, Angela M

    2015-09-01

    Prenatal alcohol exposure (PAE) programs the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA dysregulation and hyperresponsiveness to stressors in adulthood. Molecular mechanisms mediating these alterations are not fully understood. Disturbances in one-carbon metabolism, a source of methyl donors for epigenetic processes, contributes to alcoholic liver disease. We assessed whether PAE affects one-carbon metabolism (including Mtr, Mat2a, Mthfr, and Cbs mRNA) and programming of HPA function genes (Nr3c1, Nr3c2, and Slc6a4) in offspring from ethanol-fed (E), pair-fed (PF), and ad libitum-fed control (C) dams. At gestation day 21, plasma total homocysteine and methionine concentrations were higher in E compared with C dams, and E fetuses had higher plasma methionine concentrations and lower whole brain Mtr and Mat2a mRNA compared with C fetuses. In adulthood (55 days), hippocampal Mtr and Cbs mRNA was lower in E compared with C males, whereas Mtr, Mat2a, Mthfr, and Cbs mRNA were higher in E compared with C females. We found lower Nr3c1 mRNA and lower nerve growth factor inducible protein A (NGFI-A) protein in the hippocampus of E compared with PF females, whereas hippocampal Slc6a4 mRNA was higher in E than C males. By contrast, hypothalamic Slc6a4 mRNA was lower in E males and females compared with C offspring. This was accompanied by higher hypothalamic Slc6a4 mean promoter methylation in E compared with PF females. These findings demonstrate that PAE is associated with alterations in one-carbon metabolism and has long-term and region-specific effects on gene expression in the brain. These findings advance our understanding of mechanisms of HPA dysregulation associated with PAE. PMID:26180184

  11. Exposure of Persian sturgeon (Acipenser persicus) to cadmium results in biochemical, histological and transcriptional alterations.

    PubMed

    Miandare, Hamed Kolangi; Niknejad, Mahtab; Shabani, Ali; Safari, Roghieh

    2016-01-01

    Sturgeon is one of the endangered families of fish in the Caspian Sea region, where there is up to 80% of their global caching. Unfortunately, in recent years, increase of pollutants has been resulted in their total population reduction. Due to their benthic nature, sturgeons are at great risk of exposing to contaminants such as cadmium. Despite their endangered status in the Caspian Sea, there are only a few studies on characterizing the relative sensitivity of sturgeons to cadmium. Adverse effects associated with pollution on angiogenesis are mediated by hypoxia inducing factor-1 (HIF-1) and vascular endothelial growth factor (VEGF). In this investigation, gene expression of two distinct HIFs-1, HIF-1α and HIF-2α, and VEGF was investigated at the mRNA transcript levels after exposure of Persian sturgeon (Acipenser persicus) to cadmium. VEGF, HIF-1α and HIF-2α expressions in treated Persian sturgeon were greater than controls. Significant increases (P<0.05) were also observed in cortisol and glucose levels compared to the control group especially in the fish exposed to higher cadmium concentration (800 μg/L). Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactic acid dehydrogenase (LDH) levels were increased in the cadmium-exposed fish, although the observed increases were not significant between the control and 200 μg/L cadmium treatment at some sampling time points. Gill tissues also showed histopathological changes in the cadmium treatments. Overall, results indicated that cadmium resulted in some alterations in biochemical parameters, mRNA transcript level expression of two important angiogenesis related genes as well as histological alterations in Persian sturgeon. PMID:26687766

  12. The timing of embryonic exposure to elevated temperature alters stress endocrinology in domestic chickens (Gallus domesticus).

    PubMed

    Wilsterman, Kathryn; Mast, Andrew D; Luu, Thuyvan H; Haussmann, Mark F

    2015-02-01

    Patterns of glucocorticoid (GC) release in response to stimuli vary both among individuals and within individuals across their lifetime. While much work has focused on how the prenatal steroid environment can affect GC release, relatively little is known about how environmental parameters, such as incubation temperature affect GCs. We tested the hypothesis that variation and timing of elevated incubation temperature within the thermoneutral zone can alter the pattern of GC release. We incubated domestic chicken eggs (Gallus domesticus) at the optimal incubation temperature (37.5 °C) or at a slightly higher temperature (+1.1 °C) either early, late, or throughout incubation. At three weeks post-hatch, all birds were (i) exposed to a capture-restraint stress to measure stress-induced GC release (naïve). Three days following the naïve stressor, birds were (ii) exposed to a heat challenge, which was followed the next day by a second capture-restraint stress (post-heat challenge). Regardless of treatment, birds had similar patterns of GC release following the naïve stress series. However, during the post-heat challenge stress series, birds incubated at optimal temperatures increased their peak GC release. In contrast, birds exposed to slightly elevated temperatures for any period of development failed to increase peak GC release, and their specific response varied with timing of exposure to the elevated incubation temperature. Our results demonstrate that subtle variation in the embryonic environment, such as elevated incubation temperature within the thermoneutral zone, can impact the pattern of GC release of offspring. Further work is needed to understand the mechanisms underlying these changes and the relationship between fitness and environmentally-altered phenotypes. PMID:25623149

  13. Exposure to Synthetic Gray Water Inhibits Amoeba Encystation and Alters Expression of Legionella pneumophila Virulence Genes

    PubMed Central

    Lu, Jingrang; Ashbolt, Nicholas J.

    2014-01-01

    Water conservation efforts have focused on gray water (GW) usage, especially for applications that do not require potable water quality. However, there is a need to better understand environmental pathogens and their free-living amoeba (FLA) hosts within GW, given their growth potential in stored gray water. Using synthetic gray water (sGW) we examined three strains of the water-based pathogen Legionella pneumophila and its FLA hosts Acanthamoeba polyphaga, A. castellanii, and Vermamoeba vermiformis. Exposure to sGW for 72 h resulted in significant inhibition (P < 0.0001) of amoebal encystation versus control-treated cells, with the following percentages of cysts in sGW versus controls: A. polyphaga (0.6 versus 6%), A. castellanii (2 versus 62%), and V. vermiformis (1 versus 92%), suggesting sGW induced maintenance of the actively feeding trophozoite form. During sGW exposure, L. pneumophila culturability decreased as early as 5 h (1.3 to 2.9 log10 CFU, P < 0.001) compared to controls (Δ0 to 0.1 log10 CFU) with flow cytometric analysis revealing immediate changes in membrane permeability. Furthermore, reverse transcription-quantitative PCR was performed on total RNA isolated from L. pneumophila cells at 0 to 48 h after sGW incubation, and genes associated with virulence (gacA, lirR, csrA, pla, and sidF), the type IV secretion system (lvrB and lvrE), and metabolism (ccmF and lolA) were all shown to be differentially expressed. These results suggest that conditions within GW may promote interactions between water-based pathogens and FLA hosts, through amoebal encystment inhibition and alteration of bacterial gene expression, thus warranting further exploration into FLA and L. pneumophila behavior in GW systems. PMID:25381242

  14. Exposure of Soil Microbial Communities to Chromium and Arsenic Alters Their Diversity and Structure

    PubMed Central

    Rizvi, Fariha Z.; Rehman, Yasir; Faisal, Muhammad; Hasnain, Shahida; McInerney, Michael J.; Krumholz, Lee R.

    2012-01-01

    Extensive use of chromium (Cr) and arsenic (As) based preservatives from the leather tanning industry in Pakistan has had a deleterious effect on the soils surrounding production facilities. Bacteria have been shown to be an active component in the geochemical cycling of both Cr and As, but it is unknown how these compounds affect microbial community composition or the prevalence and form of metal resistance. Therefore, we sought to understand the effects that long-term exposure to As and Cr had on the diversity and structure of soil microbial communities. Soils from three spatially isolated tanning facilities in the Punjab province of Pakistan were analyzed. The structure, diversity and abundance of microbial 16S rRNA genes were highly influenced by the concentration and presence of hexavalent chromium (Cr (VI)) and arsenic. When compared to control soils, contaminated soils were dominated by Proteobacteria while Actinobacteria and Acidobacteria (which are generally abundant in pristine soils) were minor components of the bacterial community. Shifts in community composition were significant and revealed that Cr (VI)-containing soils were more similar to each other than to As contaminated soils lacking Cr (VI). Diversity of the arsenic resistance genes, arsB and ACR3 were also determined. Results showed that ACR3 becomes less diverse as arsenic concentrations increase with a single OTU dominating at the highest concentration. Chronic exposure to either Cr or As not only alters the composition of the soil bacterial community in general, but affects the arsenic resistant individuals in different ways. PMID:22768219

  15. Exposure of soil microbial communities to chromium and arsenic alters their diversity and structure.

    PubMed

    Sheik, Cody S; Mitchell, Tyler W; Rizvi, Fariha Z; Rehman, Yasir; Faisal, Muhammad; Hasnain, Shahida; McInerney, Michael J; Krumholz, Lee R

    2012-01-01

    Extensive use of chromium (Cr) and arsenic (As) based preservatives from the leather tanning industry in Pakistan has had a deleterious effect on the soils surrounding production facilities. Bacteria have been shown to be an active component in the geochemical cycling of both Cr and As, but it is unknown how these compounds affect microbial community composition or the prevalence and form of metal resistance. Therefore, we sought to understand the effects that long-term exposure to As and Cr had on the diversity and structure of soil microbial communities. Soils from three spatially isolated tanning facilities in the Punjab province of Pakistan were analyzed. The structure, diversity and abundance of microbial 16S rRNA genes were highly influenced by the concentration and presence of hexavalent chromium (Cr (VI)) and arsenic. When compared to control soils, contaminated soils were dominated by Proteobacteria while Actinobacteria and Acidobacteria (which are generally abundant in pristine soils) were minor components of the bacterial community. Shifts in community composition were significant and revealed that Cr (VI)-containing soils were more similar to each other than to As contaminated soils lacking Cr (VI). Diversity of the arsenic resistance genes, arsB and ACR3 were also determined. Results showed that ACR3 becomes less diverse as arsenic concentrations increase with a single OTU dominating at the highest concentration. Chronic exposure to either Cr or As not only alters the composition of the soil bacterial community in general, but affects the arsenic resistant individuals in different ways. PMID:22768219

  16. Tobacco Smoke Exposure and Altered Nasal Responses to Live Attenuated Influenza Virus

    PubMed Central

    Noah, Terry L.; Zhou, Haibo; Monaco, Jane; Horvath, Katie; Herbst, Margaret; Jaspers, Ilona

    2011-01-01

    Background Epidemiologic evidence links tobacco smoke and increased risk for influenza in humans, but the specific host defense pathways involved are unclear. Objective We developed a model to examine influenza-induced innate immune responses in humans and test the hypothesis that exposure to cigarette smoke alters nasal inflammatory and antiviral responses to live attenuated influenza virus (LAIV). Methods This was an observational cohort study comparing nasal mucosal responses to LAIV among young adult active smokers (n = 17), nonsmokers exposed to secondhand smoke (SHS; n = 20), and unexposed controls (n = 23). Virus RNA and inflammatory factors were measured in nasal lavage fluids (NLF) serially after LAIV inoculation. For key end points, peak and total (area under curve) responses were compared among groups. Results Compared with controls, NLF interleukin-6 (IL-6) responses to LAIV (peak and total) were suppressed in smokers. Virus RNA in NLF cells was significantly increased in smokers, as were interferon-inducible protein 10:virus ratios. Responses in SHS-exposed subjects were generally intermediate between controls and smokers. We observed significant associations between urine cotinine and NLF IL-6 responses (negative correlation) or virus RNA in NLF cells (positive correlation) for all subjects combined. Conclusions Nasal inoculation with LAIV results in measurable inflammatory and antiviral responses in human volunteers, thus providing a model for investigating environmental effects on influenza infections in humans. Exposure to cigarette smoke was associated with suppression of specific nasal inflammatory and antiviral responses, as well as increased virus quantity, after nasal inoculation with LAIV. These data suggest mechanisms for increased susceptibility to influenza infection among persons exposed to tobacco smoke. PMID:20920950

  17. TIME-DEPENDENT EFFECTS ON GENE EXPRESSION IN RAT SEMINAL VESICLE DEVELOPMENTALLY ALTERED BY IN UTERO EXPOSURE TO TCDD

    EPA Science Inventory

    TIME-DEPENDENT EFFECTS ON GENE EXPRESSION IN RAT SEMINAL VESICLE DEVELOPMENTALLY ALTERED BY IN UTERO EXPOSURE TO TCDD. V M Richardson', J T Hamm2, and L S Birnbaum1. 'USEPA, ORD/NHEERL/ETD, Research Triangle Park, NC, USA, 'Curriculum in Toxicology, University of North Carolina, ...

  18. Adaptations of the vestibular system to short and long-term exposures to altered gravity

    NASA Astrophysics Data System (ADS)

    Bruce, L.

    Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival. We are studying two aspects of this vestibular adaptation: (1) How does long-term exposure to microgravity and hypergravity affect the development of vestibular afferents? (2) How does short- term exposure to extremely rapid changes in gravity, such as those that occur during launch and landing, affect the vestibular system. During space flight the gravistatic receptors in the otolith organs are effectively unloaded. In hypergravity conditions they are overloaded. However, the angular acceleration receptors of the semicircular canals receive relatively normal stimulation in both micro- and hypergravity.Rat embryos exposed to microgravity from gestation day 10 (prior to vestibular function) until gestation day 20 (vestibular system is somewhat functional) showed that afferents from the posterior vertical canal projecting to the medial vestibular nucleus developed similarly in microgravity, hypergravity, and in controls . However, afferents from the saccule showed delayed development in microgravity as compared to development in hypergravity and in controls. Cerebellar plasticity is crucial for modification of sensory-motor control and learning. Thus we explored the possibility that strong vestibular stimuli would modify cerebellar motor control (i.e., eye movement, postural control, gut motility) by altering the morphology of cerebellar Purkinje cells. To study the effects of short-term exposures to strong vestibular stimuli we focused on structural changes in the vestibulo-cerebellum that are caused by strong vestibular stimuli. Adult mice were exposed to various combinations of constant and/or rapidly changing angular and linear accelerations for 8.5 min (the time length of shuttle launch). Our data shows that these stimuli cause intense excitation of cerebellar Purkinje cells, inducing up-regulation of clathrin-mediated endocytosis

  19. Microbial exposure alters HIV-1-induced mucosal CD4+ T cell death pathways Ex vivo

    PubMed Central

    2014-01-01

    bystander CD4+ T cells, but microbial exposure shifted the PCD mechanism toward apoptosis of productively infected T cells. These results suggest that mucosal CD4+ T cell death pathways may be altered in HIV-infected individuals after gut barrier function is compromised, with potential consequences for mucosal inflammation, viral dissemination and systemic immune activation. PMID:24495380

  20. Prenatal exposure to gamma/neutron irradiation: Sensorimotor alterations and paradoxical effects on learning

    SciTech Connect

    Di Cicco, D.; Antal, S.; Ammassari-Teule, M. )

    1991-01-01

    The effects of prenatal exposure on gamma/neutron radiations (0.5 Gy at about the 18th day of fetal life) were studied in a hybrid strain of mice (DBA/Cne males x C57BL/Cne females). During ontogeny, measurements of sensorimotor reflexes revealed in prenatally irradiated mice (1) a delay in sensorial development, (2) deficits in tests involving body motor control, and (3) a reduction of both motility and locomotor activity scores. In adulthood, the behaviour of prenatally irradiated and control mice was examined in the open field test and in reactivity to novelty. Moreover, their learning performance was compared in several situations. The results show that, in the open field test, only rearings were more frequent in irradiated mice. In the presence of a novel object, significant sex x treatment interactions were observed since ambulation and leaning against the novel object increased in irradiated females but decreased in irradiated males. Finally, when submitted to different learning tasks, irradiated mice were impaired in the radial maze, but paradoxically exhibited higher avoidance scores than control mice, possibly because of their low pain thresholds. Taken together, these observations indicate that late prenatal gamma/neutron irradiation induces long lasting alterations at the sensorimotor level which, in turn, can influence learning abilities of adult mice.

  1. Prenatal nicotine exposure alters respiratory long term facilitation in neonatal rats

    PubMed Central

    Fuller, DD; Dougherty, BJ; Sandhu, MS; Doperalski, NJ; Reynolds, CR; Hayward, LF

    2009-01-01

    Intermittent hypoxia can evoke persistent increases in ventilation (ν̇ E) in neonates (i.e. long-term facilitation, LTF) (Julien et al. Am J Physiol Regul Integr Comp Physiol 294: R1356–R1366, 2008). Since prenatal nicotine (PN) exposure alters neonatal respiratory control (Fregosi & Pilarski. Respir. Physiol. Neurobiol. 164: 80–86, 2008), we hypothesized that PN would influence LTF of ventilation (ν̇ E) in neonatal rats. An osmotic minipump delivered nicotine (6 mg/kg/day) or saline to pregnant dams. ν̇ E was assessed in unanesthetized pups via whole body plethysmography at post-natal (P) days 9–11 or 15–17 during baseline (BL, 21% O2), hypoxia (10 × 5 min, 5% O2) and 30 min post-hypoxia. PN pups had reduced BL ν̇ E (p<0.05) but greater increases in ν̇ E during hypoxia (p<0.05). Post-hypoxia ν̇ E (i.e. LTF) showed an age × treatment interaction (p<0.01) with similar values at P9-11 but enhanced LTF in saline (30±8 %BL) vs. PN pups (6±5 %BL; p=0.01) at P15-17. We conclude that the post-natal developmental time course of hypoxia-induced LTF is influenced by PN. PMID:19818419

  2. Ethanol Exposure Alters Protein Expression in a Mouse Model of Fetal Alcohol Spectrum Disorders

    PubMed Central

    Mason, Stephen; Anthony, Bruce; Lai, Xianyin; Ringham, Heather N.; Wang, Mu; Witzmann, Frank A.; You, Jin-Sam; Zhou, Feng C.

    2012-01-01

    Alcohol exposure during development can result in variable growth retardation and facial dysmorphology known as fetal alcohol spectrum disorders. Although the mechanisms underlying the disorder are not fully understood, recent progress has been made that alcohol induces aberrant changes in gene expression and in the epigenome of embryos. To inform the gene and epigenetic changes in alcohol-induced teratology, we used whole-embryo culture to identify the alcohol-signature protein profile of neurulating C6 mice. Alcohol-treated and control cultures were homogenized, isoelectrically focused, and loaded for 2D gel electrophoresis. Stained gels were cross matched with analytical software. We identified 40 differentially expressed protein spots (P < 0.01), and 9 spots were selected for LC/MS-MS identification. Misregulated proteins include serotransferrin, triosephosphate isomerase and ubiquitin-conjugating enzyme E2 N. Misregulation of serotransferrin and triosephosphate isomerase was confirmed with immunologic analysis. Alteration of proteins with roles in cellular function, cell cycle, and the ubiquitin-proteasome pathway was induced by alcohol. Several misregulated proteins interact with effectors of the NF-κB and Myc transcription factor cascades. Using a whole-embryo culture, we have identified misregulated proteins known to be involved in nervous system development and function. PMID:22745907

  3. Acute exposure to pure cylindrospermopsin results in oxidative stress and pathological alterations in tilapia (Oreochromis niloticus).

    PubMed

    Puerto, María; Jos, Angeles; Pichardo, Silvia; Moyano, Rosario; Blanco, Alfonso; Cameán, Ana M

    2014-04-01

    Cylindrospermopsin (CYN) is increasingly recognized as a potential threat to drinking water safety, due to its ubiquity. This cyanotoxin has been found to cause toxic effects in mammals, and although fish could be in contact with this toxin, acute toxicity studies on fish are nonexistent. This is the first study showing that single doses of CYN pure standard (200 or 400 μg CYN/kg fish bw) by oral route (gavage) generate histopathological effects in fish (Tilapia-Oreochromis niloticus) exposed to the toxin under laboratory condition. Among the morphological changes, disorganized parenchymal architecture in the liver, dilated Bowman's space in the kidney, fibrolysis in the heart, necrotic enteritis in the intestines, and hemorrhages in the gills, were observed. Moreover, some oxidative stress biomarkers in the liver and kidney of tilapias were altered. Thus, CYN exposure induced increased protein oxidation products in both organs, NADPH oxidase activity was significantly increased with the kidney being the most affected organ, and decreased GSH contents were also detected in both organs, at the higher dose assayed. PMID:22331699

  4. Characterization of proteome alterations in Phanerochaete chrysosporium in response to lead exposure

    PubMed Central

    2011-01-01

    Background Total soluble proteome alterations of white rot fungus Phanerochaete chrysosporium in response to different doses (25, 50 and 100 μM) of Pb (II) were characterized by 2DE in combination with MALDI-TOF-MS. Results Dose-dependent molecular response to Pb (II) involved a total of 14 up-regulated and 21 down-regulated proteins. The induction of an isoform of glyceraldehyde 3-phosphate dehydrogenase, alcohol dehydrogenase class V, mRNA splicing factor, ATP-dependent RNA helicase, thioredoxin reductase and actin required a Pb (II) dose of at least 50 μM. Analysis of the proteome dynamics of mid-exponential phase cells of P. chrysosporium subjected to 50 μM lead at exposure time intervals of 1, 2, 4 and 8 h, identified a total of 23 proteins in increased and 67 proteins in decreased amount. Overall, the newly induced/strongly up-regulated proteins involved in (i) amelioration of lipid peroxidation products, (ii) defense against oxidative damage and redox metabolism, (iii) transcription, recombination and DNA repair (iv) a yet unknown function represented by a putative protein. Conclusion The present study implicated the particular role of the elements of DNA repair, post-tanscriptional regulation and heterotrimeric G protein signaling in response to Pb (II) stress as shown for the first time for a basidiomycete. PMID:21388532

  5. Long-term in vivo polychlorinated biphenyl 126 exposure induces oxidative stress and alters proteomic profile on islets of Langerhans

    PubMed Central

    Loiola, Rodrigo Azevedo; dos Anjos, Fabyana Maria; Shimada, Ana Lúcia; Cruz, Wesley Soares; Drewes, Carine Cristiane; Rodrigues, Stephen Fernandes; Cardozo, Karina Helena Morais; Carvalho, Valdemir Melechco; Pinto, Ernani; Farsky, Sandra Helena

    2016-01-01

    It has been recently proposed that exposure to polychlorinated biphenyls (PCBs) is a risk factor to type 2 diabetes mellitus (DM2). We investigated this hypothesis using long-term in vivo PCB126 exposure to rats addressing metabolic, cellular and proteomic parameters. Male Wistar rats were exposed to PCB126 (0.1, 1 or 10 μg/kg of body weight/day; for 15 days) or vehicle by intranasal instillation. Systemic alterations were quantified by body weight, insulin and glucose tolerance, and blood biochemical profile. Pancreatic toxicity was measured by inflammatory parameters, cell viability and cycle, free radical generation, and proteomic profile on islets of Langerhans. In vivo PCB126 exposure enhanced the body weight gain, impaired insulin sensitivity, reduced adipose tissue deposit, and elevated serum triglycerides, cholesterol, and insulin levels. Inflammatory parameters in the pancreas and cell morphology, viability and cycle were not altered in islets of Langerhans. Nevertheless, in vivo PCB126 exposure increased free radical generation and modified the expression of proteins related to oxidative stress on islets of Langerhans, which are indicative of early β-cell failure. Data herein obtained show that long-term in vivo PCB126 exposure through intranasal route induced alterations on islets of Langerhans related to early end points of DM2. PMID:27292372

  6. Long-term in vivo polychlorinated biphenyl 126 exposure induces oxidative stress and alters proteomic profile on islets of Langerhans.

    PubMed

    Loiola, Rodrigo Azevedo; Dos Anjos, Fabyana Maria; Shimada, Ana Lúcia; Cruz, Wesley Soares; Drewes, Carine Cristiane; Rodrigues, Stephen Fernandes; Cardozo, Karina Helena Morais; Carvalho, Valdemir Melechco; Pinto, Ernani; Farsky, Sandra Helena

    2016-01-01

    It has been recently proposed that exposure to polychlorinated biphenyls (PCBs) is a risk factor to type 2 diabetes mellitus (DM2). We investigated this hypothesis using long-term in vivo PCB126 exposure to rats addressing metabolic, cellular and proteomic parameters. Male Wistar rats were exposed to PCB126 (0.1, 1 or 10 μg/kg of body weight/day; for 15 days) or vehicle by intranasal instillation. Systemic alterations were quantified by body weight, insulin and glucose tolerance, and blood biochemical profile. Pancreatic toxicity was measured by inflammatory parameters, cell viability and cycle, free radical generation, and proteomic profile on islets of Langerhans. In vivo PCB126 exposure enhanced the body weight gain, impaired insulin sensitivity, reduced adipose tissue deposit, and elevated serum triglycerides, cholesterol, and insulin levels. Inflammatory parameters in the pancreas and cell morphology, viability and cycle were not altered in islets of Langerhans. Nevertheless, in vivo PCB126 exposure increased free radical generation and modified the expression of proteins related to oxidative stress on islets of Langerhans, which are indicative of early β-cell failure. Data herein obtained show that long-term in vivo PCB126 exposure through intranasal route induced alterations on islets of Langerhans related to early end points of DM2. PMID:27292372

  7. Long-term in vivo polychlorinated biphenyl 126 exposure induces oxidative stress and alters proteomic profile on islets of Langerhans

    NASA Astrophysics Data System (ADS)

    Loiola, Rodrigo Azevedo; Dos Anjos, Fabyana Maria; Shimada, Ana Lúcia; Cruz, Wesley Soares; Drewes, Carine Cristiane; Rodrigues, Stephen Fernandes; Cardozo, Karina Helena Morais; Carvalho, Valdemir Melechco; Pinto, Ernani; Farsky, Sandra Helena

    2016-06-01

    It has been recently proposed that exposure to polychlorinated biphenyls (PCBs) is a risk factor to type 2 diabetes mellitus (DM2). We investigated this hypothesis using long-term in vivo PCB126 exposure to rats addressing metabolic, cellular and proteomic parameters. Male Wistar rats were exposed to PCB126 (0.1, 1 or 10 μg/kg of body weight/day; for 15 days) or vehicle by intranasal instillation. Systemic alterations were quantified by body weight, insulin and glucose tolerance, and blood biochemical profile. Pancreatic toxicity was measured by inflammatory parameters, cell viability and cycle, free radical generation, and proteomic profile on islets of Langerhans. In vivo PCB126 exposure enhanced the body weight gain, impaired insulin sensitivity, reduced adipose tissue deposit, and elevated serum triglycerides, cholesterol, and insulin levels. Inflammatory parameters in the pancreas and cell morphology, viability and cycle were not altered in islets of Langerhans. Nevertheless, in vivo PCB126 exposure increased free radical generation and modified the expression of proteins related to oxidative stress on islets of Langerhans, which are indicative of early β-cell failure. Data herein obtained show that long-term in vivo PCB126 exposure through intranasal route induced alterations on islets of Langerhans related to early end points of DM2.

  8. Inhalation exposure of rats to asphalt fumes generated at paving temperatures alters pulmonary xenobiotic metabolism pathways without lung injury.

    PubMed Central

    Ma, Jane Y C; Rengasamy, Apavoo; Frazer, Dave; Barger, Mark W; Hubbs, Ann F; Battelli, Lori; Tomblyn, Seith; Stone, Samuel; Castranova, Vince

    2003-01-01

    Asphalt fumes are complex mixtures of various organic compounds, including polycyclic aromatic hydrocarbons (PAHs). PAHs require bioactivation by the cytochrome P-450 monooxygenase system to exert toxic/carcinogenic effects. The present study was carried out to characterize the acute pulmonary inflammatory responses and the alterations of pulmonary xenobiotic pathways in rats exposed to asphalt fumes by inhalation. Rats were exposed at various doses and time periods to air or to asphalt fumes generated at paving temperatures. To assess the acute damage and inflammatory responses, differential cell counts, acellular lactate dehydrogenase (LDH) activity, and protein content of bronchoalveolar lavage fluid were determined. Alveolar macrophage (AM) function was assessed by monitoring generation of chemiluminescence and production of tumor necrosis factor-alpha and interleukin-1. Alteration of pulmonary xenobiotic pathways was determined by monitoring the protein levels and activities of P-450 isozymes (CYP1A1 and CYP2B1), glutathioneS-transferase (GST), and NADPH:quinone oxidoreductase (QR). The results show that acute asphalt fume exposure did not cause neutrophil infiltration, alter LDH activity or protein content, or affect AM function, suggesting that short-term asphalt fume exposure did not induce acute lung damage or inflammation. However, acute asphalt fume exposure significantly increased the activity and protein level of CYP1A1 whereas it markedly reduced the activity and protein level of CYP2B1 in the lung. The induction of CYP1A1 was localized in nonciliated bronchiolar epithelial (Clara) cells, alveolar septa, and endothelial cells by immunofluorescence microscopy. Cytosolic QR activity was significantly elevated after asphalt fume exposure, whereas GST activity was not affected by the exposure. This induction of CYP1A1 and QR with the concomitant down-regulation of CYP2B1 after asphalt fume exposure could alter PAH metabolism and may lead to potential

  9. Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation.

    PubMed

    Szutorisz, Henrietta; DiNieri, Jennifer A; Sweet, Eric; Egervari, Gabor; Michaelides, Michael; Carter, Jenna M; Ren, Yanhua; Miller, Michael L; Blitzer, Robert D; Hurd, Yasmin L

    2014-05-01

    Recent attention has been focused on the long-term impact of cannabis exposure, for which experimental animal studies have validated causal relationships between neurobiological and behavioral alterations during the individual's lifetime. Here, we show that adolescent exposure to Δ(9)-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, results in behavioral and neurobiological abnormalities in the subsequent generation of rats as a consequence of parental germline exposure to the drug. Adult F1 offspring that were themselves unexposed to THC displayed increased work effort to self-administer heroin, with enhanced stereotyped behaviors during the period of acute heroin withdrawal. On the molecular level, parental THC exposure was associated with changes in the mRNA expression of cannabinoid, dopamine, and glutamatergic receptor genes in the striatum, a key component of the neuronal circuitry mediating compulsive behaviors and reward sensitivity. Specifically, decreased mRNA and protein levels, as well as NMDA receptor binding were observed in the dorsal striatum of adult offspring as a consequence of germline THC exposure. Electrophysiologically, plasticity was altered at excitatory synapses of the striatal circuitry that is known to mediate compulsive and goal-directed behaviors. These findings demonstrate that parental history of germline THC exposure affects the molecular characteristics of the striatum, can impact offspring phenotype, and could possibly confer enhanced risk for psychiatric disorders in the subsequent generation. PMID:24385132

  10. Prenatal diazepam exposure alters respiratory control system and GABAA and adenosine receptor gene expression in newborn rats.

    PubMed

    Picard, Nathalie; Guénin, Stéphanie; Perrin, Yolande; Hilaire, Gérard; Larnicol, Nicole

    2008-07-01

    In experimental animals, prenatal diazepam exposure has clearly been associated with behavioral disturbances. Its impact on newborn breathing has not been documented despite potential deleterious consequences for later brain development. We addressed this issue in neonatal rats (0-2 d) born from dams, which consumed 2 mg/kg/d diazepam via drinking fluid throughout gestation. In vivo, prenatal diazepam exposure significantly altered the normoxic-breathing pattern, lowering breathing frequency (105 vs. 125 breaths/min) and increasing tidal volume (16.2 vs. 12.7 mL/kg), and the ventilatory response to hypoxia, inducing an immediate and marked decrease in tidal volume (-30%) absent in controls. In vitro, prenatal diazepam exposure significantly increased the respiratory-like frequency produced by pontomedullary and medullary preparations (+38% and +19%, respectively) and altered the respiratory-like response to application of nonoxygenated superfusate. Both in vivo and in vitro, the recovery from oxygen deprivation challenges was delayed by prenatal diazepam exposure. Finally, real-time PCR showed that prenatal diazepam exposure affected mRNA levels of alpha1 and alpha2 GABAA receptor subunits and of A1 and A2A adenosine receptors in the brainstem. These mRNA changes, which are region-specific, suggest that prenatal diazepam exposure interferes with developmental events whose impact on the respiratory system maturation deserves further studies. PMID:18360306

  11. Binge Toluene Exposure Alters Glutamate, Glutamine and GABA in the Adolescent Rat Brain as Measured by Proton Magnetic Resonance Spectroscopy*

    PubMed Central

    Perrine, Shane A.; O'Leary-Moore, Shonagh K.; Galloway, Matthew P.; Hannigan, John H.; Bowen, Scott E.

    2010-01-01

    Despite the high incidence of toluene abuse in adolescents, little is known regarding the effect of binge exposure on neurochemical profiles during this developmental stage. In the current study, the effects of binge toluene exposure during adolescence on neurotransmitter levels were determined using high-resolution proton magnetic resonance spectroscopy ex vivo at 11.7 T. Adolescent male Sprague-Dawley rats were exposed to toluene (0, 8,000 , or 12,000 ppm) for 15 min twice daily from postnatal day 28 (P28) through P34 and then euthanized either one or seven days later (on P35 or P42) to assess glutamate, glutamine, and GABA levels in intact tissue punches from the medial prefrontal cortex (mPFC), anterior striatum and hippocampus. In the mPFC, toluene reduced glutamate one day after exposure, with no effect on GABA, while after seven days, glutamate was no longer affected but there was an increase in GABA levels. In the hippocampus, neither GABA nor glutamate was altered one day after exposure, whereas seven days after exposure, increases were observed in GABA and glutamate. Striatal glutamate and GABA levels measured after either one or seven days were not altered after toluene exposure. These findings show that one week of binge toluene inhalation selectively alters these neurotransmitters in the mPFC and hippocampus in adolescent rats, and that some of these effects endure at least one week after the exposure. The results suggest that age-dependent, differential neurochemical responses to toluene may contribute to the unique behavioral patterns associated with drug abuse among older children and young teens. PMID:21126832

  12. Association between occupational exposure to benzene and chromosomal alterations in lymphocytes of Brazilian petrochemical workers removed from exposure.

    PubMed

    Gonçalves, Rozana Oliveira; de Almeida Melo, Neli; Rêgo, Marco Antônio Vasconcelos

    2016-06-01

    We aimed to investigate the association between chronic exposure to benzene and genotoxicity in the lymphocytes of workers removed from exposure. The study included 20 workers with hematological disorders who had previously worked in the petrochemical industry of Salvador, Bahia, Brazil; 16 workers without occupational exposure to benzene served as the control group. Chromosomal analysis was performed on lymphocytes from peripheral blood, to assess chromosomal breaks and gaps and to identify aneuploidy. The Kruskal-Wallis test was used to compare the mean values between two groups, and Student's t test for comparison of two independent means. The frequency of gaps was statistically higher in and the exposed group than in the controls (2.13 ± 2.86 vs. 0.97 ± 1.27, p = 0.001). The frequency of chromosomal breaks was significantly higher among cases (0.21 ± 0.58) than among controls (0.12 ± 0.4) (p = 0.0002). An association was observed between chromosomal gaps and breaks and occupational exposure to benzene. Our study showed that even when removed from exposure for several years, workers still demonstrated genotoxic damage. Studies are still needed to clarify the long-term genotoxic potential of benzene after removal from exposure. PMID:27155858

  13. Alteration of Bacterial Antibiotic Sensitivity After Short-Term Exposure to Diagnostic Ultrasound

    PubMed Central

    Mortazavi, Seyed Mohammad Javad; Darvish, Leili; Abounajmi, Mohammad; Zarei, Samira; Zare, Tahereh; Taheri, Mohammad; Nematollahi, Samaneh

    2015-01-01

    inhibition zones in exposed and non-exposed samples of Klebsiella pneumonia and Streptococcus. Conclusions This study clearly shows that short-term exposure of microorganisms to diagnostic ultrasonic waves can significantly alter their sensitivity to antibiotics. We believe that this physical method of making the antibiotic-resistant population susceptible can open new horizons in antibiotic therapy of a broad range of diseases, including tuberculosis. PMID:26732124

  14. Acute Exposure to Microcystin-Producing Cyanobacterium Microcystis aeruginosa Alters Adult Zebrafish (Danio rerio) Swimming Performance Parameters

    PubMed Central

    Kist, Luiza Wilges; Piato, Angelo Luis; da Rosa, João Gabriel Santos; Koakoski, Gessi; Barcellos, Leonardo José Gil; Yunes, João Sarkis; Bonan, Carla Denise; Bogo, Maurício Reis

    2011-01-01

    Microcystins (MCs) are toxins produced by cyanobacteria (blue-green algae), primarily Microcystis aeruginosa, forming water blooms worldwide. When an organism is exposed to environmental perturbations, alterations in normal behavioral patterns occur. Behavioral repertoire represents the consequence of a diversity of physiological and biochemical alterations. In this study, we assessed behavioral patterns and whole-body cortisol levels of adult zebrafish (Danio rerio) exposed to cell culture of the microcystin-producing cyanobacterium M. aeruginosa (MC-LR, strain RST9501). MC-LR exposure (100 μg/L) decreased by 63% the distance traveled and increased threefold the immobility time when compared to the control group. Interestingly, no significant alterations in the number of line crossings were found at the same MC-LR concentration and time of exposure. When animals were exposed to 50 and 100 μg/L, MC-LR promoted a significant increase (around 93%) in the time spent in the bottom portion of the tank, suggesting an anxiogenic effect. The results also showed that none of the MC-LR concentrations tested promoted significant alterations in absolute turn angle, path efficiency, social behavior, or whole-body cortisol level. These findings indicate that behavior is susceptible to MC-LR exposure and provide evidence for a better understanding of the ecological consequences of toxic algal blooms. PMID:22253623

  15. An embryonic atrazine exposure results in reproductive dysfunction in adult zebrafish and morphological alterations in their offspring.

    PubMed

    Wirbisky, Sara E; Weber, Gregory J; Sepúlveda, Maria S; Lin, Tsang-Long; Jannasch, Amber S; Freeman, Jennifer L

    2016-01-01

    The herbicide atrazine, a suspected endocrine disrupting chemical (EDC), frequently contaminates potable water supplies. Studies suggest alterations in the neuroendocrine system along the hypothalamus-pituitary-gonadal axis; however, most studies address either developmental, pubertal, or adulthood exposures, with few investigations regarding a developmental origins hypothesis. In this study, zebrafish were exposed to 0, 0.3, 3, or 30 parts per billion (ppb) atrazine through embryogenesis and then allowed to mature with no additional chemical exposure. Reproductive function, histopathology, hormone levels, offspring morphology, and the ovarian transcriptome were assessed. Embryonic atrazine exposure resulted in a significant increase in progesterone levels in the 3 and 30 ppb groups. A significant decrease in spawning and a significant increase in follicular atresia in the 30 ppb group were observed. In offspring, a decrease in the head length to body ratio in the 30 ppb group, along with a significant increase in head width to body ratio in the 0.3 and 3 ppb groups occurred. Transcriptomic alterations involved genes associated with endocrine system development and function, tissue development, and behavior. This study provides evidence to support atrazine as an EDC causing reproductive dysfunction and molecular alterations in adults exposed only during embryogenesis and morphological alterations in their offspring. PMID:26891955

  16. An embryonic atrazine exposure results in reproductive dysfunction in adult zebrafish and morphological alterations in their offspring

    PubMed Central

    Wirbisky, Sara E.; Weber, Gregory J.; Sepúlveda, Maria S.; Lin, Tsang-Long; Jannasch, Amber S.; Freeman, Jennifer L.

    2016-01-01

    The herbicide atrazine, a suspected endocrine disrupting chemical (EDC), frequently contaminates potable water supplies. Studies suggest alterations in the neuroendocrine system along the hypothalamus-pituitary-gonadal axis; however, most studies address either developmental, pubertal, or adulthood exposures, with few investigations regarding a developmental origins hypothesis. In this study, zebrafish were exposed to 0, 0.3, 3, or 30 parts per billion (ppb) atrazine through embryogenesis and then allowed to mature with no additional chemical exposure. Reproductive function, histopathology, hormone levels, offspring morphology, and the ovarian transcriptome were assessed. Embryonic atrazine exposure resulted in a significant increase in progesterone levels in the 3 and 30 ppb groups. A significant decrease in spawning and a significant increase in follicular atresia in the 30 ppb group were observed. In offspring, a decrease in the head length to body ratio in the 30 ppb group, along with a significant increase in head width to body ratio in the 0.3 and 3 ppb groups occurred. Transcriptomic alterations involved genes associated with endocrine system development and function, tissue development, and behavior. This study provides evidence to support atrazine as an EDC causing reproductive dysfunction and molecular alterations in adults exposed only during embryogenesis and morphological alterations in their offspring. PMID:26891955

  17. Honey Bee Gut Microbiome Is Altered by In-Hive Pesticide Exposures.

    PubMed

    Kakumanu, Madhavi L; Reeves, Alison M; Anderson, Troy D; Rodrigues, Richard R; Williams, Mark A

    2016-01-01

    Honey bees (Apis mellifera) are the primary pollinators of major horticultural crops. Over the last few decades, a substantial decline in honey bees and their colonies have been reported. While a plethora of factors could contribute to the putative decline, pathogens, and pesticides are common concerns that draw attention. In addition to potential direct effects on honey bees, indirect pesticide effects could include alteration of essential gut microbial communities and symbionts that are important to honey bee health (e.g., immune system). The primary objective of this study was to determine the microbiome associated with honey bees exposed to commonly used in-hive pesticides: coumaphos, tau-fluvalinate, and chlorothalonil. Treatments were replicated at three independent locations near Blacksburg Virginia, and included a no-pesticide amended control at each location. The microbiome was characterized through pyrosequencing of V2-V3 regions of the bacterial 16S rRNA gene and fungal ITS region. Pesticide exposure significantly affected the structure of bacterial but not fungal communities. The bee bacteriome, similar to other studies, was dominated by sequences derived from Bacilli, Actinobacteria, α-, β-, γ-proteobacteria. The fungal community sequences were dominated by Ascomycetes and Basidiomycetes. The Multi-response permutation procedures (MRPP) and subsequent Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis indicated that chlorothalonil caused significant change to the structure and functional potential of the honey bee gut bacterial community relative to control. Putative genes for oxidative phosphorylation, for example, increased while sugar metabolism and peptidase potential declined in the microbiome of chlorothalonil exposed bees. The results of this field-based study suggest the potential for pesticide induced changes to the honey bee gut microbiome that warrant further investigation. PMID:27579024

  18. Honey Bee Gut Microbiome Is Altered by In-Hive Pesticide Exposures

    PubMed Central

    Kakumanu, Madhavi L.; Reeves, Alison M.; Anderson, Troy D.; Rodrigues, Richard R.; Williams, Mark A.

    2016-01-01

    Honey bees (Apis mellifera) are the primary pollinators of major horticultural crops. Over the last few decades, a substantial decline in honey bees and their colonies have been reported. While a plethora of factors could contribute to the putative decline, pathogens, and pesticides are common concerns that draw attention. In addition to potential direct effects on honey bees, indirect pesticide effects could include alteration of essential gut microbial communities and symbionts that are important to honey bee health (e.g., immune system). The primary objective of this study was to determine the microbiome associated with honey bees exposed to commonly used in-hive pesticides: coumaphos, tau-fluvalinate, and chlorothalonil. Treatments were replicated at three independent locations near Blacksburg Virginia, and included a no-pesticide amended control at each location. The microbiome was characterized through pyrosequencing of V2–V3 regions of the bacterial 16S rRNA gene and fungal ITS region. Pesticide exposure significantly affected the structure of bacterial but not fungal communities. The bee bacteriome, similar to other studies, was dominated by sequences derived from Bacilli, Actinobacteria, α-, β-, γ-proteobacteria. The fungal community sequences were dominated by Ascomycetes and Basidiomycetes. The Multi-response permutation procedures (MRPP) and subsequent Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis indicated that chlorothalonil caused significant change to the structure and functional potential of the honey bee gut bacterial community relative to control. Putative genes for oxidative phosphorylation, for example, increased while sugar metabolism and peptidase potential declined in the microbiome of chlorothalonil exposed bees. The results of this field-based study suggest the potential for pesticide induced changes to the honey bee gut microbiome that warrant further investigation. PMID:27579024

  19. Developmental exposure to chlorpyrifos alters reactivity to environmental and social cues in adolescent mice.

    PubMed

    Ricceri, Laura; Markina, Nadja; Valanzano, Angela; Fortuna, Stefano; Cometa, Maria Francesca; Meneguz, Annarita; Calamandrei, Gemma

    2003-09-15

    Neonatal mice were treated daily on postnatal days (pnds) 1 through 4 or 11 through 14 with the organophosphate pesticide chlorpyrifos (CPF), at doses (1 or 3 mg/kg) that do not evoke systemic toxicity. Brain acetylcholinesterase (AChE) activity was evaluated within 24 h from termination of treatments. Pups treated on pnds 1-4 underwent ultrasonic vocalization tests (pnds 5, 8, and 11) and a homing test (orientation to home nest material, pnd 10). Pups in both treatment schedules were then assessed for locomotor activity (pnd 25), novelty-seeking response (pnd 35), social interactions with an unfamiliar conspecific (pnd 45), and passive avoidance learning (pnd 60). AChE activity was reduced by 25% after CPF 1-4 but not after CPF 11-14 treatment. CPF selectively affected only the G(4) (tetramer) molecular isoform of AChE. Behavioral analysis showed that early CPF treatment failed to affect neonatal behaviors. Locomotor activity on pnd 25 was increased in 11-14 CPF-treated mice at both doses, and CPF-treated animals in both treatment schedules were more active when exposed to environmental novelty in the novelty-seeking test. All CPF-treated mice displayed more agonistic responses, and such effect was more marked in male mice exposed to the low CPF dose on pnds 11-14. Passive avoidance learning was not affected by CPF. These data indicate that developmental exposure to CPF induces long-term behavioral alterations in the mouse species and support the involvement of neural systems in addition to the cholinergic system in the delayed behavioral toxicity of CPF. PMID:13678652

  20. ONTOGENETIC ALTERATIONS IN MOLECULAR AND STRUCTURAL CORRELATES OF DENDRITIC GROWTH FOLLOWING DEVELOPMENTAL EXPOSURE TO POLYCHLORINATED BIPHENYLS.

    EPA Science Inventory

    This is the first report showing both molecular and structural changes in brain following developmental exposure to a neurotoxicant. It is known that perinatal exposure to a neurotoxicant, polychlorinated biphenyls (PCBs), is associated with decreased IQ scores, impaired learnin...

  1. Wastewater treatment plant effluent alters pituitary gland gonadotropin mRNA levels in juvenile coho salmon (Oncorhynchus kisutch).

    PubMed

    Harding, Louisa B; Schultz, Irvin R; da Silva, Denis A M; Ylitalo, Gina M; Ragsdale, Dave; Harris, Stephanie I; Bailey, Stephanie; Pepich, Barry V; Swanson, Penny

    2016-09-01

    It is well known that endocrine disrupting compounds (EDCs) present in wastewater treatment plant (WWTP) effluents interfere with reproduction in fish, including altered gonad development and induction of vitellogenin (Vtg), a female-specific egg yolk protein precursor produced in the liver. As a result, studies have focused on the effects of EDC exposure on the gonad and liver. However, impacts of environmental EDC exposure at higher levels of the hypothalamic-pituitary-gonad axis are less well understood. The pituitary gonadotropins, follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh) are involved in all aspects of gonad development and are subject to feedback from gonadal steroids making them a likely target of endocrine disruption. In this study, the effects of WWTP effluent exposure on pituitary gonadotropin mRNA expression were investigated to assess the utility of Lh beta-subunit (lhb) as a biomarker of estrogen exposure in juvenile coho salmon (Oncorhynchus kisutch). First, a controlled 72-h exposure to 17α-ethynylestradiol (EE2) and 17β-trenbolone (TREN) was performed to evaluate the response of juvenile coho salmon to EDC exposure. Second, juvenile coho salmon were exposed to 0, 20 or 100% effluent from eight WWTPs from the Puget Sound, WA region for 72h. Juvenile coho salmon exposed to 2 and 10ng EE2L(-1) had 17-fold and 215-fold higher lhb mRNA levels relative to control fish. Hepatic vtg mRNA levels were dramatically increased 6670-fold, but only in response to 10ng EE2L(-1) and Fsh beta-subunit (fshb) mRNA levels were not altered by any of the treatments. In the WWTP effluent exposures, lhb mRNA levels were significantly elevated in fish exposed to five of the WWTP effluents. In contrast, transcript levels of vtg were not affected by any of the WWTP effluent exposures. Mean levels of natural and synthetic estrogens in fish bile were consistent with pituitary lhb expression, suggesting that the observed lhb induction may be due to

  2. Associations between personal exposures to VOCs and alterations in cardiovascular physiology: Detroit Exposure and Aerosol Research Study (DEARS) - presentation

    EPA Science Inventory

    Introduction: An adult cohort consisting of 63 participants engaged in the US EPA’s recent Detroit Exposure and Aerosol Research Study (DEARS) and a University of Michigan cardiovascular sub-study conducted during summer and winter periods over 3 years between 2004 and 2007...

  3. Associations between Personal Exposures to VOCs and Alterations in Cardiovascular Physiology: Detroit Exposure and Aerosol Research Study (DEARS)

    EPA Science Inventory

    Background: An adult cohort consisting of 63 participants engaged in the US EPA’s recent Detroit Exposure and Aerosol Research Study (DEARS) and a University of Michigan cardiovascular sub-study conducted during summer and winter periods over 3 years between 2004 and 2007 (5 seas...

  4. Exposure to ozone reduces influenza disease severity and alters distribution of influenza viral antigens in murine lungs.

    PubMed

    Wolcott, J A; Zee, Y C; Osebold, J W

    1982-09-01

    Exposure to ambient levels of ozone (0.5 ppm) was shown to alter the pathogenesis of respiratory infection after aerosol infection of mice with influenza A virus. A semiquantitative method for determination of the sites of virus replication by direct immunofluorescence indicated that exposure to ozone reduced the involvement of respiratory epithelium in the infectious process and resulted in a less widespread infection of the alveolar parenchyma. Furthermore, the ozone-mediated alteration in viral antigen distribution was consistent with significantly reduced influenza disease mortality and prolonged survival time, but only when the oxidant was present during the course of infection. Reduced disease severity in ozone-exposed animals appeared to be independent of peak pulmonary virus titers, pulmonary interferon titers, and pulmonary and serum-neutralizing antibody titers. These studies suggested that the distribution of influenza virus in the murine lung was a key factor in disease severity. PMID:6182839

  5. In vivo hydroquinone exposure alters circulating neutrophil activities and impairs LPS-induced lung inflammation in mice.

    PubMed

    Ribeiro, André Luiz Teroso; Shimada, Ana Lúcia Borges; Hebeda, Cristina Bichels; de Oliveira, Tiago Franco; de Melo Loureiro, Ana Paula; Filho, Walter Dos Reis Pereira; Santos, Alcinéa Meigikos Dos Anjos; de Lima, Wothan Tavares; Farsky, Sandra Helena Poliselli

    2011-10-01

    Hydroquinone (HQ) is an environmental contaminant which causes immune toxicity. In this study, the effects of exposure to low doses of HQ on neutrophil mobilization into the LPS-inflamed lung were investigated. Male Swiss mice were exposed to aerosolized vehicle (control) or 12.5, 25 or 50ppm HQ (1h/day for 5 days). One hour later, oxidative burst, cell cycle, DNA fragmentation and adhesion molecules expressions in circulating neutrophils were determined by flow cytometry, and plasma malondialdehyde (MDA) levels were measured by HPLC. Also, 1h later the last exposures, inflammation was induced by LPS inhalation (0.1mg/ml/10min) and 3h later, the numbers of leukocytes in peripheral blood and in the bronchoalveolar lavage fluid (BALF) were determined using a Neubauer chamber and stained smears; adhesion molecules expressed on lung microvessel endothelial cells were quantified by immunohistochemistry; myeloperoxidase (MPO) activity was measured in the lung tissue by colorimetric assay; and cytokines in the BALF were determined by ELISA. In vivo HQ exposure augmented plasma MDA levels and oxidative activity of neutrophils, but did not cause alterations in cell cycle and DNA fragmentation. Under these conditions, the number of circulating leukocytes was not altered, but HQ exposure reduced LPS-induced neutrophil migration into the alveolar space, as these cells remained in the lung tissue. The impaired neutrophil migration into BALF may not be dependent on reduced cytokines secretions in the BALF and lung endothelial adhesion molecules expressions. However, HQ exposure increased the expression of β(2) and β(3) integrins and platelet-endothelial cell adhesion molecule-1 (PECAM-1) in neutrophils, which were not further enhanced by fMLP in vitro stimulation, indicating that HQ exposure activates circulating neutrophils, impairing further stimulatory responses. Therefore, it has been shown, for the first time, that neutrophils are target of lower levels of in vivo HQ

  6. Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons

    PubMed Central

    de Salas-Quiroga, Adán; Díaz-Alonso, Javier; García-Rincón, Daniel; Remmers, Floortje; Vega, David; Gómez-Cañas, María; Lutz, Beat; Guzmán, Manuel; Galve-Roperh, Ismael

    2015-01-01

    The CB1 cannabinoid receptor, the main target of Δ9-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling. PMID:26460022

  7. Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons.

    PubMed

    de Salas-Quiroga, Adán; Díaz-Alonso, Javier; García-Rincón, Daniel; Remmers, Floortje; Vega, David; Gómez-Cañas, María; Lutz, Beat; Guzmán, Manuel; Galve-Roperh, Ismael

    2015-11-01

    The CB1 cannabinoid receptor, the main target of Δ(9)-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling. PMID:26460022

  8. Tissue and cellular alterations in Asian clam (Potamocorbula amurensis) from San Francisco Bay: toxicological indicators of exposure and effect?

    PubMed

    Clark, S L; Teh, S J; Hinton, D E

    2000-01-01

    The US Geological Survey has reported the presence of a metal contamination gradient in clam tissues, decreased condition indices, and irregular reproductive patterns have been reported in the Asian clam, Potamocorbula amurensis, from San Francisco Bay. If metals are driving the observed patterns in the field, then biomarkers of exposure, and possibly deleterious effect, should show a corresponding gradient. In this study, biomarkers from sub-cellular to tissue levels of biological organization were assessed in P. amurensis collected from the Bay or exposed to cadmium in the laboratory. Cellular and tissue alterations were assessed using histopathology and enzyme histochemistry (EH). Alterations in the ovary, testis, kidney, and gill tissues were most common at the most contaminated station when data were averaged over a 12-month sampling period. EH analysis indicated decreased active transport, energy status, and glucose oxidation in kidney and digestive gland at the most contaminated site which may indicate a decreased potential for growth. Ovarian lesions observed in feral Asian clams were experimentally induced in healthy clams by cadmium exposure in laboratory exposures. Our results suggest a contaminant etiology for tissue alterations. PMID:11460709

  9. Postnatal manganese exposure alters dopamine transporter function in adult rats: Potential impact on nonassociative and associative processes.

    PubMed

    McDougall, S A; Reichel, C M; Farley, C M; Flesher, M M; Der-Ghazarian, T; Cortez, A M; Wacan, J J; Martinez, C E; Varela, F A; Butt, A E; Crawford, C A

    2008-06-23

    In the present study, we examined whether exposing rats to a high-dose regimen of manganese chloride (Mn) during the postnatal period would depress presynaptic dopamine functioning and alter nonassociative and associative behaviors. To this end, rats were given oral supplements of Mn (750 microg/day) on postnatal days (PD) 1-21. On PD 90, dopamine transporter (DAT) immunoreactivity and [3H]dopamine uptake were assayed in the striatum and nucleus accumbens, while in vivo microdialysis was used to measure dopamine efflux in the same brain regions. The effects of postnatal Mn exposure on nigrostriatal functioning were evaluated by assessing rotorod performance and amphetamine-induced stereotypy in adulthood. In terms of associative processes, both cocaine-induced conditioned place preference (CPP) and sucrose-reinforced operant responding were examined. Results showed that postnatal Mn exposure caused persistent declines in DAT protein expression and [3H]dopamine uptake in the striatum and nucleus accumbens, as well as long-term reductions in striatal dopamine efflux. Rotorod performance did not differ according to exposure condition, however Mn-exposed rats did exhibit substantially more amphetamine-induced stereotypy than vehicle controls. Mn exposure did not alter performance on any aspect of the CPP task (preference, extinction, or reinstatement testing), nor did Mn affect progressive ratio responding (a measure of motivation). Interestingly, acquisition of a fixed ratio task was impaired in Mn-exposed rats, suggesting a deficit in procedural learning. In sum, these results indicate that postnatal Mn exposure causes persistent declines in various indices of presynaptic dopaminergic functioning. Mn-induced alterations in striatal functioning may have long-term impact on associative and nonassociative behavior. PMID:18485605

  10. Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus

    PubMed Central

    Blossom, Sarah J.; Melnyk, Stepan; Cooney, Craig A.; Gilbert, Kathleen M.; James, S. Jill

    2012-01-01

    Previous studies have shown that continuous exposure throughout gestation until the juvenile period to environmentally-relevant doses of trichloroethylene (TCE) in the drinking water of MRL+/+ mice promoted adverse behavior associated with glutathione depletion in the cerebellum indicating increased sensitivity to oxidative stress. The purpose of this study was to extend our findings and further characterize the impact of TCE exposure on redox homeostasis and biomarkers of oxidative stress in the hippocampus, a brain region prone to oxidative stress. Instead of a continuous exposure, the mice were exposed to water only or two environmentally relevant doses of TCE in the drinking water postnatally from birth until 6 weeks of age. Biomarkers of plasma metabolites in the transsulfuration pathway and the transmethylation pathway of the methionine cycle were also examined. Gene expression of neurotrophins was examined to investigate a possible relationship between oxidative stress, redox imbalance and neurotrophic factor expression with TCE exposure. Our results show that hippocampi isolated from male mice exposed to TCE showed altered glutathione redox homeostasis indicating a more oxidized state. Also observed was a significant, dose dependent increase in glutathione precursors. Plasma from the TCE treated mice showed alterations in metabolites in the transsulfuration and transmethylation pathways indicating redox imbalance and altered methylation capacity. 3-Nitrotyrosine, a biomarker of protein oxidative stress, was also significantly higher in plasma and hippocampus of TCE-exposed mice compared to controls. In contrast, expression of key neurotrophic factors in the hippocampus (BDNF, NGF, and NT-3) was significantly reduced compared to controls. Our results demonstrate that low-level postnatal and early life TCE exposure modulates neurotrophin gene expression in the mouse hippocampus and may provide a mechanism for TCE-mediated neurotoxicity. PMID:22421312

  11. Cannabinoid exposure during zebra finch sensorimotor vocal learning persistently alters expression of endocannabinoid signaling elements and acute agonist responsiveness

    PubMed Central

    2011-01-01

    Background Previously we have found that cannabinoid treatment of zebra finches during sensorimotor stages of vocal development alters song patterns produced in adulthood. Such persistently altered behavior must be attributable to changes in physiological substrates responsible for song. We are currently working to identify the nature of such physiological changes, and to understand how they contribute to altered vocal learning. One possibility is that developmental agonist exposure results in altered expression of elements of endocannabinoid signaling systems. To test this hypothesis we have studied effects of the potent cannabinoid receptor agonist WIN55212-2 (WIN) on endocannabinoid levels and densities of CB1 immunostaining in zebra finch brain. Results We found that late postnatal WIN treatment caused a long-term global disregulation of both levels of the endocannabinoid, 2-arachidonyl glycerol (2-AG) and densities of CB1 immunostaining across brain regions, while repeated cannabinoid treatment in adults produced few long-term changes in the endogenous cannabinoid system. Conclusions Our findings indicate that the zebra finch endocannabinoid system is particularly sensitive to exogenous agonist exposure during the critical period of song learning and provide insight into susceptible brain areas. PMID:21211022

  12. Perinatal Lead Exposure Alters Gut Microbiota Composition and Results in Sex-specific Bodyweight Increases in Adult Mice.

    PubMed

    Wu, Jianfeng; Wen, Xiaoquan William; Faulk, Christopher; Boehnke, Kevin; Zhang, Huapeng; Dolinoy, Dana C; Xi, Chuanwu

    2016-06-01

    Heavy metal pollution is a principle source of environmental contamination. Epidemiological and animal data suggest that early life lead (Pb) exposure results in critical effects on epigenetic gene regulation and child and adult weight trajectories. Using a mouse model of human-relevant exposure, we investigated the effects of perinatal Pb exposure on gut microbiota in adult mice, and the link between gut microbiota and bodyweight changes. Following Pb exposure during gestation and lactation via maternal drinking water, bodyweight in A(vy) strain wild-type non-agouti (a/a) offspring was tracked through adulthood. Gut microbiota of adult mice were characterized by deep DNA sequencing of bacterial 16S ribosomal RNA genes. Data analyses were stratified by sex and adjusted for litter effects. A Bayesian variable selection algorithm was used to analyze associations between bacterial operational taxonomic units and offspring adult bodyweight. Perinatal Pb exposure was associated with increased adult bodyweight in male (P < .05) but not in female offspring (P = .24). Cultivable aerobes decreased and anaerobes increased in Pb-exposed offspring (P < .005 and P < .05, respectively). Proportions of the 2 predominant phyla (Bacteroidetes and Firmicutes) shifted inversely with Pb exposure, and whole bacterial compositions were significantly different (analysis of molecular variance, P < .05) by Pb exposure without sex bias. In males, changes in gut microbiota were highly associated with adult bodyweight (P = .028; effect size = 2.59). Thus, perinatal Pb exposure results in altered adult gut microbiota regardless of sex, and these changes are highly correlated with increased bodyweight in males. Adult gut microbiota can be shaped by early exposures and may contribute to disease risks in a sex-specific manner. PMID:26962054

  13. Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS

    PubMed Central

    Hiolski, Emma M; Kendrick, Preston S; Frame, Elizabeth R; Myers, Mark S; Bammler, Theo K; Beyer, Richard P; Farin, Federico M; Wilkerson, Hui-wen; Smith, Donald R; Marcinek, David J; Lefebvre, Kathi A

    2014-01-01

    Domoic acid is an algal-derived seafood toxin that functions as a glutamate agonist and exerts excitotoxicity via overstimulation of glutamate receptors (AMPA, NMDA) in the central nervous system (CNS). At high (symptomatic) doses, domoic acid is well-known to cause seizures, brain lesions and memory loss; however, a significant knowledge gap exists regarding the health impacts of repeated low-level (asymptomatic) exposure. Here, we investigated the impacts of low-level repetitive domoic acid exposure on gene transcription and mitochondrial function in the vertebrate CNS using a zebrafish model in order to: 1) identify transcriptional biomarkers of exposure; and 2) examine potential pathophysiology that may occur in the absence of overt excitotoxic symptoms. We found that transcription of genes related to neurological function and development were significantly altered, and that asymptomatic exposure impaired mitochondrial function. Interestingly, the transcriptome response was highly-variable across the exposure duration (36 weeks), with little to no overlap of specific genes across the six exposure time points (2, 6, 12, 18, 24, and 36 weeks). Moreover, there were no apparent similarities at any time point with the gene transcriptome profile exhibited by the glud1 mouse model of chronic moderate excess glutamate release. These results suggest that although the fundamental mechanisms of toxicity may be similar, gene transcriptome responses to domoic acid exposure do not extrapolate well between different exposure durations. However, the observed impairment of mitochondrial function based on respiration rates and mitochondrial protein content suggests that repetitive low-level exposure does have fundamental cellular level impacts that could contribute to chronic health consequences. PMID:25033243

  14. Alteration of blood glucose levels in the rat following exposure to hyperbaric oxygen.

    PubMed

    Eynan, Mirit; Mullokandov, Michael; Krinsky, Nitzan; Biram, Adi; Arieli, Yehuda

    2015-09-01

    Findings regarding blood glucose level (BGL) on exposure to hyperbaric oxygen (HBO) are contradictory. We investigated the influence of HBO on BGL, and of BGL on latency to central nervous system oxygen toxicity (CNS-OT). The study was conducted on five groups of rats: Group 1, exposure to oxygen at 2.5 atmospheres absolute (ATA), 90 min/day for 7 days; Group 2, exposure to oxygen once a week from 2 to 6 ATA in increments of 1 ATA/wk, for a period of time calculated as 60% of the latency to CNS-OT (no convulsions); Group 3, exposure to 6 ATA breathing a gas mixture with a pO2 of 0.21; Group 4, received 10 U/kg insulin to induce hypoglycemia before exposure to HBO; Group 5, received 33% glucose to induce hyperglycemia before exposure to HBO. Blood samples were drawn before and after exposures for measurement of BGL. No change was observed in BGL after exposure to oxygen at 2.5 ATA, 90 min/day for 7 days. BGL was significantly elevated after exposure to oxygen at 6 ATA until the appearance of convulsions, and following exposure to 4, 5, and 6 ATA without convulsions (P < 0.01). No change was observed in BGL after exposure to 6 ATA breathing a gas mixture with a pO2 of 0.21. Hypoglycemia shortened latency to CNS oxygen toxicity, whereas hyperglycemia had no effect. Our results demonstrate an influence of HBO exposure on elevation of BGL, starting at 4 ATA. This implies that BGL may serve as a marker for the generation of CNS-OT. PMID:26183474

  15. Altered levels of endocrine biomarkers in juvenile barramundi (Lates calcarifer; Bloch) following exposure to commercial herbicide and surfactant formulations.

    PubMed

    Kroon, Frederieke J; Hook, Sharon E; Metcalfe, Suzanne; Jones, Dean

    2015-08-01

    Agricultural pesticides that are known endocrine disrupting chemicals have been detected in waters in the Great Barrier Reef catchment and lagoon. Altered transcription levels of liver vitellogenin (vtg) have been documented in wild populations of 2 Great Barrier Reef fisheries species and were strongly associated with pesticide-containing runoff from sugarcane plantations. The present study examined endocrine and physiological biomarkers in juvenile barramundi (Lates calcarifer) exposed to environmentally relevant concentrations of commercial herbicide (ATRADEX(®) WG Herbicide, DIUREX(®) WG Herbicide) and surfactant (ACTIVATOR(®) 90) formulations commonly used on sugarcane in the Great Barrier Reef catchment. Estrogenic biomarkers (namely, liver vtg messenger RNA and plasma 17β-estradiol) increased following exposure to commercial mixtures but not to the analytical grade chemical, suggesting an estrogenic response to the additives. In contrast, brain aromatase (cyp19a1b) transcription levels, plasma testosterone and 11-ketotestosterone concentrations, and gill ventilation rates were not affected by any of the experimental exposures. These findings support the assertion that exposure to pesticide-containing runoff from sugarcane plantations is a potential causative agent of altered liver vtg transcription levels in wild barramundi. Whether exposure patterns in the Great Barrier Reef catchment and lagoon are sufficient to impair fish sexual and reproductive development and ultimately influence fish population dynamics remains to be determined. These findings highlight the need to consider both active and so-called inert ingredients in commercial pesticide formulations for environmental risk assessments. PMID:25858168

  16. Alteration of extracellular enzymes in pinto bean leaves upon exposure to air pollutants, ozone and sulfur dioxide

    SciTech Connect

    Peters, J.L.; Castillo, F.J.; Heath, R.L. )

    1989-01-01

    Diamine oxidase and peroxidase, associated with the wall in pinto bean (Phaseolus vulgaris L. var Pinto) leaves, can be washed out by vacuum infiltration and assayed without grinding the leaf. The diamine oxidase activity is inhibited in vivo by exposure of the plants to ozone (dose of 0.6 microliters per liter {times} hour), whereas the peroxidase activity associated with the wall space is stimulated. This dose does not cause obvious necrosis or chlorosis of the leaf. These alterations are greater when the dose of ozone exposure is given as a triangular pulse (a slow rise to a peak of 0.24 microliters per liter followed by a slow fall) compared to that given as a constant square wave pulse of 0.15 microliters per liter for the same 4 hour period. Exposure of the plants to sulfur dioxide (at a concentration of 0.4 microliters per liter for 4 hours) does not result in any change in the diamine oxidase or peroxidase activities, yet the total sulfhydryl content of the leaf is increased, demonstrating the entry of sulfur dioxide. These two pollutants, with different chemical reactivities, affect the activities of the extracellular enzymes in different manners. In the case of ozone exposure, the inhibition of extracellular diamine oxidase could profoundly alter the movements of polyamines from cell to cell.

  17. Fetal Liver Bisphenol A Concentrations and Biotransformation Gene Expression Reveal Variable Exposure and Altered Capacity for Metabolism in Humans

    PubMed Central

    Nahar, Muna S.; Liao, Chunyang; Kannan, Kurunthachalam; Dolinoy, Dana C.

    2013-01-01

    Widespread exposure to the endocrine active compound, bisphenol A (BPA), is well documented in humans. A growing body of literature suggests adverse health outcomes associated with varying ranges of exposure to BPA. In the current study, we measured the internal dose of free BPA and conjugated BPA and evaluated gene expression of bio-transformation enzymes specific for BPA metabolism in 50 first- and second-trimester human fetal liver samples. Both free BPA and conjugated BPA concentrations varied widely, with free BPA exhibiting three times higher concentrations than conjugated BPA concentrations. As compared to gender-matched adult liver controls, UDP-glucuronyltransferase, sulfotransferase, and steroid sulfatase genes exhibited reduced expression whereas β-glucuronidase mRNA expression remained unchanged in the fetal tissues. This study provides evidence that there is considerable exposure to BPA during human pregnancy and that the capacity for BPA metabolism is altered in the human fetal liver. PMID:23208979

  18. Bisphenol A Exposure during Adulthood Causes Augmentation of Follicular Atresia and Luteal Regression by Decreasing 17β-Estradiol Synthesis via Downregulation of Aromatase in Rat Ovary

    PubMed Central

    Lee, Seung Gee; Chung, Jin-Yong; Park, Ji-Eun; Oh, Seunghoon; Yoon, Yong-Dal; Yoo, Ki Soo; Yoo, Young Hyun

    2013-01-01

    Background: Bisphenol A (BPA) has been detected in human body fluids, such as serum and ovarian follicular fluids. Several reports indicated that BPA exposure is associated with the occurrence of several female reproductive diseases resulting from the disruption of steroid hormone biosynthesis in the adult ovary. Objective: We hypothesized that long-term exposure to low concentrations of BPA disrupts 17β-estradiol (E2) production in granulosa cells via an alteration of steroidogenic proteins in ovarian cells. Methods: Adult female rats received BPA for 90 days by daily gavage at doses of 0, 0.001, or 0.1 mg/kg body weight. We determined serum levels of E2, testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). We also analyzed the expressions of steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase isomerase (3β-HSD), and aromatase cytochrome P450 (P450arom) in the ovary. Results: Exposure to BPA significantly decreased E2 serum concentration, which was accompanied by augmented follicular atresia and luteal regression via increase of caspase-3–associated apoptosis in ovarian cells. After BPA exposure, P450arom and StAR protein levels were significantly decreased in granulosa cells and theca-interstitial (T-I) cells, respectively. However, P450scc and 3β-HSD protein levels remained unchanged. The increase in LH levels appeared to be associated with the decreased synthesis of T in T-I cells after BPA exposure via homeostatic positive feedback regulation. Conclusions: BPA exposure during adulthood can disturb the maintenance of normal ovarian functions by reducing E2. The steroidogenic proteins StAR and P450arom appear to be targeted by BPA. PMID:23512349

  19. Maternal Dexamethasone Exposure Alters Synaptic Inputs to Gonadotropin-Releasing Hormone Neurons in the Early Postnatal Rat

    PubMed Central

    Lim, Wei Ling; Idris, Marshita Mohd; Kevin, Felix Suresh; Soga, Tomoko; Parhar, Ishwar S.

    2016-01-01

    Maternal dexamethasone [(DEX); a glucocorticoid receptor agonist] exposure delays pubertal onset and alters reproductive behavior in the adult offspring. However, little is known whether maternal DEX exposure affects the offspring’s reproductive function by disrupting the gonadotropin-releasing hormone (GnRH) neuronal function in the brain. Therefore, this study determined the exposure of maternal DEX on the GnRH neuronal spine development and synaptic cluster inputs to GnRH neurons using transgenic rats expressing enhanced green fluorescent protein (EGFP) under the control of GnRH promoter. Pregnant females were administered with DEX (0.1 mg/kg) or vehicle (VEH, water) daily during gestation day 13–20. Confocal imaging was used to examine the spine density of EGFP–GnRH neurons by three-dimensional rendering and synaptic cluster inputs to EGFP–GnRH neurons by synapsin I immunohistochemistry on postnatal day 0 (P0) males. The spine morphology and number on GnRH neurons did not change between the P0 males following maternal DEX and VEH treatment. The number of synaptic clusters within the organum vasculosum of the lamina terminalis (OVLT) was decreased by maternal DEX exposure in P0 males. Furthermore, the number and levels of synaptic cluster inputs in close apposition with GnRH neurons was decreased following maternal DEX exposure in the OVLT region of P0 males. In addition, the postsynaptic marker molecule, postsynaptic density 95, was observed in GnRH neurons following both DEX and VEH treatment. These results suggest that maternal DEX exposure alters neural afferent inputs to GnRH neurons during early postnatal stage, which could lead to reproductive dysfunction during adulthood.

  20. Low-Dose, Gestational Exposure to Atrazine Does Not Alter Postnatal Reproductive Development of Male Offspring

    EPA Science Inventory

    There is growing evidence that xenobiotic exposure during the perinatal period may result in a variety of adverse outcomes when the developing organism attains adulthood. Maternal stress and subsequent exposure of the fetus to excess glucocorticoids may underlie these effects. Pr...

  1. Early Exposure to Intermediate-Frequency Magnetic Fields Alters Brain Biomarkers without Histopathological Changes in Adult Mice

    PubMed Central

    Win-Shwe, Tin-Tin; Ohtani, Shin; Ushiyama, Akira; Kunugita, Naoki

    2015-01-01

    Recently we have reported that intermediate-frequency magnetic field (IF-MF) exposure transiently altered the mRNA expression levels of memory function-related genes in the hippocampi of adult male mice. However, the effects of IF-MF exposure during brain development on neurological biomarkers have not yet been clarified. In the present study, we investigated the effect of IF-MF exposure during development on neurological and immunological markers in the mouse hippocampus in 3- and 7-week-old male mice. Pregnant C57BL/6J mice were exposed to IF-MF (21 kHz, 3.8 mT) for one hour per day from organogenesis period day 7 to 17. At adolescence, some IF-MF-exposed mice were further divided into exposure, recovery, and sham-exposure groups. The adolescent-exposure groups were exposed again to IF-MF from postnatal day 27 to 48. The expression of mRNA in the hippocampi was examined using a real-time RT-PCR method, and microglia activation was examined by immunohistochemical analysis. The expression levels of NR1 and NR2B as well as transcription factors (CaMKIV, CREB1), inflammatory mediators (COX2, IL-1 β,TNF-α), and the oxidative stress marker heme-oxygenase (HO)-1 were significantly increased in the IF-MF-exposed mice, compared with the control group, in the 7-week-old mice, but not in the 3-week-old mice. Microglia activation was not different between the control and other groups. This study provides the first evidence that early exposure to IF-MF reversibly affects the NMDA receptor, its related signaling pathways, and inflammatory mediators in the hippocampus of young adult mice; these changes are transient and recover after termination of exposure without histopathological changes. PMID:25913185

  2. Early exposure to intermediate-frequency magnetic fields alters brain biomarkers without histopathological changes in adult mice.

    PubMed

    Win-Shwe, Tin-Tin; Ohtani, Shin; Ushiyama, Akira; Kunugita, Naoki

    2015-04-01

    Recently we have reported that intermediate-frequency magnetic field (IF-MF) exposure transiently altered the mRNA expression levels of memory function-related genes in the hippocampi of adult male mice. However, the effects of IF-MF exposure during brain development on neurological biomarkers have not yet been clarified. In the present study, we investigated the effect of IF-MF exposure during development on neurological and immunological markers in the mouse hippocampus in 3- and 7-week-old male mice. Pregnant C57BL/6J mice were exposed to IF-MF (21 kHz, 3.8 mT) for one hour per day from organogenesis period day 7 to 17. At adolescence, some IF-MF-exposed mice were further divided into exposure, recovery, and sham-exposure groups. The adolescent-exposure groups were exposed again to IF-MF from postnatal day 27 to 48. The expression of mRNA in the hippocampi was examined using a real-time RT-PCR method, and microglia activation was examined by immunohistochemical analysis. The expression levels of NR1 and NR2B as well as transcription factors (CaMKIV, CREB1), inflammatory mediators (COX2, IL-1 b,TNF-α), and the oxidative stress marker heme-oxygenase (HO)-1 were significantly increased in the IF-MF-exposed mice, compared with the control group, in the 7-week-old mice, but not in the 3-week-old mice. Microglia activation was not different between the control and other groups. This study provides the first evidence that early exposure to IF-MF reversibly affects the NMDA receptor, its related signaling pathways, and inflammatory mediators in the hippocampus of young adult mice; these changes are transient and recover after termination of exposure without histopathological changes. PMID:25913185

  3. Prenatal Bisphenol A Exposure Alters Sex-Specific Estrogen Receptor Expression in the Neonatal Rat Hypothalamus and Amygdala

    PubMed Central

    Patisaul, Heather B.

    2013-01-01

    Bisphenol A (BPA) exposure is ubiquitous, and in laboratory animals, early-life BPA exposure has been shown to alter sex-specific neural organization, neuroendocrine physiology, and behavior. The specific mechanisms underlying these brain-related outcomes, however, remain largely unknown, constraining the capacity to ascertain the potential human relevance of neural effects observed in animal models. In the perinatal rat brain, estrogen is masculinizing, suggesting that BPA-induced perturbation of estrogen receptor (ESR) expression may underpin later in-life neuroendocrine effects. We hypothesized that prenatal BPA exposure alters sex-specific ESR1 (ERα) and ESR2 (ERβ) expression in postnatal limbic nuclei. Sprague Dawley rats were mated and gavaged on gestational days (GDs) 6–21 with vehicle, 2.5 or 25 μg/kg bw/day BPA, or 5 or 10 μg/kg bw/day ethinyl estradiol. An additional group was restrained but not gavaged (naïve control). Offspring were sacrificed the day after birth to quantify ESR gene expression throughout the hypothalamus and amygdala by in situ hybridization. Relative to the vehicle group, significant effects of BPA were observed on ESR1 and ESR2 expression throughout the mediobasal hypothalamus and amygdala in both sexes. Significant differences in ESR expression were also observed in the mediobasal hypothalamus and amygdala of the naïve control group compared with the vehicle group, highlighting the potential for gavage to influence gene expression in the developing brain. These results indicate that ESR expression in the neonatal brain of both sexes can be altered by low-dose prenatal BPA exposure. PMID:23457122

  4. Repeated exposure to vicarious pain alters electrocortical processing of pain expressions.

    PubMed

    Coll, Michel-Pierre; Grégoire, Mathieu; Prkachin, Kenneth M; Jackson, Philip L

    2016-09-01

    Repeated exposure to others in pain has been shown to bias vicarious pain perception, but the neural correlates of this effect are currently not known. The current study therefore aimed at measuring electrocortical responses to facial expressions of pain following exposure to expressions of pain. To this end, a between-subject design was adopted. Participants in the Exposure group were exposed to facial expressions of intense pain, while the participants in the Control group were exposed to neutral expressions before performing the same pain detection task. As in previous studies, participants in the Exposure group showed a significantly more conservative bias when judging facial expressions pain, meaning that they were less inclined to judge moderate pain expressions as painful compared to participants in the Control group. Event-related potential analyses in response to pain or neutral expressions indicated that this effect was related to a relative decrease in the central late positive potential responses to pain expressions. Furthermore, while the early N170 response was not influenced by repeated exposure to pain expressions, the P100 component showed an adaptation effect in the Control group only. These results suggest that repeated exposure to vicarious pain do not influence early event-related potential responses to pain expressions but decreases the late central positive potential. These results are discussed in terms of changes in the perceived saliency of pain expressions following repeated exposure. PMID:27156101

  5. Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats

    PubMed Central

    Albores-Garcia, Damaris; Hernandez, Alberto J.; Loera, Miriam J.

    2016-01-01

    Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 μg/kg/day MeHg, (3) 500 μg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined. PMID:26885512

  6. Continuous exposure to the deterrents cis-jasmone and methyl jasmonate does not alter the behavioural responses of Frankliniella occidentalis

    PubMed Central

    Egger, Barbara; Spangl, Bernhard; Koschier, Elisabeth Helene

    2016-01-01

    Behavioural responses of Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), a generalist, cell sap-feeding insect species with piercing-sucking mouthparts, after continuous exposure to two deterrent secondary plant compounds are investigated. We compared in choice assays on bean leaf discs, the settling, feeding, and oviposition preferences of F. occidentalis females that had no experience with the two fatty acid derivatives methyl jasmonate and cis-jasmone before testing (naïve thrips) vs. females that had been exposed to the deterrent compounds before testing (experienced thrips). The thrips were exposed to the deterrents at low or high concentrations for varied time periods and subsequently tested on bean leaf discs treated with the respective deterrent at either a low or a high concentration. Frankliniella occidentalis females avoided settling on the deterrent-treated bean leaf discs for an observation period of 6 h, independent of their previous experience. Our results demonstrate that feeding and oviposition deterrence of the jasmonates to the thrips were not altered by continuous exposure of the thrips to the jasmonates. Habituation was not induced, neither by exposure to the low concentration of the deterrents nor by exposure to the high concentration. These results indicate that the risk of habituation to two volatile deterrent compounds after repeated exposure is not evident in F. occidentalis. This makes the two compounds potential candidates to be integrated in pest management strategies. PMID:26726263

  7. Pubertal bisphenol A exposure alters murine mammary stem cell function leading to early neoplasia in regenerated glands.

    PubMed

    Wang, Danhan; Gao, Hui; Bandyopadhyay, Abhik; Wu, Anqi; Yeh, I-Tien; Chen, Yidong; Zou, Yi; Huang, Changjiang; Walter, Christi A; Dong, Qiaoxiang; Sun, Lu-Zhe

    2014-04-01

    Perinatal exposure to bisphenol A (BPA) has been shown to cause aberrant mammary gland morphogenesis and mammary neoplastic transformation. Yet, the underlying mechanism is poorly understood. We tested the hypothesis that mammary glands exposed to BPA during a susceptible window may lead to its susceptibility to tumorigenesis through a stem cell-mediated mechanism. We exposed 21-day-old Balb/c mice to BPA by gavage (25 μg/kg/d) during puberty for 3 weeks, and a subset of animals were further challenged with one oral dose (30 mg/kg) of 7,12-dimethylbenz(a)anthracene (DMBA) at 2 months of age. Primary mammary cells were isolated at 6 weeks, and 2 and 4 months of age for murine mammary stem cell (MaSC) quantification and function analysis. Pubertal exposure to the low-dose BPA increased lateral branches and hyperplasia in adult mammary glands and caused an acute increase of MaSC in 6-week-old glands and a delayed increase of luminal progenitors in 4-month-old adult gland. Most importantly, pubertal BPA exposure altered the function of MaSC from different age groups, causing early neoplastic lesions in their regenerated glands similar to those induced by DMBA exposure, which indicates that MaSCs are susceptible to BPA-induced transformation. Deep sequencing analysis on MaSC-enriched mammospheres identified a set of aberrantly expressed genes associated with early neoplastic lesions in patients with human breast cancer. Thus, our study for the first time shows that pubertal BPA exposure altered MaSC gene expression and function such that they induced early neoplastic transformation. PMID:24520039

  8. Paternal BPA exposure in early life alters Igf2 epigenetic status in sperm and induces pancreatic impairment in rat offspring.

    PubMed

    Mao, Zhenxing; Xia, Wei; Chang, Huailong; Huo, Wenqian; Li, Yuanyuan; Xu, Shunqing

    2015-11-01

    Exposure to endocrine disruptors in utero appears to alter epigenetics in the male germ-line and subsequently promote adult-onset disease in subsequent generations. Fetal exposure to bisphenol A (BPA), a highly prevalent endocrine disruptor in environment, has been shown to alter epigenetic modification and result in glucose intolerance in adulthood. However, whether fetal exposure to BPA can induce epigenetic modification and phenotypic changes in their subsequent offspring are still unclear. The present study was designed to investigate whether exposure to BPA in early life induced glucose intolerance in the offspring through male germ line, and the underlying epigenetic molecular basis. F0 pregnant SD rats were received corn oil or 40 μg/kg/day of BPA during gestation and lactation. F1 male rats were maintained to generate F2 offspring by mating with untreated female rats. Both the F1 rats after weaning and the F2 offspring were not received any other treatments. Our results showed that male F2 offspring in the BPA group exhibited glucose intolerance and β-cell dysfunction. Decreased expression of Igf2 and associated hypermethylation of Igf2 were observed in islets of male F2 offspring. In addition, similar effects were observed in female F2 animals, but the effects were more pronounced in males. Moreover, abnormal expression and methylation of Igf2 was observed in sperm of adult F1 male rats, indicating that epigenetic modification in germ cells can be partly progressed to the next generation. Overall, our study suggests that BPA exposure during early life can result in generational transmission of glucose intolerance and β-cell dysfunction in the offspring through male germ line, which is associated with hypermethylation of Igf2 in islets. The changes of epigenetics in germ cells may contribute to this generational transmission. PMID:26276081

  9. VANADIUM EXPOSURE ALTERS SPONTANEOUS BEAT RATE AND GENE EXPRESSION OF CULTURED CARDIAC MYOCYTES

    EPA Science Inventory

    Ambient air pollution particulate matter (PM) exposure is associated with increased morbidity and mortality. Recent toxicological studies report PM-induced changes in a number of cardiac parameters, including heart rate variability, arrhythmias, repolarization, and internal defib...

  10. Developmental Exposure to PCBs Differentially Alters Sensitivity to Audiogenic and Kindling-Induced Seizures in Rats

    EPA Science Inventory

    Previously we reported an increased incidence of audiogenic seizures in offspring of pregnant rats exposed to an environmental mixture of polychlorinated biphenyls (PCBs). This study compares the proconvulsant properties of PCB exposure in audiogenic and electrical kindling seizu...

  11. Identification of neural biomarkers of altered sexual differentiation following gestational exposure###

    EPA Science Inventory

    Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) duri...

  12. IDENTIFICATION OF NEURAL BIOMARKERS OF ALTERED SEXUAL DIFFERENTIATION FOLLOWING GESTATIONAL EXPOSURE***

    EPA Science Inventory

    Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) duri...

  13. Identification of neural biomarkers of altered sexual differentiation following gestational exposure

    EPA Science Inventory

    Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) during...

  14. Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat: in vivo studies.

    EPA Science Inventory

    Perchlorate, a contaminant found in food and water supplies throughout the USA, blocks iodine uptake into the thyroid gland to reduce circulating levels of thyroid hormone. Neurological function accompanying developmental exposure to perchlorate was evaluated in the present study...

  15. Alteration of Blood Parameters and Histoarchitecture of Liver and Kidney of Silver Barb after Chronic Exposure to Quinalphos

    PubMed Central

    Mohammod Mostakim, Golam; Zahangir, Md. Mahiuddin; Monir Mishu, Mahbuba; Rahman, Md. Khalilur; Islam, M. Sadiqul

    2015-01-01

    Quinalphos (QP) is commonly used for pest control in the agricultural fields surrounding freshwater reservoirs. This study was conducted to evaluate the chronic toxicity of this pesticide on blood parameters and some organs of silver barb, Barbonymus gonionotus. Fish were exposed to two sublethal concentrations, 0.47 ppm and 0.94 ppm, of QP for a period of 28 days. All the blood parameters (red blood cell, hematocrit, and hemoglobin) and blood glucose except for white blood cells decreased with increasing concentration of toxicant and become significantly lower (p < 0.05) at higher concentration when compared with control. The derived hematological indices of mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were equally altered compared to control. Histoarchitectural changes of liver and kidney were observed after exposure to the QP. Hypertrophy of hepatocytes, mild to severe necrosis, ruptured central vein, and vacuolation were observed in the liver of treated groups. Highly degenerated kidney tubules and hematopoietic tissue, degeneration of renal corpuscle, vacuolization, and necrosis were evident in the kidney of treated groups. In conclusion, chronic exposure to QP at sublethal concentrations induced hematological and histological alterations in silver barb and offers a simple tool to evaluate toxicity derived alterations. PMID:26635877

  16. Chronic fetal exposure to caffeine altered resistance vessel functions via RyRs-BKCa down-regulation in rat offspring

    PubMed Central

    Li, Na; Li, Yongmei; Gao, Qinqin; Li, Dawei; Tang, Jiaqi; Sun, Miao; Zhang, Pengjie; Liu, Bailin; Mao, Caiping; Xu, Zhice

    2015-01-01

    Caffeine modifies vascular/cardiac contractility. Embryonic exposure to caffeine altered cardiac functions in offspring. This study determined chronic influence of prenatal caffeine on vessel functions in offspring. Pregnant Sprague-Dawley rats (5-month-old) were exposed to high dose of caffeine, their offspring (5-month-old) were tested for vascular functions in mesenteric arteries (MA) and ion channel activities in smooth muscle cells. Prenatal exposure to caffeine increased pressor responses and vasoconstrictions to phenylephrine, accompanied by enhanced membrane depolarization. Large conductance Ca2+-activated K+ (BKCa) channels in buffering phenylephrine-induced vasoconstrictions was decreased, whole cell BKCa currents and spontaneous transient outward currents (STOCs) were decreased. Single channel recordings revealed reduced voltage/Ca2+ sensitivity of BKCa channels. BKCa α-subunit expression was unchanged, BKCa β1-subunit and sensitivity of BKCa to tamoxifen were reduced in the caffeine offspring as altered biophysical properties of BKCa in the MA. Simultaneous [Ca2+]i fluorescence and vasoconstriction testing showed reduced Ca2+, leading to diminished BKCa activation via ryanodine receptor Ca2+ release channels (RyRs), causing enhanced vascular tone. Reduced RyR1 was greater than that of RyR3. The results suggest that the altered STOCs activity in the caffeine offspring could attribute to down-regulation of RyRs-BKCa, providing new information for further understanding increased risks of hypertension in developmental origins. PMID:26277840

  17. Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring.

    PubMed

    Boulle, Fabien; Pawluski, Jodi L; Homberg, Judith R; Machiels, Barbie; Kroeze, Yvet; Kumar, Neha; Steinbusch, Harry W M; Kenis, Gunter; van den Hove, Daniel L A

    2016-04-01

    A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms. PMID:26844865

  18. Sleep alterations following exposure to stress predict fear-associated memory impairments in a rodent model of PTSD.

    PubMed

    Vanderheyden, William M; George, Sophie A; Urpa, Lea; Kehoe, Michaela; Liberzon, Israel; Poe, Gina R

    2015-08-01

    Sleep abnormalities, such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of posttraumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stressor exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops. SPS resulted in acute increases in REM sleep and transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. Reductions in theta (4-10 Hz) and sigma (10-15 Hz) band power during transition to REM sleep also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. PMID:26019008

  19. Grapevine Plasticity in Response to an Altered Microclimate: Sauvignon Blanc Modulates Specific Metabolites in Response to Increased Berry Exposure.

    PubMed

    Young, Philip R; Eyeghe-Bickong, Hans A; du Plessis, Kari; Alexandersson, Erik; Jacobson, Dan A; Coetzee, Zelmari; Deloire, Alain; Vivier, Melané A

    2016-03-01

    In this study, the metabolic and physiological impacts of an altered microclimate on quality-associated primary and secondary metabolites in grape (Vitis vinifera) 'Sauvignon Blanc' berries was determined in a high-altitude vineyard. The leaf and lateral shoot removal in the bunch zones altered the microclimate by increasing the exposure of the berries. The physical parameters (berry diameter and weight), primary metabolites (sugars and organic acids), as well as bunch temperature and leaf water potential were predominantly not affected by the treatment. The increased exposure led to higher levels of specific carotenoids and volatile terpenoids in the exposed berries, with earlier berry stages reacting distinctly from the later developmental stages. Plastic/nonplastic metabolite responses could be further classified to identify metabolites that were developmentally controlled and/or responded to the treatment in a predictable fashion (assessed over two consecutive vintages). The study demonstrates that grapevine berries exhibit a degree of plasticity within their secondary metabolites and respond physiologically to the increased exposure by increasing metabolites with potential antioxidant activity. Taken together, the data provide evidence that the underlying physiological responses relate to the maintenance of stress pathways by modulating antioxidant molecules in the berries. PMID:26628747

  20. Sleep Alterations Following Exposure to Stress Predict Fear-Associated Memory Impairments in a Rodent Model of PTSD

    PubMed Central

    Vanderheyden, William M.; George, Sophie A.; Urpa, Lea; Kehoe, Michaela; Liberzon, Israel; Poe, Gina R.

    2015-01-01

    Sleep abnormalities such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of post-traumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating these sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stress exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops in rats. SPS resulted in acutely increased REM sleep, transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. We also report reductions in theta (4–10 Hz) and sigma (10–15 Hz) band power during transition to REM sleep which also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. PMID:26019008

  1. Chromosome alterations associated with in vitro exposure of human fibroblasts to chemical or physical carcinogens

    SciTech Connect

    Popescu, N.C.; Amsbaugh, S.C.; Milo, G.; DiPaolo, J.A.

    1986-09-01

    Normal human foreskin fibroblasts treated in vitro with a chemical carcinogen or irradiated with ultraviolet light subsequently acquired anchorage independent growth and an extended but finite capacity for exponential growth. All cell lines were derived from cells recovered from colonies that had grown in semisolid medium; cell lines originally treated with a chemical carcinogen produced nodules after s.c. inoculation into nude mice. G-banding analysis of 10 cell lines (including one ultraviolet light line) revealed that seven were chromosomally abnormal with structural and numerical chromosome alterations, one was characterized by a consistent trisomy, and the other two were normal diploid. Structural alterations consisted of chromosome deletions, translocations, and partial chromosome duplications. Although no common structural or numerical abnormality was detected, several structural alterations were observed involving chromosomes 1, 7, 11, and 22, where fgr, erb-B, H-ras-1, and sis protooncogenes, respectively, are located. In one cell line trisomy 17 was a unique chromosome alteration. The induction of chromosome changes may have influenced the proliferative capacity of the treated cells relative to nontreated cells. However, the two cell lines without detectable chromosome changes also had an increased proliferative life span, suggesting that other submicroscopic genetic alterations may have affected cell multiplication. Although carcinogen induced chromosome abnormalities may represent a step in the process of neoplastic development, additional genetic and/or epigenetic changes, are required for indefinite growth and the expression of malignancy.

  2. Kolaviron protects against benzo[a]pyrene-induced functional alterations along the brain-pituitary-gonadal axis in male rats.

    PubMed

    Adedara, Isaac A; Owoeye, Olatunde; Aiyegbusi, Motunrayo A; Dagunduro, Joshua O; Daramola, Yetunde M; Farombi, Ebenezer O

    2015-09-01

    Exposure to benzo[a]pyrene (B[a]P) is well reported to be associated with neurological and reproductive dysfunctions. The present study investigated the influence of kolaviron, an isolated biflavonoid from the seed of Garcinia kola, on functional alterations along the brain-pituitary-gonadal axis in male rats exposed to B[a]P. Benzo[a]pyrene was orally administered at a dose of 10mg/kg alone or orally co-administered with kolaviron at 100 and 200mg/kg for 15 consecutive days. Administration of B[a]P significantly (p<0.05) decreased plasma levels of pituitary hormones namely follicle-stimulating hormone (FSH) and prolactin but increased luteinizing hormone (LH) by 47%, 55% and 20.9%, respectively, when compared with the control. The significant decrease in gonadosomatic index (GSI) was accompanied by significant decrease in testosterone production and sperm functional parameters in the B[a]P-treated rats. Moreover, B[a]P-treated rats showed significant elevation in the circulatory concentrations of pro-inflammatory cytokines and oxidative stress indices in the brain, testes and sperm of B[a]P-treated rats. Light microscopy revealed severe necrosis of the Purkinje cells in the cerebellum, neuronal degeneration of the cerebral cortex, neuronal necrosis of the hippocampus and testicular atrophy in B[a]P-treated rats. Kolaviron co-treatment significantly ameliorated B[a]P mediated damages by suppressing pro-inflammatory mediators and enhancing the antioxidant status, neuroendocrine function, sperm characteristics and improving the architecture of the brain and testes in B[a]P-treated rats. The findings in the present investigation highlight that kolaviron may be developed to novel therapeutic agent against toxicity resulting from B[a]P exposure. PMID:26280929

  3. Repeated exposure to amphetamine during adolescence alters inhibitory tone in the medial prefrontal cortex following drug re-exposure in adulthood.

    PubMed

    Paul, Kush; Kang, Shuo; Cox, Charles L; Gulley, Joshua M

    2016-08-01

    Behavioral sensitization following repeated amphetamine (AMPH) exposure is associated with changes in GABA function in the medial prefrontal cortex (mPFC). In rats exposed to AMPH during adolescence compared to adulthood, there are unique patterns of sensitization that may reflect age-dependent differences in drug effects on prefrontal GABAergic function. In the current study, we used a sensitizing regimen of repeated AMPH exposure in adolescent and adult rats to determine if a post-withdrawal AMPH challenge would alter inhibitory transmission in the mPFC in a manner that depends on age of exposure. Male Sprague-Dawley rats were treated with saline or 3mg/kg AMPH (i.p.) during adolescence [postnatal day (P) 27-P45] or adulthood (P85- P103) and were sacrificed either at similar ages in adulthood (∼P133; experiment 1) or after similar withdrawal times (3-4 weeks; experiment 2). Spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in vitro from deep layer pyramidal cells in the mPFC using the whole-cell configuration. We found no effect of AMPH pre-exposure on baseline sIPSC frequency. Subsequent application of AMPH (25μM) produced a stable increase in sIPSC frequency in controls, suggesting that AMPH increases inhibitory tone in the mPFC. However, AMPH failed to increase sIPSCs in adolescent- or adult-exposed rats. In experiment 2, where withdrawal period was kept similar for both exposure groups, AMPH induced a suppression of sIPSC activity in adolescent-exposed rats. These results suggest that sensitizing treatment with AMPH during adolescence or adulthood dampens inhibitory influences on mPFC pyramidal cells, but potentially through different mechanisms. PMID:27085589

  4. Alteration in Pimephales promelas mucus production after exposure to nanosilver or silver nitrate.

    PubMed

    Hawkins, Adam D; Thornton, Cammi; Steevens, Jeffery A; Willett, Kristine L

    2014-12-01

    The fish gill's ability to produce mucus effectively is a critical part of the stress response and protection against xenobiotic toxicity. Adult fathead minnows were exposed to silver nitrate (0.82 µg/L or 13.2 µg/L), polyvinylpyrrolidone-coated silver nanoparticles (11.1 µg/L or 208 µg/L), and citrate-coated silver nanoparticles (10.1 µg/L or 175 µg/L) for 96 h. Mucus concentrations based on glucose as a surrogate were determined at 0 h, 1 h, 2 h, 3 h, 4 h and 24 h after re-dosing each day. Higher mucus production rates following silver treatment were observed at the beginning as compared to controls and compared to after 3 d of exposure. Control fish produced consistent mucus concentrations throughout the exposure (0.62 mg/L and 0.40 mg/L at 24 h and 96 h, respectively). Following 24 h of exposure, all silver treatment groups produced significantly more mucus than controls. Following 96 h of exposure, mucus concentrations in treatment groups were significantly reduced compared with each respective treatment at 24 h. Reduced mucus production following long-term silver exposure could prevent the gills from removing silver, and thus increase toxicity. PMID:25262928

  5. Developmental timing of sodium perchlorate exposure alters angiogenesis, thyroid follicle proliferation and sexual maturation in stickleback

    PubMed Central

    Furin, Christoff G.; von Hippel, Frank A.; Postlethwait, John H.; Buck, C. Loren; Cresko, William A.; O’Hara, Todd M.

    2015-01-01

    Perchlorate, a common aquatic contaminant, is well known to disrupt homeostasis of the hypothalamus-pituitary-thyroid axis. This study utilizes the threespine stickleback (Gasterosteus aculeatus) fish to determine if perchlorate exposure during certain windows of development has morphological effects on thyroid and gonads. Fish were moved from untreated water to perchlorate-contaminated water (30 and 100 mg/L) starting at 0, 3, 7, 14, 21, 42, 154 and 305 days post fertilization until approximately one year old. A reciprocal treatment (fish in contaminated water switched to untreated water) was conducted on the same schedule. Perchlorate exposure increased angiogenesis and follicle proliferation in thyroid tissue, delayed gonadal maturity, and skewed sex ratios towards males; effects depended on concentration and timing of exposure. This study demonstrates that perchlorate exposure beginning during the first 42 days of development has profound effects on stickleback reproductive and thyroid tissues, and by implication can impact population dynamics. Long-term exposure studies that assess contaminant effects at various stages of development provide novel information to characterize risk to aquatic organisms, to facilitate management of resources, and to determine sensitive developmental windows for further study of underlying mechanisms. PMID:25865142

  6. Exposure to Radiofrequency Radiation Emitted from Common Mobile Phone Jammers Alters the Pattern of Muscle Contractions: an Animal Model Study

    PubMed Central

    Rafati, A.; Rahimi, S.; Talebi, A.; Soleimani, A.; Haghani, M.; Mortazavi, S. M. J.

    2015-01-01

    Introduction The rapid growth of wireless communication technologies has caused public concerns regarding the biological effects of electromagnetic radiations on human health. Some early reports indicated a wide variety of non-thermal effects of electromagnetic radiation on amphibians such as the alterations of the pattern of muscle extractions. This study is aimed at investigating the effects of exposure to radiofrequency (RF) radiation emitted from mobile phone jammers on the pulse height of contractions, the time interval between two subsequent contractions and the latency period of frog’s isolated gastrocnemius muscle after stimulation with single square pulses of 1V (1 Hz). Materials and Methods Frogs were kept in plastic containers in a room. Animals in the jammer group were exposed to radiofrequency (RF) radiation emitted from a common Jammer at a distance of 1m from the jammer’s antenna for 2 hours while the control frogs were only sham exposed. Then animals were sacrificed and isolated gastrocnemius muscles were exposed to on/off jammer radiation for 3 subsequent 10 minute intervals. Isolated gastrocnemius muscles were attached to the force transducer with a string. Using a PowerLab device (26-T), the pattern of muscular contractions was monitored after applying single square pulses of 1V (1 Hz) as stimuli. Results The findings of this study showed that the pulse height of muscle contractions could not be affected by the exposure to electromagnetic fields. However, the latency period was effectively altered in RF-exposed samples. However, none of the experiments could show an alteration in the time interval between two subsequent contractions after exposure to electromagnetic fields. Conclusion These findings support early reports which indicated a wide variety of non-thermal effects of electromagnetic radiation on amphibians including the effects on the pattern of muscle extractions. PMID:26396969

  7. Prenatal Alcohol Exposure and Chronic Mild Stress Differentially Alter Depressive- and Anxiety-Like Behaviors in Male and Female Offspring

    PubMed Central

    Hellemans, Kim G. C.; Verma, Pamela; Yoon, Esther; Yu, Wayne K.; Young, Allan H.; Weinberg, Joanne

    2016-01-01

    Background Fetal Alcohol Spectrum Disorder (FASD) is associated with numerous neuro behavioral alterations, as well as disabilities in a number of domains, including a high incidence of depression and anxiety disorders. Prenatal alcohol exposure (PAE) also alters hypothalamic-pituitary-adrenal (HPA) function, resulting in increased responsiveness to stressors and HPA dysregulation in adulthood. Interestingly, data suggest that pre-existing HPA abnormalities may be a major contributory factor to some forms of depression, particularly when an individual is exposed to stressors later in life. We tested the hypothesis that exposure to stressors in adulthood may unmask an increased vulnerability to depressive- and anxiety-like behaviors in PAE animals. Methods Male and female offspring from prenatal alcohol (PAE), pair-fed (PF), and ad libitumfed control (C) treatment groups were tested in adulthood. Animals were exposed to 10 consecutive days of chronic mild stress (CMS), and assessed in a battery of well-validated tasks sensitive to differences in depressive- and / or anxiety-like behaviors. Results We report here that the combination of PAE and CMS in adulthood increases depressive- and anxiety-like behaviors in a sexually dimorphic manner. PAE males showed impaired hedonic responsivity (sucrose contrast test), locomotor hyperactivity (open field), and alterations in affiliative and nonaffiliative social behaviors (social interaction test) compared to control males. By contrast, PAE and, to a lesser extent, PF, females showed greater levels of “behavioral despair” in the forced swim test, and PAE females showed altered behavior in the final 5 minutes of the social interaction test compared to control females. Conclusions These data support the possibility that stress may be a mediating or contributing factor in the psychopathologies reported in FASD populations. PMID:20102562

  8. Prenatal di-n-butyl phthalate exposure alters reproductive functions at adulthood in male rats.

    PubMed

    Giribabu, Nelli; Sainath, Sri Bhashyam; Sreenivasula Reddy, Pamanji

    2014-05-01

    This study was aimed to investigate the reproductive health in adult male rats exposed to di-n-butyl phthalate (DBP) during embryonic development. Pregnant rats were injected with DBP and F1 male rats were weaned and on postnatal day 100, used for mating with normal cycling females to assess reproductive performance. After completion of cohabitation period, rats were analyzed for other reproductive end points. Transplacental exposure to DBP significantly decreased fertility in adult male rats. Prenatal exposure to DBP significantly decreased sperm density, number of motile sperms, viable sperms, and hypoosmotic swelling tail coiled sperms with an increase in morphological abnormalities in sperms. Testicular steroidogenic enzyme activity levels and serum testosterone levels were significantly decreased in rats exposed to DBP during embryonic development. In conclusion, transplacental exposure to DBP impairs male reproductive performance by decreasing steroidogenesis and spermatogenesis. PMID:22489061

  9. EXPOSURE TO CONCENTRATED AMBIENT PARTICLES IN DETROIT ALTERS HEART RATE VARIABILITY IN SPONTANEOUSLY HYPERTENSIVE RATS

    EPA Science Inventory

    Elevations in airborne particulate matter (PM) are linked to increased mortality and morbidity in humans with cardiopulmonary disease. Clinical studies show that PM is associated with altered heart rate variability (HRV) and suggests that loss of autonomic control may underlie ca...

  10. POTENTIAL ALTERATIONS IN GENE EXPRESSION ASSOCIATED WITH CARCINOGEN EXPOSURE IN MYA ARENARIA

    EPA Science Inventory

    Gonadal cancers in soft-shell clams (Mya arenaria) have been found at high prevalences (20-40%) in populations in eastern Maine. The aetiology of these tumours is unknown. We hypothesized that gene expression would be altered in gonadal tumours and that examination of gene expres...

  11. [Alteration of thyroid hormone secretion after long-term exposure to low doses of endocrine disruptor DDT].

    PubMed

    Iaglova, N V; Iaglov, V V

    2014-01-01

    Endocrine disruptors are exogenous substances that exhibit hormone-like action and consequently disrupt homeostatic action of endogenous hormones. DDT is the most common disruptor. The objective was to evaluate changes in thyroid hormone secretion after long-term exposure to low doses of DDT. The experiment was performed on male Wistar rats. The rats were given DDT at doses of 1.89±0.86 мg/kg/day and 7.77±0.17 мg/kg/day for 6 and 10 weeks. Dose dependent increase of serum total thyroxine, total triiodthyronine, and thyroid peroxidase was revealed after 6 weeks exposure. After 10 weeks free thyroxine secretion was reduced. Such alterations of the thyroid status are typical for iodine deficient goiter. The data obtained indicate that the main mechanism of DDT action includes disruption of thyroxine secretion by thyrocytes, but not inhibition of deiodinase activity and decrease of blood thyroid binding proteins. PMID:25552505

  12. Long-term exposure of 3T3 fibroblast cells to endocrine disruptors alters sensitivity to oxidative injury.

    PubMed

    Nishimura, Yuka; Nakai, Yasuyoshi; Tanaka, Aiko; Nagao, Tetsuji; Fukushima, Nobuyuki

    2014-07-01

    When Swiss 3T3 fibroblasts were exposed to bisphenol A (BPA) or nonylphenol (NP) within a range of 0.1-100 nM for 30-45 days, increased resistance to oxidative injury was found. Western blot analysis indicated concomitant increased expression of bcl-2 protein and reduced histone methylation levels in cells after BPA or NP exposure. Using a heterologous expression system, both chemicals could stimulate G protein-coupled receptor 30 (GPR30), a transmembrane estrogen receptor predominantly expressed in 3T3 cells, at lower concentrations, which gave increased survival. Taken together, these results suggest that BPA or NP exposure might cause alterations in cellular activity against oxidative stress, possibly through GPR30. PMID:24604882

  13. Prenatal cadmium exposure dysregulates sonic hedgehog and Wnt/beta-catenin signaling in the thymus resulting in altered thymocyte development

    SciTech Connect

    Hanson, Miranda L.; Brundage, Kathleen M.; Schafer, Rosana; Tou, Janet C.; Barnett, John B.

    2010-01-15

    Cadmium (Cd) is both an environmental pollutant and a component of cigarette smoke. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports in the literature of immunomodulatory effects of prenatal exposure to Cd. The sonic hedgehog (Shh) and Wnt/beta-catenin pathways are required for thymocyte maturation. Several studies have demonstrated that Cd exposure affects these pathways in different organ systems. This study was designed to investigate the effect of prenatal Cd exposure on thymocyte development, and to determine if these effects were linked to dysregulation of Shh and Wnt/beta-catenin pathways. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose (10 ppm) of Cd throughout pregnancy and effects on the thymus were assessed on the day of birth. Thymocyte phenotype was determined by flow cytometry. A Gli:luciferase reporter cell line was used to measure Shh signaling. Transcription of target genes and translation of key components of both signaling pathways were assessed using real-time RT-PCR and western blot, respectively. Prenatal Cd exposure increased the number of CD4{sup +} cells and a subpopulation of double-negative cells (DN; CD4{sup -}CD8{sup -}), DN4 (CD44{sup -}CD25{sup -}). Shh and Wnt/beta-catenin signaling were both decreased in the thymus. Target genes of Shh (Patched1 and Gli1) and Wnt/beta-catenin (c-fos, and c-myc) were affected differentially among thymocyte subpopulations. These findings suggest that prenatal exposure to Cd dysregulates two signaling pathways in the thymus, resulting in altered thymocyte development.

  14. Exposure to a Social Stressor Alters the Structure of the Intestinal Microbiota: Implications for Stressor-Induced Immunomodulation

    PubMed Central

    Bailey, Michael T.; Dowd, Scot E.; Galley, Jeffrey D.; Hufnagle, Amy R.; Allen, Rebecca G.; Lyte, Mark

    2010-01-01

    The bodies of most animals are populated by highly complex and genetically diverse communities of microorganisms. The majority of these microbes reside within the intestines in largely stable but dynamically interactive climax communities that positively interact with their host. Studies from this laboratory have shown that stressor exposure impacts the stability of the microbiota and leads to bacterial translocation. The biological importance of these alterations, however, is not well understood. To determine whether the microbiome contributes to stressor-induced immunoenhancement, mice were exposed to a social stressor called social disruption (SDR), that increases circulating cytokines and primes the innate immune system for enhanced reactivity. Bacterial populations in the cecum were characterized using bacterial tag-encoded FLX amplicon pyrosequencing. Stressor exposure significantly changed the community structure of the microbiota, particularly when the microbiota were assessed immediately after stressor exposure. Most notably, stressor exposure decreased the relative abundance of bacteria in the genus Bacteroides, while increasing the relative abundance of bacteria in the genus Clostridium. The stressor also increased circulating levels of IL-6 and MCP-1, which were significantly correlated with stressor-induced changes to three bacterial genera (i.e., Coprococcus, Pseudobutyrivibrio, and Dorea). In follow up experiments, mice were treated with an antibiotic cocktail to determine whether reducing the microbiota would abrogate the stressor-induced increases in circulating cytokines. Exposure to SDR failed to increase IL-6 and MCP-1 in the antibiotic treated mice. These data show that exposure to SDR significantly affects bacterial populations in the intestines, and remarkably also suggest that the microbiota are necessary for stressor-induced increases in circulating cytokines. PMID:21040780

  15. Acute chlorine gas exposure produces transient inflammation and a progressive alteration in surfactant composition with accompanying mechanical dysfunction.

    PubMed

    Massa, Christopher B; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L; Gow, Andrew J

    2014-07-01

    Acute Cl2 exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl2 inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60ppm-hour Cl2 dose, and were euthanized 3, 24 and 48h later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24h, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24h. Cl2 exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO3(-) or NO2(-). Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl2 exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48h, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl2 inhalation. PMID:24582687

  16. Acute Chlorine Gas Exposure Produces Transient Inflammation and a Progressive Alteration in Surfactant Composition with Accompanying Mechanical Dysfunction

    PubMed Central

    Massa, Christopher B; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L; Gow, Andrew J

    2014-01-01

    Acute Cl2 exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl2 inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60 ppm-hour Cl2 dose, and were sacrificed 3, 24 and 48 hours later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24 hours, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24 hours. Cl2 exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO3− or NO2−. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl2 exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48 hours, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl2 inhalation. PMID:24582687

  17. Developmental neurotoxicity of organophosphorous pesticides: fetal and neonatal exposure to chlorpyrifos alters sex-specific behaviors at adulthood in mice.

    PubMed

    Ricceri, Laura; Venerosi, Aldina; Capone, Francesca; Cometa, Maria Francesca; Lorenzini, Paola; Fortuna, Stefano; Calamandrei, Gemma

    2006-09-01

    Developmental exposure to the organophosphorous insecticide chlorpyrifos (CPF) induces long-term effects on brain and behavior in laboratory rodents. We evaluated in adult mice the behavioral effects of either fetal and/or neonatal CPF exposure at doses not inhibiting fetal and neonatal brain cholinesterase. CPF (3 or 6 mg/kg) was given by oral treatment to pregnant females on gestational days 15-18 and offspring were treated sc (1 or 3 mg/kg) on postnatal days (PNDs) 11-14. Serum and brain acetylcholinesterase (AChE) activity was evaluated at birth and 24 h from termination of postnatal treatments. On PND 70, male mice were assessed for spontaneous motor activity in an open-field test and in a socioagonistic encounter with an unfamiliar conspecific. Virgin females underwent a maternal induction test following presentation of foster pups. Both sexes were subjected to a plus-maze test to evaluate exploration and anxiety levels. Gestational and postnatal CPF exposure (higher doses) affected motor activity in the open field and enhanced synergically agonistic behavior. Postnatal CPF exposure increased maternal responsiveness toward pups in females. Mice of both sexes exposed to postnatal CPF showed reduced anxiety response in the plus-maze, an effect greater in females. Altogether, developmental exposure to CPF at doses that do not cause brain AChE inhibition induces long-term alterations in sex-specific behavior patterns of the mouse species. Late neonatal exposure on PNDs 11-14 was the most effective in causing behavioral changes. These findings support the hypothesis that developmental CPF may represent a risk factor for increased vulnerability to neurodevelopmental disorders in humans. PMID:16760416

  18. Exposure to N-Ethyl-N-Nitrosourea in Adult Mice Alters Structural and Functional Integrity of Neurogenic Sites

    PubMed Central

    Capilla-Gonzalez, Vivian; Gil-Perotin, Sara; Ferragud, Antonio; Bonet-Ponce, Luis; Canales, Juan Jose; Garcia-Verdugo, Jose Manuel

    2012-01-01

    Background Previous studies have shown that prenatal exposure to the mutagen N-ethyl-N-nitrosourea (ENU), a N-nitroso compound (NOC) found in the environment, disrupts developmental neurogenesis and alters memory formation. Previously, we showed that postnatal ENU treatment induced lasting deficits in proliferation of neural progenitors in the subventricular zone (SVZ), the main neurogenic region in the adult mouse brain. The present study is aimed to examine, in mice exposed to ENU, both the structural features of adult neurogenic sites, incorporating the dentate gyrus (DG), and the behavioral performance in tasks sensitive to manipulations of adult neurogenesis. Methodology/Principal Findings 2-month old mice received 5 doses of ENU and were sacrificed 45 days after treatment. Then, an ultrastructural analysis of the SVZ and DG was performed to determine cellular composition in these regions, confirming a significant alteration. After bromodeoxyuridine injections, an S-phase exogenous marker, the immunohistochemical analysis revealed a deficit in proliferation and a decreased recruitment of newly generated cells in neurogenic areas of ENU-treated animals. Behavioral effects were also detected after ENU-exposure, observing impairment in odor discrimination task (habituation-dishabituation test) and a deficit in spatial memory (Barnes maze performance), two functions primarily related to the SVZ and the DG regions, respectively. Conclusions/Significance The results demonstrate that postnatal exposure to ENU produces severe disruption of adult neurogenesis in the SVZ and DG, as well as strong behavioral impairments. These findings highlight the potential risk of environmental NOC-exposure for the development of neural and behavioral deficits. PMID:22238669

  19. The characteristics of coarse particulate matter air pollution associated with alterations in blood pressure and heart rate during controlled exposures

    PubMed Central

    Morishita, Masako; Bard, Robert L.; Wang, Lu; Das, Ritabrata; Dvonch, J. Timothy; Spino, Catherine; Mukherjee, Bhramar; Sun, Qinghua; Harkema, Jack R.; Rajagopalan, Sanjay; Brook, Robert D.

    2015-01-01

    Although fine particulate matter (PM) air pollution <2.5 μm in aerodynamic diameter (PM2.5) is a leading cause of global morbidity and mortality, the potential health effects of coarse PM (2.5–10 μm in aerodynamic diameter; PM10–2.5) remain less clearly understood. We aimed to elucidate the components within coarse PM most likely responsible for mediating these hemodynamic alterations. Thirty-two healthy adults (25.9 ± 6.6 years) were exposed to concentrated ambient coarse PM (CAP) (76.2 ± 51.5 μg/m3) and filtered air (FA) for 2 h in a rural location in a randomized double-blind crossover study. The particle constituents (24 individual elements, organic and elemental carbon) were analyzed from filter samples and associated with the blood pressure (BP) and heart rate (HR) changes occurring throughout CAP and FA exposures in mixed model analyses. Total coarse PM mass along with most of the measured elements were positively associated with similar degrees of elevations in both systolic BP and HR. Conversely, total PM mass was unrelated, whereas only two elements (Cu and Mo) were positively associated with and Zn was inversely related to diastolic BP changes during exposures. Inhalation of coarse PM from a rural location rapidly elevates systolic BP and HR in a concentration-responsive manner, whereas the particulate composition does not appear to be an important determinant of these responses. Conversely, exposure to certain PM elements may be necessary to trigger a concomitant increase in diastolic BP. These findings suggest that particulate mass may be an adequate metric of exposure to predict some, but not all, hemodynamic alterations induced by coarse PM mass. PMID:25227729

  20. Acute prenatal exposure to a moderate dose of valproic acid increases social behavior and alters gene expression in rats.

    PubMed

    Cohen, Ori S; Varlinskaya, Elena I; Wilson, Carey A; Glatt, Stephen J; Mooney, Sandra M

    2013-12-01

    Prenatal exposure to moderate doses of valproic acid (VPA) produces brainstem abnormalities, while higher doses of this teratogen elicit social deficits in the rat. In this pilot study, we examined effects of prenatal exposure to a moderate dose of VPA on behavior and on transcriptomic expression in three brain regions that mediate social behavior. Pregnant Long Evans rats were injected with 350 mg/kg VPA or saline on gestational day 13. A modified social interaction test was used to assess social behavior and social preference/avoidance during early and late adolescence and in adulthood. VPA-exposed animals demonstrated more social investigation and play fighting than control animals. Social investigation, play fighting, and contact behavior also differed as a function of age; the frequency of these behaviors increased in late adolescence. Social preference and locomotor activity under social circumstances were unaffected by treatment or age. Thus, a moderate prenatal dose of VPA produces behavioral alterations that are substantially different from the outcomes that occur following exposure to a higher dose. At adulthood, VPA-exposed subjects exhibited transcriptomic abnormalities in three brain regions: anterior amygdala, cerebellar vermis, and orbitofrontal cortex. A common feature among the proteins encoded by the dysregulated genes was their ability to be modulated by acetylation. Analysis of the expression of individual exons also revealed that genes involved in post-translational modification and epigenetic regulation had particular isoforms that were ubiquitously dysregulated across brain regions. The vulnerability of these genes to the epigenetic effects of VPA may highlight potential mechanisms by which prenatal VPA exposure alters the development of social behavior. PMID:24055786

  1. Environmental enrichment alters structural plasticity of the adolescent brain but does not remediate the effects of prenatal nicotine exposure.

    PubMed

    Mychasiuk, Richelle; Muhammad, Arif; Kolb, Bryan

    2014-07-01

    Exposure to both drugs of abuse and environmental enrichment (EE) are widely studied experiences that induce large changes in dendritic morphology and synaptic connectivity. As there is an abundance of literature using EE as a treatment strategy for drug addiction, we sought to determine whether EE could remediate the effects of prenatal nicotine (PN) exposure. Using Golgi-Cox staining, we examined eighteen neuroanatomical parameters in four brain regions [medial prefrontal cortex (mPFC), orbital frontal cortex (OFC), nucleus accumben, and Par1] of Long-Evans rats. EE in adolescence dramatically altered structural plasticity in the male and female brain, modifying 60% of parameters investigated. EE normalized three parameters (OFC spine density and dendritic branching and mPFC dendritic branching) in male offspring exposed to nicotine prenatally but did not remediate any measures in female offspring. PN exposure interfered with adolescent EE-induced changes in five neuroanatomical measurements (Par1 spine density and dendritic branching in both male and female offspring, and mPFC spine density in male offspring). And in four neuroanatomical parameters examined, PN exposure and EE combined to produce additive effects [OFC spine density in females and mPFC dendritic length (apical and basilar) and branching in males]. Despite demonstrated efficacy in reversing drug addiction, EE was not able to reverse many of the PN-induced changes in neuronal morphology, indicating that modifications in neural circuitry generated in the prenatal period may be more resistant to change than those generated in the adult brain. PMID:24616009

  2. Influence of triphenyltin exposure on the hypothalamus-pituitary-gonad axis in male Sebastiscus marmoratus.

    PubMed

    Sun, Lingbin; Zhang, Jiliang; Zuo, Zhenghong; Chen, Yixin; Wang, Xinhong; Huang, Xin; Wang, Chonggang

    2011-08-01

    Both triphenyltin (TPT) and tributyltin (TBT) have been used as ingredients of antifouling biocides. However, far fewer studies addressing the reproductive toxicity of TPT on fishes are available than for TBT. The present study was conducted to investigate the effects of TPT at environmentally relevant concentrations on testicular development in male rockfish Sebastiscus marmoratus and to gain insight into its mechanism of action. After exposure for 48 days, the gonadosomatic index had decreased, and there was a reduced number of mature sperm and an abundance of the late stages of spermatocysts in the testes. Although the testosterone levels in the testes were elevated and the 17β-estradiol levels were decreased, spermatogenesis was suppressed. The activity of γ-glutamyl transpeptidase (which is used as a Sertoli cell marker) was decreased after TPT exposure, and serious interstitial fibrosis was observed in the interlobular septa of the testes exposed to TPT. The increased expression of cGnRH-II (chicken-II type gonadotropin-releasing hormone) and sGnRH (salmon-type GnRH), and the decreased expression of LHβ (luteinizing hormone) in the fish brains were detected. The expression of FSHβ (follicle-stimulating hormone) was decreased at day 21, while was increased slightly at day 48. The changes of cGnRH-II, sGnRH, FSHβ and LHβ mRNA levels might have mainly resulted from the alteration of the sex steroids via feedback mechanisms. The decrease of the FSHβ mRNA might have been one of the reasons causing the dysfunction of Sertoli cells, which play a critical role during spermatogenesis. The results suggested that TPT could perturb the function of hypothalamus-pituitary-gonad axis, and inhibiting the spermatogenesis. PMID:21641294

  3. Exposure of fluid milk to LED light negatively affects consumer perception and alters underlying sensory properties.

    PubMed

    Martin, Nicole; Carey, Nancy; Murphy, Steven; Kent, David; Bang, Jae; Stubbs, Tim; Wiedmann, Martin; Dando, Robin

    2016-06-01

    Fluid milk consumption per capita in the United States has been steadily declining since the 1940s. Many factors have contributed to this decline, including the increasing consumption of carbonated beverages and bottled water. To meet the challenge of stemming the decline in consumption of fluid milk, the dairy industry must take a systematic approach to identifying and correcting for factors that negatively affect consumers' perception of fluid milk quality. To that end, samples of fluid milk were evaluated to identify factors, with a particular focus on light-emitting diode (LED) light exposure, which negatively affect the perceived sensory quality of milk, and to quantify their relative effect on the consumer's experience. Fluid milk samples were sourced from 3 processing facilities with varying microbial postprocessing contamination patterns based on historical testing. The effect of fat content, light exposure, age, and microbiological content were assayed across 23 samples of fluid milk, via consumer, descriptive sensory, and instrumental analyses. Most notably, light exposure resulted in a broad negative reaction from consumers, more so than samples with microbiological contamination exceeding 20,000 cfu/mL on days approaching code. The predominant implication of the study is that a component of paramount importance in ensuring the success of the dairy industry would be to protect fluid milk from all sources of light exposure, from processing plant to consumer. PMID:27060830

  4. PERINATAL EXPOSURE TO ENDOCRINE DISRUPTING CHEMICALS: POTENTIAL ROLE OF HORMONAL ALTERATIONS IN INITIATING ADULT REPRODUCTIVE ANOMALIES

    EPA Science Inventory

    The primary hypothesis to be tested in this series of studies is whether or not exposure to environmental agents, during certain key periods of development, will increase the risk of specific anomalies of the reproductive system. Embedded in this hypothesis is the assumption that...

  5. Neonatal hyperoxic lung injury favorably alters adult right ventricular remodeling response to chronic hypoxia exposure

    PubMed Central

    Goss, Kara N.; Cucci, Anthony R.; Fisher, Amanda J.; Albrecht, Marjorie; Frump, Andrea; Tursunova, Roziya; Gao, Yong; Brown, Mary Beth; Petrache, Irina; Tepper, Robert S.; Ahlfeld, Shawn K.

    2015-01-01

    The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0–4 or 0–10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults. PMID:25659904

  6. Developmental Exposure to a Dopaminergic Toxicant Produces Altered Locomotor Activity in Larval Zebrafish

    EPA Science Inventory

    In an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after developmental exposure to various classes of prototypic drugs that act on the central nervous system. ...

  7. Exposure to hyperoxia in the neonatal period alters bone marrow function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oxygen is often life saving in preterm infants, however, excessive exposure may lead to blood vessel and tissue injury in the lung and retina. Oxygen-treated neonates often exhibit bone marrow (BM) suppression requiring blood product transfusions. However, we do not know whether oxygen is directly t...

  8. Perinatal ethanol exposure alters met-enkephalin levels of male and female rats.

    PubMed

    Lugo, Joaquin N; Wilson, Marlene A; Kelly, Sandra J

    2006-01-01

    This study used a rat model of Fetal Alcohol Syndrome to investigate whether combined prenatal and postnatal ethanol exposure affects met-enkephalin levels in the brains of male and female Long-Evans adult rats. Intragastric ethanol was administered to a group of rats (ET) from gestational day (GD) 1 through 22 and from postnatal day (PD) 2 through 10. The control groups consisted of a nontreated control group (NTC) and an intubated control group (IC) that received the intragastric intubation procedure but no exposure to ethanol. We measured met-enkephalin levels in the prefrontal cortex, nucleus accumbens, hypothalamus, central and basolateral nucleus of amygdala and ventral tegmental area. Met-enkephalin levels in the hypothalamus of male and female ET animals were significantly higher than those in either the NTC or IC animals. Met-enkephalin levels in the central nucleus of the amygdala of male and female ET animals were significantly lower than the levels in the NTC animals. Met-enkephalin levels in the nucleus accumbens of ET females were significantly greater than those in the IC females. These results demonstrate that the combination of prenatal and postnatal ethanol exposure affects basal met-enkephalin levels in specific regions in a sex-specific manner. These changes in met-enkephalin levels may explain how early ethanol exposure affects opioid-regulated behaviors such as social play, sexual behavior, and other social behaviors. PMID:16457985

  9. GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE PERMANENTLY ALTERS REPRODUCTIVE COMPETENCE IN THE CD-1 MOUSE

    EPA Science Inventory

    While the adult mouse Leydig cell (LC) has been considered refractory to cytotoxic destruction by ethane dimethanesulfonate (EDS), the potential consequences of exposure during reproductive development in this species are unknown. Herein pregnant CD-1 mice were treated with 160 m...

  10. Neonatal hyperoxic lung injury favorably alters adult right ventricular remodeling response to chronic hypoxia exposure.

    PubMed

    Goss, Kara N; Cucci, Anthony R; Fisher, Amanda J; Albrecht, Marjorie; Frump, Andrea; Tursunova, Roziya; Gao, Yong; Brown, Mary Beth; Petrache, Irina; Tepper, Robert S; Ahlfeld, Shawn K; Lahm, Tim

    2015-04-15

    The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0-4 or 0-10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults. PMID:25659904

  11. Tracheal Morphologic and Protein Alterations FollowingShort-Term Cigarette Mainstream Smoke Exposure to Rats.

    PubMed

    Carter, Charleata A; Misra, Manoj; Maronpot, Robert R

    2012-09-01

    A short-term 5-day nose-only cigarette smoke exposure study was conducted in Fisher 344 rats to identify smoke-induced tracheal protein changes. Groups of 10 male and female 5 week old rats were assigned to 1 of 4 exposure groups. Animals received filtered air, or 75, 200 or 400 mg total particulate matter (TPM)/m(3) of diluted 3R4F Kentucky reference cigarette mainstream smoke. Exposures were conducted for 3 hrs/day, for 5 consecutive days. Tracheas from half the rats were processed for pathology, and tracheas from the other half of the rats frozen immediately for proteomics. We hypothesized that smoke will activate tracheal inflammatory, apoptotic, proliferative, and stress-induced pathways. Mucosal epithelial toxicity from the inhaled material was evidenced by cilia shortening and loss of tracheal mucosal epithelium in smoke-exposed animals. Mucosal thinning occurred in all smoke-exposed groups with hyperplastic reparative responses in the 200 and 400 mg TPM/m(3) groups. Tracheal lysates from control vs. treated animals were screened for 800 proteins using antibody-based microarray technology and subsequently the most changed proteins evaluated by Western blot. Tracheal proteins expressed at high levels that were markedly increased or decreased by smoke exposure depended on dose and gender and included caspase 5, ERK 1/2 and p38. Signaling pathways common between the morphologic and protein changes were stress, apoptosis, cell cycle control, cell proliferation and survival. Changes in identified proteins affected by smoke exposure were associated with tracheal mucosal pathology, may induce functional tracheal changes, and could serve as early indicators of tracheal damage and associated disease. PMID:22988338

  12. Temperature, hydric environment, and prior pathogen exposure alter the experimental severity of chytridiomycosis in boreal toads

    USGS Publications Warehouse

    Murphy, Peter J.; St-Hilaire, Sophie; Corn, Paul Stephen

    2011-01-01

    Prevalence of the pathogen Batrachochytrium dendrobatidis (Bd), implicated in amphibian population declines worldwide, is associated with habitat moisture and temperature, but few studies have varied these factors and measured the response to infection in amphibian hosts. We evaluated how varying humidity, contact with water, and temperature affected the manifestation of chytridiomycosis in boreal toads Anaxyrus (Bufo) boreas boreas and how prior exposure to Bd affects the likelihood of survival after re-exposure, such as may occur seasonally in long-lived species. Humidity did not affect survival or the degree of Bd infection, but a longer time in contact with water increased the likelihood of mortality. After exposure to ~106 Bd zoospores, all toads in continuous contact with water died within 30 d. Moreover, Bd-exposed toads that were disease-free after 64 d under dry conditions, developed lethal chytridiomycosis within 70 d of transfer to wet conditions. Toads in unheated aquaria (mean = 15°C) survived less than 48 d, while those in moderately heated aquaria (mean = 18°C) survived 115 d post-exposure and exhibited behavioral fever, selecting warmer sites across a temperature gradient. We also found benefits of prior Bd infection: previously exposed toads survived 3 times longer than Bd-naïve toads after re-exposure to 106 zoospores (89 vs. 30 d), but only when dry microenvironments were available. This study illustrates how the outcome of Bd infection in boreal toads is environmentally dependent: when continuously wet, high reinfection rates may overwhelm defenses, but periodic drying, moderate warming, and previous infection may allow infected toads to extend their survival.

  13. Acute chlorine gas exposure produces transient inflammation and a progressive alteration in surfactant composition with accompanying mechanical dysfunction

    SciTech Connect

    Massa, Christopher B.; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L.; Gow, Andrew J.

    2014-07-01

    Acute Cl{sub 2} exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl{sub 2} inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60 ppm-hour Cl{sub 2} dose, and were euthanized 3, 24 and 48 h later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24 h, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24 h. Cl{sub 2} exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO{sub 3}{sup −} or NO{sub 2}{sup −}. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl{sub 2} exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48 h, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl{sub 2} inhalation. - Highlights: • Effect of 60 ppm*hr Cl{sub 2} gas on lung inflammation and mechanical function examined. • Pulmonary inflammation is transient and minor.

  14. Previous exposure of predatory fish to a pesticide alters palatability of larval amphibian prey.

    PubMed

    Hanlon, Shane M; Parris, Matthew J

    2013-12-01

    Habitat preferences of organisms are reliant on a variety of factors. For amphibians specifically, preferences can depend on factors such as food availability, water quality, and the presence of potential predators. Because some amphibians breed in permanent bodies of water (e.g., ponds), the threat of predation (e.g., from fish) is constant. Thus, some amphibians are unpalatable to many predators, allowing them to coexist in the same habitats. However, the addition of anthropogenic stressors (i.e., pesticides) may alter the perceived palatability of prey items to predators. The authors tested the hypothesis that bluegill fish (Lepomis macrochirus), previously exposed to the pesticide carbaryl, would consume more unpalatable prey (Fowler's toad [Anaxyrus fowleri] tadpoles) than unexposed predators. Carbaryl is a pesticide that attacks the nervous system and is linked to taste sense in organisms. Moreover, the authors conducted an identical test using palatable prey (gray treefrog [Hyla versicolor] tadpoles) and predicted that no change in preference would be observed. In support of the primary hypothesis, bluegill exposed to the highest concentration of carbaryl consumed more A. fowleri tadpoles compared with those exposed to carbaryl at the lowest concentration or water control. Moreover, an effect of carbaryl on predation success on H. versicolor tadpoles was not observed. The present study shows that an anthropogenic stressor (carbaryl) can alter the perceived palatability of noxious prey to fish predators, potentially altering predator-prey relationships in natural settings. PMID:24383102

  15. Previous exposure of predatory fish to a pesticide alters palatability of larval amphibian prey.

    PubMed

    Hanlon, Shane M; Parris, Matthew J

    2013-09-01

    Habitat preferences of organisms are reliant upon a variety of factors. Specifically with amphibians, preferences can depend on factors such as food availability, water quality, or the presence of potential predators. Because some amphibians breed in permanent bodies of water (e.g., ponds), the threat of predation (e.g., from fish) is constant. Thus, some amphibians are unpalatable to many predators, allowing them to coexist in the same habitats. However, the addition of anthropogenic stressors (i.e., pesticides) may alter the perceived palatability of prey items to predators. We tested the hypothesis that bluegill fish (Lepomis macrochirus), previously exposed to the pesticide carbaryl, would consume more unpalatable prey (Fowler's toad [Anaxyrus fowleri] tadpoles) than unexposed predators. Carbaryl is a pesticide that attacks the nervous system and is linked to taste sense in organisms. Moreover, we conducted an identical test using palatable prey (gray treefrog [Hyla versicolor] tadpoles) and predicted that no change in preference would be observed. In support of our primary hypothesis, bluegill exposed to the highest concentration of carbaryl consumed more A. folweri tadpoles compared to those exposed to carbaryl at the lowest concentration or water control. Moreover, an effect of carbaryl on predation success on H. versicolor tadpoles was not observed. Our study shows that an anthropogenic stressor (carbaryl) can alter the perceived palatability of noxious prey to fish predators, potentially altering predator-prey relationships in natural settings. Environ Toxicol Chem © 2013 SETAC. PMID:23996644

  16. Low-frequency pulsed electromagnetic field exposure can alter neuroprocessing in humans

    PubMed Central

    Robertson, John A.; Théberge, Jean; Weller, Julie; Drost, Dick J.; Prato, Frank S.; Thomas, Alex W.

    2010-01-01

    Extremely low-frequency magnetic fields (from DC to 300 Hz) have been shown to affect pain sensitivity in snails, rodents and humans. Here, a functional magnetic resonance imaging study demonstrates how the neuromodulation effect of these magnetic fields influences the processing of acute thermal pain in normal volunteers. Significant interactions were found between pre- and post-exposure activation between the sham and exposed groups for the ipsilateral (right) insula, anterior cingulate and bilateral hippocampus/caudate areas. These results show, for the first time, that the neuromodulation induced by exposure to low-intensity low-frequency magnetic fields can be observed in humans using functional brain imaging and that the detection mechanism for these effects may be different from those used by animals for orientation and navigation. Magnetoreception may be more common than presently thought. PMID:19656823

  17. Dietary exposure to Aroclor 1254 alters gene expression in Xenopus laevis frogs.

    PubMed

    Jelaso, Anna M; DeLong, Cari; Means, Jay; Ide, Charles F

    2005-05-01

    Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that contribute to worldwide health problems. Despite data associating PCBs with adverse health effects, decisions to clean up contaminated sites remain controversial. Cleanup decisions are typically based on risk assessment methods that are not sensitive enough to detect subtle changes in health. We have recently shown that gene expression signatures can serve as sensitive molecular biomarkers of exposure and related health effects. Our initial studies were carried out with developing Xenopus laevis tadpoles that were exposed to the PCB mixture Aroclor 1254 (A1254) for 2 days. A1254 was dissolved in dimethyl sulfoxide and added to the aquarium water for rapid loading of PCBs into the tadpole tissue. These studies showed that increases in the expression of specific genes occurred independent of adverse health effects, and decreases in specific genes correlated with the appearance of observable health effects, including decreased survival and gross morphological and behavioral abnormalities. In this report, we extend our previous work to test the use of gene expression signatures as biomarkers in frogs exposed to PCBs through the diet from early tadpole stages through metamorphosis. This work showed that chronic low-dose exposure to A1254 (24 ppm) in food produced tissue levels of 17 ppm and increased gene expression of nerve growth factor and proopiomelanocortin independent of adverse health effects. Exposure to higher doses of A1254 (200 ppm) produced tissue levels of 80 ppm and increased expression of p450 1A1, also, independent of adverse health effects. This work provides further evidence for the use of gene expression changes as biomarkers of exposure to PCBs. PMID:15721885

  18. Subacute Microcystin-LR Exposure Alters the Metabolism of Thyroid Hormones in Juvenile Zebrafish (Danio Rerio)

    PubMed Central

    Liu, Zidong; Tang, Rong; Li, Dapeng; Hu, Qing; Wang, Ying

    2015-01-01

    Microcystin-LR (MC-LR) has been detected extensively in the aquatic environment and has the potential to disturb the thyroid endocrine system. However, limited information is available on the effects of subacute MC-LR exposure on fish thyroid hormone (TH) metabolism. In the present study, juvenile zebrafish (Danio rerio) were exposed to MC-LR at environmentally relevant concentrations (0, 1, 5, and 25 μg/L) for 28 days. Whole-body TH content and thyroid follicle histology were used as direct endpoints to assess thyroid disruption. The activities of iodothyronine deiodinases (IDs) and the transcription of selected genes associated with TH synthesis were also investigated to study the underlying mechanisms of endocrine disruption. Exposure of zebrafish to MC-LR significantly increased whole-body thyroxine (T4) content but decreased whole-body triiodothyronine (T3) content. We also observed hypertrophy and hyperplasia of the thyroid follicle epithelial cells, as well as up-regulation of corticotropin-releasing hormone (CRH), thyroid-stimulating hormone (TSH), thyroid peroxidase (TPO), and transthyretin (TTR) genes. The decreases in ID1 and ID2 activities coupled with an increase in ID3 activity were observed in MC-LR treatment groups. These results demonstrate that exposure to MC-LR at environmental concentrations results in the disturbance of TH homeostasis by disrupting the synthesis and conversion of THs. PMID:25647779

  19. Developmental lead exposure alters gene expression of metabotropic glutamate receptors in rat hippocampal neurons.

    PubMed

    Xu, Jian; Yan, Chong-Huai; Wu, Sheng-Hu; Yu, Xiao-Dan; Yu, Xiao-Gang; Shen, Xiao-Ming

    2007-02-21

    Exposure to lead in utero and in infancy is associated with a risk of impaired cognitive development. Increasing evidence suggests that the family of metabotropic glutamate receptors (mGluRs) plays an important role in synaptic plasticity and memory formation. We determined whether mGluRs subtypes 1, 3, and 7 (mGluR1, mGluR3, and mGluR7) were involved in developmental neurotoxicity due to lead. Embryonic rat hippocampal neurons were cultured for 21 days and exposed to lead chloride beginning on the fourth day of incubation. We investigated levels of mGluR1, mGluR3, and mGluR7 mRNA expression by using quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) with lead exposure at 10 nM, 1 microM, and 100 microM. Lead exposure in vitro downregulated the expression of mGluR1 mRNA and upregulated the expression of mGluR3 and mGluR7 mRNA in a dose-dependent manner. We speculate that mGluRs may be involved in lead neurotoxicity. Pathways that likely contribute to lead neurotoxicity by means of mGluRs are impairment of long-term potentiation, effects on N-methyl-D-aspartate (NMDA) receptor functions, and depotentiation. PMID:17267122

  20. Subacute microcystin-LR exposure alters the metabolism of thyroid hormones in juvenile zebrafish (Danio Rerio).

    PubMed

    Liu, Zidong; Tang, Rong; Li, Dapeng; Hu, Qing; Wang, Ying

    2015-02-01

    Microcystin-LR (MC-LR) has been detected extensively in the aquatic environment and has the potential to disturb the thyroid endocrine system. However, limited information is available on the effects of subacute MC-LR exposure on fish thyroid hormone (TH) metabolism. In the present study, juvenile zebrafish (Danio rerio) were exposed to MC-LR at environmentally relevant concentrations (0, 1, 5, and 25 μg/L) for 28 days. Whole-body TH content and thyroid follicle histology were used as direct endpoints to assess thyroid disruption. The activities of iodothyronine deiodinases (IDs) and the transcription of selected genes associated with TH synthesis were also investigated to study the underlying mechanisms of endocrine disruption. Exposure of zebrafish to MC-LR significantly increased whole-body thyroxine (T4) content but decreased whole-body triiodothyronine (T3) content. We also observed hypertrophy and hyperplasia of the thyroid follicle epithelial cells, as well as up-regulation of corticotropin-releasing hormone (CRH), thyroid-stimulating hormone (TSH), thyroid peroxidase (TPO), and transthyretin (TTR) genes. The decreases in ID1 and ID2 activities coupled with an increase in ID3 activity were observed in MC-LR treatment groups. These results demonstrate that exposure to MC-LR at environmental concentrations results in the disturbance of TH homeostasis by disrupting the synthesis and conversion of THs. PMID:25647779

  1. Histopathologic alterations associated with global gene expression due to chronic dietary TCDD exposure in juvenile zebrafish.

    PubMed

    Liu, Qing; Spitsbergen, Jan M; Cariou, Ronan; Huang, Chun-Yuan; Jiang, Nan; Goetz, Giles; Hutz, Reinhold J; Tonellato, Peter J; Carvan, Michael J

    2014-01-01

    The goal of this project was to investigate the effects and possible developmental disease implication of chronic dietary TCDD exposure on global gene expression anchored to histopathologic analysis in juvenile zebrafish by functional genomic, histopathologic and analytic chemistry methods. Specifically, juvenile zebrafish were fed Biodiet starter with TCDD added at 0, 0.1, 1, 10 and 100 ppb, and fish were sampled following 0, 7, 14, 28 and 42 d after initiation of the exposure. TCDD accumulated in a dose- and time-dependent manner and 100 ppb TCDD caused TCDD accumulation in female (15.49 ppb) and male (18.04 ppb) fish at 28 d post exposure. Dietary TCDD caused multiple lesions in liver, kidney, intestine and ovary of zebrafish and functional dysregulation such as depletion of glycogen in liver, retrobulbar edema, degeneration of nasal neurosensory epithelium, underdevelopment of intestine, and diminution in the fraction of ovarian follicles containing vitellogenic oocytes. Importantly, lesions in nasal epithelium and evidence of endocrine disruption based on alternatively spliced vasa transcripts are two novel and significant results of this study. Microarray gene expression analysis comparing vehicle control to dietary TCDD revealed dysregulated genes involved in pathways associated with cardiac necrosis/cell death, cardiac fibrosis, renal necrosis/cell death and liver necrosis/cell death. These baseline toxicological effects provide evidence for the potential mechanisms of developmental dysfunctions induced by TCDD and vasa as a biomarker for ovarian developmental disruption. PMID:24988445

  2. Histopathologic Alterations Associated with Global Gene Expression Due to Chronic Dietary TCDD Exposure in Juvenile Zebrafish

    PubMed Central

    Liu, Qing; Spitsbergen, Jan M.; Cariou, Ronan; Huang, Chun-Yuan; Jiang, Nan; Goetz, Giles; Hutz, Reinhold J.; Tonellato, Peter J.; Carvan, Michael J.

    2014-01-01

    The goal of this project was to investigate the effects and possible developmental disease implication of chronic dietary TCDD exposure on global gene expression anchored to histopathologic analysis in juvenile zebrafish by functional genomic, histopathologic and analytic chemistry methods. Specifically, juvenile zebrafish were fed Biodiet starter with TCDD added at 0, 0.1, 1, 10 and 100 ppb, and fish were sampled following 0, 7, 14, 28 and 42 d after initiation of the exposure. TCDD accumulated in a dose- and time-dependent manner and 100 ppb TCDD caused TCDD accumulation in female (15.49 ppb) and male (18.04 ppb) fish at 28 d post exposure. Dietary TCDD caused multiple lesions in liver, kidney, intestine and ovary of zebrafish and functional dysregulation such as depletion of glycogen in liver, retrobulbar edema, degeneration of nasal neurosensory epithelium, underdevelopment of intestine, and diminution in the fraction of ovarian follicles containing vitellogenic oocytes. Importantly, lesions in nasal epithelium and evidence of endocrine disruption based on alternatively spliced vasa transcripts are two novel and significant results of this study. Microarray gene expression analysis comparing vehicle control to dietary TCDD revealed dysregulated genes involved in pathways associated with cardiac necrosis/cell death, cardiac fibrosis, renal necrosis/cell death and liver necrosis/cell death. These baseline toxicological effects provide evidence for the potential mechanisms of developmental dysfunctions induced by TCDD and vasa as a biomarker for ovarian developmental disruption. PMID:24988445

  3. Chronic fluoxetine exposure alters movement and burrowing in adult freshwater mussels.

    PubMed

    Hazelton, Peter D; Du, Bowen; Haddad, Samuel P; Fritts, Andrea K; Chambliss, C Kevin; Brooks, Bryan W; Bringolf, Robert B

    2014-06-01

    The antidepressant fluoxetine is commonly found in aquatic fauna living near or downstream from point-sources of municipal waste effluent. Continuous release of fluoxetine results in increased effective exposure duration in surface waters, resulting in a chronic exposure for animals downstream, particularly in effluent dominated ecosystems. Fluoxetine is known to cause disruptions in reproductive behavior of freshwater mussels (order Unionoida), including stimulating release of gametes, parturition of glochidia (larvae), and changes in lure display and foot protrusion. However, the ecological relevance of these effects at environmental concentrations is unknown. We conducted a 67-d exposure of adult Lampsilis fasciola to fluoxetine concentrations of 0, 0.5, 2.5, and 22.3μg/L and assessed impacts on behavior (lateral movement, burrowing, and filtering) and metabolism (glycogen storage and respiration). Mussels treated with 2.5 and 22.3μg/L fluoxetine displayed mantle lures significantly (p<0.05) more than controls. Animals treated with 22.3μg/L fluoxetine were statistically more likely to have shorter time-to-movement, greater total movement, and initiate burrowing sooner than control animals. These observations suggest that increased activity of mussels exposed to fluoxetine may result in increased susceptibility to predators and may lead to a reduction in energy stores. PMID:24438840

  4. Traffic pollution exposure is associated with altered brain connectivity in school children.

    PubMed

    Pujol, Jesus; Martínez-Vilavella, Gerard; Macià, Dídac; Fenoll, Raquel; Alvarez-Pedrerol, Mar; Rivas, Ioar; Forns, Joan; Blanco-Hinojo, Laura; Capellades, Jaume; Querol, Xavier; Deus, Joan; Sunyer, Jordi

    2016-04-01

    Children are more vulnerable to the effects of environmental elements due to their active developmental processes. Exposure to urban air pollution has been associated with poorer cognitive performance, which is thought to be a result of direct interference with brain maturation. We aimed to assess the extent of such potential effects of urban pollution on child brain maturation using general indicators of vehicle exhaust measured in the school environment and a comprehensive imaging evaluation. A group of 263 children, aged 8 to 12years, underwent MRI to quantify regional brain volumes, tissue composition, myelination, cortical thickness, neural tract architecture, membrane metabolites, functional connectivity in major neural networks and activation/deactivation dynamics during a sensory task. A combined measurement of elemental carbon and NO2 was used as a putative marker of vehicle exhaust. Air pollution exposure was associated with brain changes of a functional nature, with no evident effect on brain anatomy, structure or membrane metabolites. Specifically, a higher content of pollutants was associated with lower functional integration and segregation in key brain networks relevant to both inner mental processes (the default mode network) and stimulus-driven mental operations. Age and performance (motor response speed) both showed the opposite effect to that of pollution, thus indicating that higher exposure is associated with slower brain maturation. In conclusion, urban air pollution appears to adversely affect brain maturation in a critical age with changes specifically concerning the functional domain. PMID:26825441

  5. Chronic diclofenac (DCF) exposure alters both enzymatic and haematological profile of African catfish, Clarias gariepinus.

    PubMed

    Ajima, Malachy N O; Ogo, Ogo A; Audu, Bala S; Ugwoegbu, Kyrian C

    2015-10-01

    Pharmaceuticals are used extensively in human and veterinary medicine to eradicate or prevent diseases. The residues of these drugs have been detected in aquatic ecosystem; nevertheless, their toxicological effects on Clarias gariepinus have not been critically investigated. In this study, the toxic effects of diclofenac (DCF), a non-steroid anti-inflammatory drug, were studied in C. gariepinus by acute and chronic static renewable bioassay. The 96 h LC50 of DCF to C. gariepinus was 25.12 mg/L. Exposure to acute toxicity resulted in abnormal behavior and mortality of some fish. Compared with the control, chronic exposure of the fish to concentration (1.57, 3.14 and 6.28 mg/L) showed significantly higher mean corpuscular haemoglobin concentration (MCHC), mean corpuscular volume (MCV) and white blood cell (WBC), with significantly lower haemoglobin (Hb), haematocrit, red blood cell (RBC) and mean corpuscular haemoglobin (MCH) with increase in the concentration of the drug. Furthermore, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and glucose values significantly increased while protein levels were reduced (p < 0.05) in serum and gills throughout the 42-day exposure period. The study reports that DCF-induced enzymatic and haematological changes in the fish and recommends that these parameters be used as potential biomarkers for assessing residual pharmaceuticals available in aquatic ecosystem. PMID:25367777

  6. Acute cocaine exposure alters spine density and long-term potentiation in the ventral tegmental area.

    PubMed

    Sarti, Federica; Borgland, Stephanie L; Kharazia, Viktor N; Bonci, Antonello

    2007-08-01

    Growing evidence indicates that the expression of synaptic plasticity in the central nervous system results in dendritic reorganization and spine remodeling. Although long-term potentiation of glutamatergic synapses after cocaine exposure in the ventral tegmental area (VTA) has been proposed as a cellular mechanism underlying addictive behaviors, the relationship between long-term potentiation and dendritic remodeling induced by cocaine on the dopaminergic neurons of the VTA has not been demonstrated. Here we report that rat VTA cells classified as type I and II showed distinct morphological responses to cocaine, as a single cocaine exposure significantly increased dendritic spine density in type I but not in type II cells. Further, only type I cells had a significant increase in the AMPA receptor:NMDA receptor ratio after a single cocaine exposure. Taken together, our data provide evidence that increased spine density and synaptic plasticity are coexpressed within the same VTA neuronal population and that only type I neurons are structurally and synaptically modified by cocaine. PMID:17686047

  7. Time Course of Behavioral Alteration and mRNA Levels of Neurotrophic Factor Following Stress Exposure in Mouse.

    PubMed

    Hashikawa, Naoya; Ogawa, Takumi; Sakamoto, Yusuke; Ogawa, Mami; Matsuo, Yumi; Zamami, Yoshito; Hashikawa-Hobara, Narumi

    2015-08-01

    Stress is known to affect neurotrophic factor expression, which induces depression-like behavior. However, whether there are time-dependent changes in neurotrophic factor mRNA expression following stress remains unclear. In the present study, we tested whether chronic stress exposure induces long-term changes in depression-related behavior, serum corticosterone, and hippocampal proliferation as well as neurotrophic factor family mRNA levels, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and ciliary neurotrophic factor (CNTF), in the mouse hippocampus. The mRNA level of neurotrophic factors (BDNF, NGF, NT-3, and CNTF) was measured using the real-time PCR. The serum corticosterone level was evaluated by enzyme-linked immunosorbent assay, and, for each subject, the hippocampal proliferation was examined by 5-bromo-2-deoxyuridine immunostaining. Mice exhibited depression-like behavior in the forced-swim test (FST) and decreased BDNF mRNA and hippocampal proliferation in the middle of the stress exposure. After 15 days of stress exposure, we observed increased immobility in the FST, serum corticosterone levels, and BDNF mRNA levels and degenerated hippocampal proliferation, maintained for at least 2 weeks. Anhedonia-like behavior in the sucrose preference test and NGF mRNA levels were decreased following 15 days of stress. NGF mRNA levels were significantly higher 1 week after stress exposure. The current data demonstrate that chronic stress exposure induces prolonged BDNF and NGF mRNA changes and increases corticosterone levels and depression-like behavior in the FST, but does not alter other neurotrophic factors or performance in the sucrose preference test. PMID:25820756

  8. Altered resistance to Trichinella spiralis infection following subchronic exposure of adult mice to chemicals of environmental concern

    SciTech Connect

    Luebke, R.W.

    1981-01-01

    The effects of subchronic chemical exposure on expulsion of adult Trichinella spiralis from the small intestine of mice and encystment of newborn larvae in the host's musculature were investigated. Exposure to diethylstilbestrol, benzo(a)pyrene, tris-(1,3-dichloro-2-propyl) phosphate, cyclophosphamide, phorbol myristate acetate, and dimethylvinylchloride prior to infection of mice with 200 infective larvae resulted in larger worm burdens in treated animals than in controls 14 days after infection. Worm expulsion was not affected by exposure to tris-(2,3-dibromopropyl)phosphate, orthophenylphenol, and indomethacin. Increased burdens of muscle-phase larvae were found in animals that maintained significant numbers of adult worms in the gut at 14 days, except in mice administered diethylstilbestrol and dimethylvinylchloride. Exposure to diethylstilbestrol and cyclophosphamide resulted in decreased inflammatory reactions in the tissues of the small intestine and development of bone marrow eosinophilia in infected mice. Marrow eosinophilia was likewise decreased in mice given tris-(1,3-dichloro-2-propyl)phosphate before infection. Additional studies with diethylstilbestrol administered either before, at the time of, or after infection showed inhibition of worm expulsion. Drug exposure during a primary infection inhibited the expulsion of a second T. spiralis infection, but did not affect worm elimination when given during a second infection. Treatment with diethylstilbestrol after artificial sensitization of mice with Trichinella antigens decreased delayed hypersensitivity responses to the sensitizing antigen. Immune functions, assessed by lymphoproliferative responses to mitogens and antibody responses to sheep red blood cells, generally correlated with altered host resistance to T. spiralis infection.

  9. Prenatal exposure to dexamethasone in the mouse alters cardiac growth patterns and increases pulse pressure in aged male offspring.

    PubMed

    O'Sullivan, Lee; Cuffe, James S M; Paravicini, Tamara M; Campbell, Sally; Dickinson, Hayley; Singh, Reetu R; Gezmish, Oksan; Black, M Jane; Moritz, Karen M

    2013-01-01

    Exposure to synthetic glucocorticoids during development can result in later cardiovascular and renal disease in sheep and rats. Although prenatal glucocorticoid exposure is associated with impaired renal development, less is known about effects on the developing heart. This study aimed to examine the effects of a short-term exposure to dexamethasone (60 hours from embryonic day 12.5) on the developing mouse heart, and cardiovascular function in adult male offspring. Dexamethasone (DEX) exposed fetuses were growth restricted compared to saline treated controls (SAL) at E14.5, but there was no difference between groups at E17.5. Heart weights of the DEX fetuses also tended to be smaller at E14.5, but not different at E17.5. Cardiac AT1aR, Bax, and IGF-1 mRNA expression was significantly increased by DEX compared to SAL at E17.5. In 12-month-old offspring DEX exposure caused an increase in basal blood pressure of ~3 mmHg. In addition, DEX exposed mice had a widened pulse pressure compared to SAL. DEX exposed males at 12 months had an approximate 25% reduction in nephron number compared to SAL, but no difference in cardiomyocyte number. Exposure to DEX in utero appears to adversely impact on nephrogenesis and heart growth but is not associated with a cardiomyocyte deficit in male mice in adulthood, possibly due to compensatory growth of the myocardium following the initial insult. However, the widened pulse pressure may be indicative of altered vascular compliance. PMID:23935943

  10. Prenatal Exposure to Dexamethasone in the Mouse Alters Cardiac Growth Patterns and Increases Pulse Pressure in Aged Male Offspring

    PubMed Central

    O'Sullivan, Lee; Cuffe, James S. M.; Paravicini, Tamara M.; Campbell, Sally; Dickinson, Hayley; Singh, Reetu R.; Gezmish, Oksan; Black, M. Jane; Moritz, Karen M.

    2013-01-01

    Exposure to synthetic glucocorticoids during development can result in later cardiovascular and renal disease in sheep and rats. Although prenatal glucocorticoid exposure is associated with impaired renal development, less is known about effects on the developing heart. This study aimed to examine the effects of a short-term exposure to dexamethasone (60 hours from embryonic day 12.5) on the developing mouse heart, and cardiovascular function in adult male offspring. Dexamethasone (DEX) exposed fetuses were growth restricted compared to saline treated controls (SAL) at E14.5, but there was no difference between groups at E17.5. Heart weights of the DEX fetuses also tended to be smaller at E14.5, but not different at E17.5. Cardiac AT1aR, Bax, and IGF-1 mRNA expression was significantly increased by DEX compared to SAL at E17.5. In 12-month-old offspring DEX exposure caused an increase in basal blood pressure of ∼3 mmHg. In addition, DEX exposed mice had a widened pulse pressure compared to SAL. DEX exposed males at 12 months had an approximate 25% reduction in nephron number compared to SAL, but no difference in cardiomyocyte number. Exposure to DEX in utero appears to adversely impact on nephrogenesis and heart growth but is not associated with a cardiomyocyte deficit in male mice in adulthood, possibly due to compensatory growth of the myocardium following the initial insult. However, the widened pulse pressure may be indicative of altered vascular compliance. PMID:23935943

  11. Alteration of the Carbon and Nitrogen Isotopic Composition in the Martian Surface Rocks Due to Cosmic Ray Exposure

    NASA Technical Reports Server (NTRS)

    Pavlov, A. A.; Pavlov, A. K.; Ostryakov, V. M.; Vasilyev, G. I.; Mahaffy, P.; Steele, A.

    2014-01-01

    C-13/C-12 and N-15/N-14 isotopic ratios are pivotal for our understanding of the Martian carbon cycle, history of the Martian atmospheric escape, and origin of the organic compounds on Mars. Here we demonstrate that the carbon and nitrogen isotopic composition of the surface rocks on Mars can be significantly altered by the continuous exposure of Martian surface to cosmic rays. Cosmic rays can effectively produce C-13 and N-15 isotopes via spallation nuclear reactions on oxygen atoms in various Martian rocks. We calculate that in the top meter of the Martian rocks, the rates of production of both C-13 and N-15 due to galactic cosmic rays (GCRs) exposure can vary within 1.5-6 atoms/cm3/s depending on rocks' depth and chemical composition. We also find that the average solar cosmic rays can produce carbon and nitrogen isotopes at a rate comparable to GCRs in the top 5-10 cm of the Martian rocks. We demonstrate that if the total carbon content in a surface Martian rock is <10 ppm, then the "light," potentially "biological" C-13/C-12 ratio would be effectively erased by cosmic rays over 3.5 billion years of exposure. We found that for the rocks with relatively short exposure ages (e.g., 100 million years), cosmogenic changes in N-15/N-14 ratio are still very significant. We also show that a short exposure to cosmic rays of Allan Hills 84001 while on Mars can explain its high-temperature heavy nitrogen isotopic composition (N-15/N-14). Applications to Martian meteorites and the current Mars Science Laboratory mission are discussed.

  12. Repeated exposure to neurotoxic levels of chlorpyrifos alters hippocampal expression of neurotrophins and neuropeptides.

    PubMed

    Lee, Young S; Lewis, John A; Ippolito, Danielle L; Hussainzada, Naissan; Lein, Pamela J; Jackson, David A; Stallings, Jonathan D

    2016-01-18

    Chlorpyrifos (CPF), an organophosphorus pesticide (OP), is one of the most widely used pesticides in the world. Subchronic exposures to CPF that do not cause cholinergic crisis are associated with problems in cognitive function (i.e., learning and memory deficits), but the biological mechanism(s) underlying this association remain speculative. To identify potential mechanisms of subchronic CPF neurotoxicity, adult male Long Evans (LE) rats were administered CPF at 3 or 10mg/kg/d (s.c.) for 21 days. We quantified mRNA and non-coding RNA (ncRNA) expression profiles by RNA-seq, microarray analysis and small ncRNA sequencing technology in the CA1 region of the hippocampus. Hippocampal slice immunohistochemistry was used to determine CPF-induced changes in protein expression and localization patterns. Neither dose of CPF caused overt clinical signs of cholinergic toxicity, although after 21 days of exposure, cholinesterase activity was decreased to 58% or 13% of control levels in the hippocampus of rats in the 3 or 10mg/kg/d groups, respectively. Differential gene expression in the CA1 region of the hippocampus was observed only in the 10mg/kg/d dose group relative to controls. Of the 1382 differentially expressed genes identified by RNA-seq and microarray analysis, 67 were common to both approaches. Differential expression of six of these genes (Bdnf, Cort, Crhbp, Nptx2, Npy and Pnoc) was verified in an independent CPF exposure study; immunohistochemistry demonstrated that CRHBP and NPY were elevated in the CA1 region of the hippocampus at 10mg/kg/d CPF. Gene ontology enrichment analysis suggested association of these genes with receptor-mediated cell survival signaling pathways. miR132/212 was also elevated in the CA1 hippocampal region, which may play a role in the disruption of neurotrophin-mediated cognitive processes after CPF administration. These findings identify potential mediators of CPF-induced neurobehavioral deficits following subchronic exposure to CPF at

  13. Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny.

    PubMed

    Haddad, Rami; Kasneci, Amanda; Mepham, Kathryn; Sebag, Igal A; Chalifour, Lorraine E

    2013-01-01

    Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5-14.5. At 3months, male progeny were left sedentary or were swim trained for 4weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males. PMID:23142472

  14. Maternal exposure to fish oil primes offspring to harbor intestinal pathobionts associated with altered immune cell balance.

    PubMed

    Gibson, D L; Gill, S K; Brown, K; Tasnim, N; Ghosh, S; Innis, S; Jacobson, K

    2015-01-01

    Our previous studies revealed that offspring from rat dams fed fish oil (at 8% and 18% energy), developed impaired intestinal barriers sensitizing the colon to exacerbated injury later in life. To discern the mechanism, we hypothesized that in utero exposure to fish oil, rich in n-3 polyunsaturated fatty acid (PUFA), caused abnormal intestinal reparative responses to mucosal injury through differences in intestinal microbiota and the presence of naïve immune cells. To identify such mechanisms, gut microbes and naïve immune cells were compared between rat pups born to dams fed either n-6 PUFA, n-3 PUFA or breeder chow. Maternal exposure to either of the PUFA rich diets altered the development of the intestinal microbiota with an overall reduction in microbial density. Using qPCR, we found that each type of PUFA differentially altered the major gut phyla; fish oil increased Bacteroidetes and safflower oil increased Firmicutes. Both PUFA diets reduced microbes known to dominate the infant gut like Enterobacteriaceae and Bifidobacteria spp. when compared to the chow group. Uniquely, maternal fish oil diets resulted in offspring showing blooms of opportunistic pathogens like Bilophila wadsworthia, Enterococcus faecium and Bacteroides fragilis in their gut microbiota. As well, fish oil groups showed a reduction in colonic CD8+ T cells, CD4+ Foxp3+ T cells and arginase+ M2 macrophages. In conclusion, fish oil supplementation in pharmacological excess, at 18% by energy as shown in this study, provides an example where excess dosing in utero can prime offspring to harbor intestinal pathobionts and alter immune cell homeostasis. PMID:25559197

  15. Acute effects of tetracycline exposure in the freshwater fish Gambusia holbrooki: antioxidant effects, neurotoxicity and histological alterations.

    PubMed

    Nunes, B; Antunes, S C; Gomes, R; Campos, J C; Braga, M R; Ramos, A S; Correia, A T

    2015-02-01

    A large body of evidence was compiled in the recent decades showing a noteworthy increase in the detection of pharmaceutical drugs in aquatic ecosystems. Due to its ubiquitous presence, chemical nature, and practical purpose, this type of contaminant can exert toxic effects in nontarget organisms. Exposure to pharmaceutical drugs can result in adaptive alterations, such as changes in tissues, or in key homeostatic mechanisms, such as antioxidant mechanisms, biochemical/physiological pathways, and cellular damage. These alterations can be monitored to determine the impact of these compounds on exposed aquatic organisms. Among pharmaceutical drugs in the environment, antibiotics are particularly important because they include a variety of substances widely used in medical and veterinary practice, livestock production, and aquaculture. This wide use constitutes a decisive factor contributing for their frequent detection in the aquatic environment. Tetracyclines are the individual antibiotic subclass with the second highest frequency of detection in environmental matrices. The characterization of the potential ecotoxicological effects of tetracycline is a much-required task; to attain this objective, the present study assessed the acute toxic effects of tetracycline in the freshwater fish species Gambusia holbrooki by the determination of histological changes in the gills and liver, changes in antioxidant defense [glutathione S-transferase (GST), catalase (CAT), and lipoperoxidative damage] as well as potential neurotoxicity (acetylcholinesterase activity). The obtained results suggest the existence of a cause-and-effect relationship between the exposure to tetracycline and histological alterations (more specifically in gills) and enzymatic activity (particularly the enzyme CAT in liver and GST in gills) indicating that this compound can exert a pro-oxidative activity. PMID:25475590

  16. Sub-lethal glyphosate exposure alters flowering phenology and causes transient male-sterility in Brassica spp

    PubMed Central

    2014-01-01

    Background Herbicide resistance in weedy plant populations can develop through different mechanisms such as gene flow of herbicide resistance transgenes from crop species into compatible weedy species or by natural evolution of herbicide resistance or tolerance following selection pressure. Results from our previous studies suggest that sub-lethal levels of the herbicide glyphosate can alter the pattern of gene flow between glyphosate resistant Canola®, Brassica napus, and glyphosate sensitive varieties of B. napus and B. rapa. The objectives of this study were to examine the phenological and developmental changes that occur in Brassica crop and weed species following sub-lethal doses of the herbicides glyphosate and glufosinate. We examined several vegetative and reproductive traits of potted plants under greenhouse conditions, treated with sub-lethal herbicide sprays. Results Our results indicate that exposure of Brassica spp. to a sub-lethal dose of glyphosate results in altering flowering phenology and reproductive function. Flowering of all sensitive species was significantly delayed and reproductive function, specifically male fertility, was suppressed. Higher dosage levels typically contributed to an increase in the magnitude of phenotypic changes. Conclusions These results demonstrate that Brassica spp. plants that are exposed to sub-lethal doses of glyphosate could be subject to very different pollination patterns and an altered pattern of gene flow that would result from changes in the overlap of flowering phenology between species. Implications include the potential for increased glyphosate resistance evolution and spread in weedy communities exposed to sub-lethal glyphosate. PMID:24655547

  17. Alteration of gene expression in MDA-MB-453 breast cancer cell line in response to continuous exposure to Trastuzumab.

    PubMed

    Sharieh, Elham Abu; Awidi, Abdulla S; Ahram, Mamoun; Zihlif, Malek A

    2016-01-10

    Development of resistance against cancer therapeutic agents is a common problem in cancer management. Trastuzumab resistance is one of the challenges in management of HER-2-positive breast cancer patients resulting in breast cancer progression, metastasis, and patient poor outcome. The aim of this study is to determine the alteration in gene expression in response to Trastuzumab resistance after long-term exposure to Trastuzumab. The Trastuzumab-resistant MDA-MB-453 (MDA-MB-453/TR) cell line was developed by exposing cells to 10 μM Trastuzumab continuously for 6 months. Sensitivity toward Trastuzumab was tested using cell viability assays. The acquisition of an epithelial-to mesenchymal transition (EMT) phenotype was also observed in parallel with the development of resistance. Based on the real-time-based PCR array technology, several genes were altered affecting multiple networks. The most up-regulated genes were TGF-β1 and EGF, and IGFBP-3. These genes are known to have a critical role in Trastuzumab resistance in breast cancer cell lines and/or in the acquisition of EMT. They are also recognized for their role in cancer progression and metastasis. These alterations indicate that the development of Trastuzumab resistance is multifactorial and involves a development of a mesenchymal like phenotype. PMID:26367328

  18. Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome.

    PubMed

    Duncan, Jhodie R; Garland, Marianne; Myers, Michael M; Fifer, William P; Yang, May; Kinney, Hannah C; Stark, Raymond I

    2009-11-01

    During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT(1A) receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors. PMID:19729586

  19. Exposure to a glyphosate-based herbicide during pregnancy and lactation induces neurobehavioral alterations in rat offspring.

    PubMed

    Gallegos, Cristina E; Bartos, Mariana; Bras, Cristina; Gumilar, Fernanda; Antonelli, Marta C; Minetti, Alejandra

    2016-03-01

    The impact of sub-lethal doses of herbicides on human health and the environment is a matter of controversy. Due to the fact that evidence particularly of the effects of glyphosate on the central nervous system of rat offspring by in utero exposure is scarce, the purpose of the present study was to assess the neurobehavioral effects of chronic exposure to a glyphosate-containing herbicide during pregnancy and lactation. To this end, pregnant Wistar rats were exposed through drinking water to 0.2% or 0.4% of a commercial formulation of glyphosate (corresponding to a concentration of 0.65 or 1.30g/L of glyphosate, respectively) during pregnancy and lactation and neurobehavioral alterations in offspring were analyzed. The postnatal day on which each pup acquired neonatal reflexes (righting, cliff aversion and negative geotaxis) and that on which eyes and auditory canals were fully opened were recorded for the assessment of sensorimotor development. Locomotor activity and anxiety levels were monitored via open field test and plus maze test, respectively, in 45- and 90-day-old offspring. Pups exposed to a glyphosate-based herbicide showed early onset of cliff aversion reflex and early auditory canal opening. A decrease in locomotor activity and in anxiety levels was also observed in the groups exposed to a glyphosate-containing herbicide. Findings from the present study reveal that early exposure to a glyphosate-based herbicide affects the central nervous system in rat offspring probably by altering mechanisms or neurotransmitter systems that regulate locomotor activity and anxiety. PMID:26632987

  20. Early life exposure to environmental tobacco smoke alters immune response to asbestos via a shift in inflammatory phenotype resulting in increased disease development.

    PubMed

    Brown, Traci Ann; Holian, Andrij; Pinkerton, Kent E; Lee, Joong Won; Cho, Yoon Hee

    2016-07-01

    Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual's lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development. PMID:27138493

  1. Chronic cigarette smoke exposure adversely alters /sup 14/C-arachidonic acid metabolism in rat lungs, aortas and platelets

    SciTech Connect

    Lubawy, W.C.; Valentovic, M.A.; Atkinson, J.E.; Gairola, G.C.

    1983-08-08

    Male rats were exposed to freshly generated cigarette smoke once daily, 5 times a week for 10 weeks. Inhalation of smoke was verified by elevated carboxyhemoglobin in blood sampled immediately after smoke exposure and by increased lung aryl hydrocarbon hydroxylase activity 24 hours after the last smoke exposure. Aortic rings isolated from smoke-exposed rats synthesized less prostacyclin (PGI2) from /sup 14/C-arachidonic acid than rings from sham rats. Platelets from smoke-exposed rats synthesized more thromboxane (TXA2) from /sup 14/C-arachidonic acid than platelets from room controls but not those from sham rats. Lung microsomes from smoke-exposed rats synthesized more TXA2 and had a lower PGI2/TXA2 ratio than lung microsomes from room controls and shams. It is concluded that chronic cigarette smoke exposure alters arachidonic acid metabolism in aortas, platelets and lungs in a manner resulting in decreased PGI2 and increased TXA2, thereby creating a condition favoring platelet aggregation and a variety of cardiovascular diseases.

  2. Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring.

    PubMed

    Zumbrun, Elizabeth E; Sido, Jessica M; Nagarkatti, Prakash S; Nagarkatti, Mitzi

    2015-06-01

    Use of marijuana during pregnancy is fairly commonplace and can be expected increase in frequency as more states legalize its recreational use. The cannabinoids present in marijuana have been shown to be immunosuppressive, yet the effect of prenatal exposure to cannabinoids on the immune system of the developing fetus, its long term consequences during adult stage of life, and transgenerational effects have not been well characterized. Confounding factors such as co-existing drug use make the impact of cannabis use on progeny inherently difficult to study in a human population. Data from various animal models suggests that in utero exposure to cannabinoids results in profound T cell dysfunction and a greatly reduced immune response to viral antigens. Furthermore, evidence from animal studies indicates that the immunosuppressive effects of cannabinoids can be mediated through epigenetic mechanisms such as altered microRNA, DNA methylation and histone modification profiles. Such studies support the hypothesis that that parental or prenatal exposure to cannabis can trigger epigenetic changes that could have significant immunological consequences for offspring as well as long term transgenerational effects. PMID:25618446

  3. Short-term exposure of arsenite disrupted thyroid endocrine system and altered gene transcription in the HPT axis in zebrafish.

    PubMed

    Sun, Hong-Jie; Li, Hong-Bo; Xiang, Ping; Zhang, Xiaowei; Ma, Lena Q

    2015-10-01

    Arsenic (As) pollution in aquatic environment may adversely impact fish health by disrupting their thyroid hormone homeostasis. In this study, we explored the effect of short-term exposure of arsenite (AsIII) on thyroid endocrine system in zebrafish. We measured As concentrations, As speciation, and thyroid hormone thyroxine levels in whole zebrafish, oxidative stress (H2O2) and damage (MDA) in the liver, and gene transcription in hypothalamic-pituitary-thyroid (HPT) axis in the brain and liver tissues of zebrafish after exposing to different AsIII concentrations for 48 h. Result indicated that exposure to AsIII increased inorganic As in zebrafish to 0.46-0.72 mg kg(-1), induced oxidative stress with H2O2 being increased by 1.4-2.5 times and caused oxidative damage with MDA being augmented by 1.6 times. AsIII exposure increased thyroxine levels by 1.3-1.4 times and modulated gene transcription in HPT axis. Our study showed AsIII caused oxidative damage, affected thyroid endocrine system and altered gene transcription in HPT axis in zebrafish. PMID:26057477

  4. Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring

    PubMed Central

    Zumbrun, Elizabeth E.; Sido, Jessica M.; Nagarkatti, Prakash S.

    2015-01-01

    Use of marijuana during pregnancy is fairly commonplace and can be expected increase in frequency as more states legalize its recreational use. The cannabinoids present in marijuana have been shown to be immunosuppressive, yet the effect of prenatal exposure to cannabinoids on the immune system of the developing fetus, its long term consequences during adult stage of life, and transgenerational effects have not been well characterized. Confounding factors such as coexisting drug use make the impact of cannabis use on progeny inherently difficult to study in a human population. Data from various animal models suggests that in utero exposure to cannabinoids results in profound T cell dysfunction and a greatly reduced immune response to viral antigens. Furthermore, evidence from animal studies indicates that the immunosuppressive effects of cannabinoids can be mediated through epigenetic mechanisms such as altered microRNA, DNA methylation and histone modification profiles. Such studies support the hypothesis that that parental or prenatal exposure to cannabis can trigger epigenetic changes that could have significant immunological consequences for offspring as well as long term transgenerational effects. PMID:25618446

  5. Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A.

    PubMed

    Yaoi, Takeshi; Itoh, Kyoko; Nakamura, Keiko; Ogi, Hiroshi; Fujiwara, Yasuhiro; Fushiki, Shinji

    2008-11-21

    Bisphenol A (BPA) is one of endocrine disrupting chemicals, being distributed widely in the environment. We have been studying the low dose effects of BPA on murine forebrain development. Here, we have investigated the genome-wide effect of maternal exposure to BPA on the epigenome in mouse forebrain at E12.5 and at E14.5. We scanned CpG methylation status in 2500 NotI loci, representing 48 (de)methylated unique loci. Methylation status in most of them was primarily developmental stage-dependent. Each of almost all cloned NotI loci was located in a CpG island (CGI) adjacent to 5' end of the transcriptional unit. The mRNA expression of two functionally related genes changed with development as well as the exposure to BPA. In both genes, changes at the transcriptional level correlated well with the changes in NotI methylation status. Taken together, epigenetic alterations in promoter-associated CGIs after exposure to BPA may underlie some effects on brain development. PMID:18804091

  6. Metabolic and feeding behavior alterations provoked by prenatal exposure to aspartame.

    PubMed

    von Poser Toigo, E; Huffell, A P; Mota, C S; Bertolini, D; Pettenuzzo, L F; Dalmaz, C

    2015-04-01

    The use of artificial sweeteners has increased together with the epidemic growth of obesity. In addition to their widespread use in sodas, artificial sweeteners are added to nearly 6000 other products sold in the US, including baby foods, frozen dinners and even yogurts. It has been suggested that the use of nonnutritive sweeteners can lead to body weight gain and an altered metabolic profile. However, very few studies have evaluated the effects of maternal consumption of artificial non-caloric sweeteners on body weight, feeding behavior or the metabolism of offspring in adult life. In this study, we found that animals exposed to aspartame during the prenatal period presented a higher consumption of sweet foods during adulthood and a greater susceptibility to alterations in metabolic parameters, such as increased glucose, LDL and triglycerides. These effects were observed in both males and females, although they were more pronounced in males. Despite the preliminary nature of this study, and the need for further confirmation of these effects, our data suggest that the consumption of sweeteners during gestation may have deleterious long-term effects and should be used with caution. PMID:25543075

  7. Skin alterations induced by long-term exposure to uranium and their effect on permeability.

    PubMed

    Ubios, A M; Marzorati, M; Cabrini, R L

    1997-05-01

    The skin is a probable route of incorporation of uranium by percutaneous absorption. The changes in epidermal thickness and their effect on skin permeability after uranium exposure are reported herein. Two experiments (A and B) were performed in Wistar rats weighing 60 g. In experiment A the animals were exposed to U3O8 (0.012 g d(-1)) in 30 daily topical applications. In experiment B the animals were treated as in experiment A, followed by a period of non-exposure of 60 d. Samples of the treated area of skin were taken for histologic studies and for the study of the skin permeability. The epidermal thickness was measured on the histological sections. Epidermis was thinner in experimental than in control animals in both experiments. The values in the control groups were 41.05 +/- 14.03 microm (A) and 38.92 +/- 16.50 microm (B) and 21.35 +/- 10.29 microm (A) and 24.06 +/- 16.50 microm (B) in the experimental groups, the differences being statistically significant. Skin permeability was measured placing skin samples in a diffusion cell, in which the upper compartment was filled with a staining solution. The determinations were made with a spectrophotometer. The results revealed that the skin permeability in both experimental groups was higher than in the respective controls, 65% in experiment A and 77% in experiment B. The results revealed that a long term uranium exposure leads to an epidermal atrophy which in turn results in an increased permeability of the skin. PMID:9106712

  8. Alterations in Rat Fetal Morphology Following Abuse Patterns of Toluene Exposure

    PubMed Central

    Bowen, Scott E.; Irtenkauf, Susan; Hannigan, John H.; Stefanski, Adrianne L.

    2009-01-01

    Toluene is a commonly abused organic solvent. Inhalant abusers are increasingly women in their prime childbearing years. Children born to mothers who abused solvents during pregnancy may exhibit characteristics of a “fetal solvent syndrome” which may include dysmorphic features. This study examined the teratological effects of an abuse pattern of binge toluene exposure during gestation on skeletal and soft tissue abnormalities, body weight, and body size in fetal rats. Pregnant Sprague–Dawley rats were exposed for 30 min, twice daily, from gestational day (GD) 8 through GD20 to either air (0 ppm), 8,000 ppm, 12,000 ppm, or 16,000 ppm toluene. Two-thirds of each litter was prepared for skeletal examination using Alizarin Red S staining while the remaining third of each litter was fixed in Bouin’s solution for Wilson’s soft tissue evaluation. Exposure to toluene at all levels significantly reduced growth, including decreases in placental weight, fetal weight, and crown-rump length. In addition, numerous gross morphological anomalies were observed such as short or missing digits and missing limbs. Skeletal examination revealed that ossification of the extremities was significantly reduced as a result of toluene exposure at all levels. Specific skeletal defects included misshapen scapula, missing and supernumerary vertebrae and ribs, and fused digits. Soft tissue anomalies were also observed at all toluene levels and there was a dose-dependent increase in the number of anomalies which included cryptorchidism, displaced abdominal organs, gastromegaly, distended/hypoplastic bladder, and delayed cardiac development, among others. These results indicate that animals exposed prenatally to levels and patterns of toluene typical of inhalant abuse are at increased risk for skeletal and soft tissue abnormalities. PMID:19429395

  9. Developmental exposure to bisphenol A (BPA) alters sexual differentiation in painted turtles (Chrysemys picta)

    USGS Publications Warehouse

    Jandegian, Caitlin M.; Deem, Sharon L.; Bhandari, Ramji K.; Holliday, Casey M.; Nicks, Diane; Rosenfeld, Cheryl S.; Selcer, Kyle; Tillitt, Donald E.; vom Saal, Fredrick S.; Velez, Vanessa; Yang, Ying; Holliday, Dawn K.

    2015-01-01

    Environmental chemicals can disrupt endocrine signaling and adversely impact sexual differentiation in wildlife. Bisphenol A (BPA) is an estrogenic chemical commonly found in a variety of habitats. In this study, we used painted turtles (Chrysemys picta), which have temperature-dependent sex determination (TSD), as an animal model for ontogenetic endocrine disruption by BPA. We hypothesized that BPA would override TSD and disrupt sexual development. We incubated farm-raised turtle eggs at the male-producing temperature (26 °C), randomly assigned individuals to treatment groups: control, vehicle control, 17β-estradiol (E2, 20 ng/g-egg) or 0.01, 1.0, 100 μg BPA/g-egg and harvested tissues at hatch. Typical female gonads were present in 89% of the E2-treated “males”, but in none of the control males (n = 35). Gonads of BPA-exposed turtles had varying amounts of ovarian-like cortical (OLC) tissue and disorganized testicular tubules in the medulla. Although the percentage of males with OLCs increased with BPA dose (BPA-low = 30%, BPA-medium = 33%, BPA-high = 39%), this difference was not significant (p = 0.85). In all three BPA treatments, SOX9 patterns revealed disorganized medullary testicular tubules and β-catenin expression in a thickened cortex. Liver vitellogenin, a female-specific liver protein commonly used as an exposure biomarker, was not induced by any of the treatments. Notably, these results suggest that developmental exposure to BPA disrupts sexual differentiation in painted turtles. Further examination is necessary to determine the underlying mechanisms of sex reversal in reptiles and how these translate to EDC exposure in wild populations.

  10. Manganese exposure among smelting workers: relationship between blood manganese-iron ratio and early onset neurobehavioral alterations.

    PubMed

    Cowan, Dallas M; Zheng, Wei; Zou, Yan; Shi, Xiujuan; Chen, Jian; Rosenthal, Frank S; Fan, Qiyuan

    2009-11-01

    A biomarker for detection of early onset neurobehavioral alterations in manganism remains unknown. The purpose of this study was to use a neurobehavioral test battery to identify subtle changes in Mn-induced motor and memory dysfunction and to relate the quantifiable neurological dysfunction to an established Mn-exposure index such as blood manganese-iron ratio (MIR). A total of 323 subjects were recruited to control (n=106), low-exposure (122), and high-exposure (95) groups. The test battery consisted of standard testing procedures including the nine-hole and groove-type steadiness tester, Benton visual retention test, and Purdue pegboard coordination test. No significant health problems or clinically diagnosed neurological dysfunctions were observed. Benton test did not reveal any abnormal memory deficits among Mn-exposed smelters, nor did the groove and nine-hole tests detect any abnormality in dynamic and static steadiness in tested subjects. Purdue pegboard test showed a remarkable age-related decline in fine movement coordination among all study participants regardless of the Mn-exposure condition. Mn exposure significantly exacerbated this age-related deterioration. Statistical modeling revealed that the plasma and erythrocyte MIR (i.e., pMIR and eMIR, respectively) were associated with Purdue pegboard scores. Among all subjects whose MIR were above the cut-off value (COV), pMIR was significantly correlated with pegboard scores (r=-0.261, p=0.002), whereas for those subjects over the age of 40, the eMIR, but not pMIR, was associated with declined pegboard performance (r=-0.219, p=0.069). When both factors were taken into account (i.e., age>40 and MIR>the COV), only pMIR was inversely associated with pegboard scores. Combining their usefulness in Mn-exposure assessment, we recommend that the blood Mn-Fe ratio may serve as a reasonable biomarker not only for assessment of Mn exposure but also for health risk assessment. PMID:19963104

  11. Short-duration exposure to radiofrequency electromagnetic radiation alters the chlorophyll fluorescence of duckweeds (Lemna minor).

    PubMed

    Senavirathna, Mudalige Don Hiranya Jayasanka; Takashi, Asaeda; Kimura, Yuichi

    2014-12-01

    Plants growing in natural environments are exposed to radiofrequency electromagnetic radiation (EMR) emitted by various communication network base stations. The environmental concentration of this radiation is increasing rapidly with the congested deployment of base stations. Although numerous scientific studies have been conducted to investigate the effects of EMR on the physiology of humans and animals, there have been few attempts to investigate the effects of EMR on plants. In this study, we attempted to evaluate the effects of EMR on photosynthesis by investigating the chlorophyll fluorescence (ChF) parameters of duckweed fronds. During the experiment, the fronds were tested with 2, 2.5, 3.5, 5.5 and 8 GHz EMR frequencies, which are not widely studied even though there is a potentially large concentration of these frequencies in the environment. The duckweed fronds were exposed to EMR for 30 min, 1 h and 24 h durations with electric field strength of 45-50 V/m for each frequency. The results indicated that exposure to EMR causes a change in the non-photochemical quenching of the duckweeds. The changes varied with the frequency of the EMR and were time-varying within a particular frequency. The temperature remained unchanged in the duckweed fronds upon exposure to EMR, which confirms that the effect is non-thermal. PMID:24131393

  12. Acute fluoxetine exposure alters crab anxiety-like behaviour, but not aggressiveness

    PubMed Central

    Hamilton, Trevor James; Kwan, Garfield T.; Gallup, Joshua; Tresguerres, Martin

    2016-01-01

    Aggression and responsiveness to noxious stimuli are adaptable traits that are ubiquitous throughout the animal kingdom. Like vertebrate animals, some invertebrates have been shown to exhibit anxiety-like behaviour and altered levels of aggression that are modulated by the neurotransmitter serotonin. To investigate whether this influence of serotonin is conserved in crabs and whether these behaviours are sensitive to human antidepressant drugs; the striped shore crab, Pachygrapsus crassipes, was studied using anxiety (light/dark test) and aggression (mirror test) paradigms. Crabs were individually exposed to acute doses of the selective serotonin reuptake inhibitor, fluoxetine (5 or 25 mg/L), commonly known as Prozac®, followed by behavioural testing. The high dose of fluoxetine significantly decreased anxiety-like behaviour but had no impact on mobility or aggression. These results suggest that anxiety-like behaviour is more sensitive to modulation of serotonin than is aggressiveness in the shore crab. PMID:26806870

  13. Sensorimotor learning in children and adults: Exposure to frequency-altered auditory feedback during speech production.

    PubMed

    Scheerer, N E; Jacobson, D S; Jones, J A

    2016-02-01

    Auditory feedback plays an important role in the acquisition of fluent speech; however, this role may change once speech is acquired and individuals no longer experience persistent developmental changes to the brain and vocal tract. For this reason, we investigated whether the role of auditory feedback in sensorimotor learning differs across children and adult speakers. Participants produced vocalizations while they heard their vocal pitch predictably or unpredictably shifted downward one semitone. The participants' vocal pitches were measured at the beginning of each vocalization, before auditory feedback was available, to assess the extent to which the deviant auditory feedback modified subsequent speech motor commands. Sensorimotor learning was observed in both children and adults, with participants' initial vocal pitch increasing following trials where they were exposed to predictable, but not unpredictable, frequency-altered feedback. Participants' vocal pitch was also measured across each vocalization, to index the extent to which the deviant auditory feedback was used to modify ongoing vocalizations. While both children and adults were found to increase their vocal pitch following predictable and unpredictable changes to their auditory feedback, adults produced larger compensatory responses. The results of the current study demonstrate that both children and adults rapidly integrate information derived from their auditory feedback to modify subsequent speech motor commands. However, these results also demonstrate that children and adults differ in their ability to use auditory feedback to generate compensatory vocal responses during ongoing vocalization. Since vocal variability also differed across the children and adult groups, these results also suggest that compensatory vocal responses to frequency-altered feedback manipulations initiated at vocalization onset may be modulated by vocal variability. PMID:26628403

  14. Ethanol exposure alters early cardiac function in the looping heart: a mechanism for congenital heart defects?

    PubMed Central

    Gu, Shi; Doughman, Yong Qiu; Peterson, Lindsy M.; Mai, Katherine; McHale, Quinn; Jenkins, Michael W.; Linask, Kersti K.; Rollins, Andrew M.; Watanabe, Michiko

    2013-01-01

    Alcohol-induced congenital heart defects are frequently among the most life threatening and require surgical correction in newborns. The etiology of these defects, collectively known as fetal alcohol syndrome, has been the focus of much study, particularly involving cellular and molecular mechanisms. Few studies have addressed the influential role of altered cardiac function in early embryogenesis because of a lack of tools with the capability to assay tiny beating hearts. To overcome this gap in our understanding, we used optical coherence tomography (OCT), a nondestructive imaging modality capable of micrometer-scale resolution imaging, to rapidly and accurately map cardiovascular structure and hemodynamics in real time under physiological conditions. In this study, we exposed avian embryos to a single dose of alcohol/ethanol at gastrulation when the embryo is sensitive to the induction of birth defects. Late-stage hearts were analyzed using standard histological analysis with a focus on the atrio-ventricular valves. Early cardiac function was assayed using Doppler OCT, and structural analysis of the cardiac cushions was performed using OCT imaging. Our results indicated that ethanol-exposed embryos developed late-stage valvuloseptal defects. At early stages, they exhibited increased regurgitant flow and developed smaller atrio-ventricular cardiac cushions, compared with controls (uninjected and saline-injected embryos). The embryos also exhibited abnormal flexion/torsion of the body. Our evidence suggests that ethanol-induced alterations in early cardiac function have the potential to contribute to late-stage valve and septal defects, thus demonstrating that functional parameters may serve as early and sensitive gauges of cardiac normalcy and abnormalities. PMID:24271490

  15. Ethanol exposure alters early cardiac function in the looping heart: a mechanism for congenital heart defects?

    PubMed

    Karunamuni, Ganga; Gu, Shi; Doughman, Yong Qiu; Peterson, Lindsy M; Mai, Katherine; McHale, Quinn; Jenkins, Michael W; Linask, Kersti K; Rollins, Andrew M; Watanabe, Michiko

    2014-02-01

    Alcohol-induced congenital heart defects are frequently among the most life threatening and require surgical correction in newborns. The etiology of these defects, collectively known as fetal alcohol syndrome, has been the focus of much study, particularly involving cellular and molecular mechanisms. Few studies have addressed the influential role of altered cardiac function in early embryogenesis because of a lack of tools with the capability to assay tiny beating hearts. To overcome this gap in our understanding, we used optical coherence tomography (OCT), a nondestructive imaging modality capable of micrometer-scale resolution imaging, to rapidly and accurately map cardiovascular structure and hemodynamics in real time under physiological conditions. In this study, we exposed avian embryos to a single dose of alcohol/ethanol at gastrulation when the embryo is sensitive to the induction of birth defects. Late-stage hearts were analyzed using standard histological analysis with a focus on the atrio-ventricular valves. Early cardiac function was assayed using Doppler OCT, and structural analysis of the cardiac cushions was performed using OCT imaging. Our results indicated that ethanol-exposed embryos developed late-stage valvuloseptal defects. At early stages, they exhibited increased regurgitant flow and developed smaller atrio-ventricular cardiac cushions, compared with controls (uninjected and saline-injected embryos). The embryos also exhibited abnormal flexion/torsion of the body. Our evidence suggests that ethanol-induced alterations in early cardiac function have the potential to contribute to late-stage valve and septal defects, thus demonstrating that functional parameters may serve as early and sensitive gauges of cardiac normalcy and abnormalities. PMID:24271490

  16. Exposure and Figure Out of Climate Induced Alterations in the Wetlands of Banglades

    NASA Astrophysics Data System (ADS)

    Siddiquee, S. A.; Rahman, M. Z.

    2015-12-01

    Unique geographic location and geo-morphological conditions of Bangladesh have made the wetlands of this country one of the most vulnerable to climate change. Wetland plays a crucial role in maintaining the ecological balance of ecosystems and cultural figures and which occupy around 50% of the area. Drought, excessive temperature, mountain snowfields and glaciers melting, riverbank erosion, salinity intrusion, flashflood, storm surges, higher water temperatures, precipitation anomalies, coastal cyclones, seasonal anomalies and extremes are main threats to the wetland ecosystem. Enhanced UV-B radiation and increased summer precipitation will significantly increase dissolved organic carbon concentrations altering major biogeochemical cycles and also will result into the expansion of range for many invasive aquatic weeds. Generally, rising temperature will lower water quality through a fall in oxygen concentrations, release of phosphorus from sediments, increased thermal stability, and altered mixing patterns. As a result biodiversity is getting degraded, many species of flora and fauna are getting threatened, and wetland-based ecosystem is getting degenerated. At the same time, the living conditions of local people are deteriorating as livelihoods, socioeconomic institutions, and extensive cultural values as well. For conserving and managing wetlands technology, legislation, educational knowledge, action plan strategy and restoration practices are required. In order to address the human needs in the changing climate community-based adaptation approaches and wetland restoration, practices had been taken in almost every type of wetlands in Bangladesh. Therefore, Bangladesh now needs a comprehensive strategy and integrated system combining political, economic, social, technological approaches and institutional supports to address sustainable wetland restoration, conservation and the newly added crisis, climate change.

  17. Juvenile exposure to a high fat diet promotes behavioral and limbic alterations in the absence of obesity.

    PubMed

    Vinuesa, Angeles; Pomilio, Carlos; Menafra, Martin; Bonaventura, Maria Marta; Garay, Laura; Mercogliano, María Florencia; Schillaci, Roxana; Lux Lantos, Victoria; Brites, Fernando; Beauquis, Juan; Saravia, Flavia

    2016-10-01

    The incidence of metabolic disorders including obesity, type 2 diabetes and metabolic syndrome have seriously increased in the last decades. These diseases - with growing impact in modern societies - constitute major risk factors for neurodegenerative disorders such as Alzheimer's disease (AD), sharing insulin resistance, inflammation and associated cognitive impairment. However, cerebral cellular and molecular pathways involved are not yet clearly understood. Thus, our aim was to study the impact of a non-severe high fat diet (HFD) that resembles western-like alimentary habits, particularly involving juvenile stages where the brain physiology and connectivity are in plain maturation. To this end, one-month-old C57BL/6J male mice were given either a control diet or HFD during 4 months. Exposure to HFD produced metabolic alterations along with changes in behavioral and central parameters, in the absence of obesity. Two-month-old HFD mice showed increased glycemia and plasmatic IL1β but these values normalized at the end of the HFD protocol at 5 months of age, probably representing an acute response that is compensated at later stages. After four months of HFD exposure, mice presented dyslipidemia, increased Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, hepatic insulin resistance and inflammation. Alterations in the behavioral profile of the HFD group were shown by the impediment in nest building behavior, deficiencies in short and mid-term spatial memories, anxious and depressive- like behavior. Regarding the latter disruptions in emotional processing, we found an increased neural activity in the amygdala, shown by a greater number of c-Fos+ nuclei. We found that hippocampal adult neurogenesis was decreased in HFD mice, showing diminished cell proliferation measured as Ki67+ cells and neuronal differentiation in SGZ by doublecortin labeling. These phenomena were accompanied by a neuroinflammatory and insulin-resistant state in the hippocampus

  18. Adolescent Δ(9)-Tetrahydrocannabinol Exposure Alters WIN55,212-2 Self-Administration in Adult Rats.

    PubMed

    Scherma, Maria; Dessì, Christian; Muntoni, Anna Lisa; Lecca, Salvatore; Satta, Valentina; Luchicchi, Antonio; Pistis, Marco; Panlilio, Leigh V; Fattore, Liana; Goldberg, Steven R; Fratta, Walter; Fadda, Paola

    2016-04-01

    Cannabis is the most commonly used illicit drug worldwide, and use is typically initiated during adolescence. The endocannabinoid system has an important role in formation of the nervous system, from very early development through adolescence. Cannabis exposure during this vulnerable period might lead to neurobiological changes that affect adult brain functions and increase the risk of cannabis use disorder. The aim of this study was to investigate whether exposure to Δ(9)-tetrahydrocannabinol (THC) in adolescent rats might enhance reinforcing effects of cannabinoids in adulthood. Male adolescent rats were treated with increasing doses of THC (or its vehicle) twice/day for 11 consecutive days (PND 45-55). When the animals reached adulthood, they were tested by allowing them to intravenously self-administer the cannabinoid CB1-receptor agonist WIN55,212-2. In a separate set of animals given the same THC (or vehicle) treatment regimen, electrophysiological and neurochemical experiments were performed to assess possible modifications of the mesolimbic dopaminergic system, which is critically involved in cannabinoid-induced reward. Behavioral data showed that acquisition of WIN55,212-2 self-administration was enhanced in THC-exposed rats relative to vehicle-exposed controls. Neurophysiological data showed that THC-exposed rats displayed a reduced capacity for WIN55,212-2 to stimulate firing of dopamine neurons in the ventral tegmental area and to increase dopamine levels in the nucleus accumbens shell. These findings-that early, passive exposure to THC can produce lasting alterations of the reward system of the brain and subsequently increase cannabinoid self-administration in adulthood-suggest a mechanism by which adolescent cannabis exposure could increase the risk of subsequent cannabis dependence in humans. PMID:26388146

  19. Atrazine-induced reproductive tract alterations after transplacental and/or lactational exposure in male Long-Evans rats

    SciTech Connect

    Rayner, Jennifer L.; Enoch, Rolondo R.; Wolf, Douglas C.; Fenton, Suzanne E. . E-mail: fenton.suzanne@epa.gov

    2007-02-01

    Studies showed that early postnatal exposure to the herbicide atrazine (ATR) delayed preputial separation (PPS) and increased incidence of prostate inflammation in adult Wistar rats. A cross-fostering paradigm was used in this study to determine if gestational exposure to ATR would also result in altered puberty and reproductive tissue effects in the male rat. Timed-pregnant Long-Evans (LE) rats were dosed by gavage on gestational days (GD) 15-19 with 100 mg ATR/kg body weight (BW) or 1% methylcellulose (controls, C). On postnatal day (PND)1, half litters were cross-fostered, creating 4 treatment groups; C-C, ATR-C, C-ATR, and ATR-ATR (transplacental-milk as source, respectively). On PND4, male offspring in the ATR-ATR group weighed significantly less than the C-C males. ATR-ATR male pups had significantly delayed preputial separation (PPS). BWs at PPS for C-ATR and ATR-ATR males were reduced by 6% and 9%, respectively, from that of C-C. On PND120, lateral prostate weights of males in the ATR-ATR group were significantly increased over C-C. Histological examination of lateral and ventral prostates identified an increased distribution of inflammation in the lateral prostates of C-ATR males. By PND220, lateral prostate weights were significantly increased for ATR-C and ATR-ATR, but there were no significant changes in inflammation in either the lateral or ventral prostate. These results suggest that in LE rats, gestational ATR exposure delays PPS when male offspring suckle an ATR dam, but leads to increased lateral prostate weight via transplacental exposure alone. Inflammation present at PND120 does not increase in severity with time.

  20. Early gestational exposure to moderate concentrations of ethanol alters adult behaviour in C57BL/6J mice.

    PubMed

    Sanchez Vega, Michelle C; Chong, Suyinn; Burne, Thomas H J

    2013-09-01

    Alcohol consumption during pregnancy has deleterious effects on the developing foetus ranging from subtle physical deficits to severe behavioural abnormalities and is encompassed under a broad umbrella term, foetal alcohol spectrum disorders (FASD). High levels of exposure show distinct effects, whereas the consequences of moderate exposures have been less well studied. The aim of this study was to examine the effects of a moderate dose ethanol exposure using an ad libitum drinking procedure during the first eight days of gestation in mice on the behavioural phenotype of adult offspring. Adult female C57Bl/6J mice were mated and exposed to either 10% (v/v) ethanol or water for the first 8 days of gestation (GD 0-8), and then offered water for the rest of gestation. Early developmental milestone achievement was assessed in offspring at postnatal days (P) 7, 14 and 21. Adult offspring underwent a comprehensive battery of behavioural tests to examine a range of behavioural domains including locomotion, exploration, anxiety, social behaviour, learned helplessness, sensorimotor gating, and nociception, as well as spatial memory in a water maze. Ethanol-exposed mice had similar postnatal developmental trajectories to water-exposed mice. However, the ethanol-exposed mice showed increased hyperlocomotion at P 14, 21 and 70 (p<0.05). Increased exploration and heightened motivation were also observed in adult mice. Furthermore, ethanol-exposed mice showed a significant improvement in memory in the water maze. The main findings were that mice had persistent and long lasting alterations in behaviour, including hyperactivity and enhanced spatial memory. These data suggest that even moderate dose ethanol exposure in early gestation has long term consequences on brain function and behaviour in mice. PMID:23756143

  1. Sublethal exposure to azamethiphos causes neurotoxicity, altered energy allocation and high mortality during simulated live transport in American lobster.

    PubMed

    Couillard, C M; Burridge, L E

    2015-05-01

    In the Bay of Fundy, New Brunswick, sea lice outbreaks in caged salmon are treated with pesticides including Salmosan(®), applied as bath treatments and then released into the surrounding seawater. The effect of chronic exposure to low concentrations of this pesticide on neighboring lobster populations is a concern. Adult male lobsters were exposed to 61 ngL(-1) of azamethiphos (a.i. in Salmosan(®) formulation) continuously for 10 days. In addition to the direct effects of pesticide exposure, effects on the ability to cope with shipping conditions and the persistence of the effects after a 24h depuration period in clean seawater were assessed. Indicators of stress and hypoxia (serum total proteins, hemocyanin and lactate), oxidative damage (protein carbonyls in gills and serum) and altered energy allocation (hepatosomatic and gonadosomati