Grace E Kissling

National Institutes of Health, Maryland, United States

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Publications (139)509.81 Total impact

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    David B Resnik, Lisa M Rasmussen, Grace E Kissling
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    ABSTRACT: Research misconduct is an international concern. Misconduct policies can play a crucial role in preventing and policing research misconduct, and many institutions have developed their own policies. While institutional policies play a key role in preventing and policing misconduct, national policies are also important to ensure consistent promulgation and enforcement of ethical standards. The purpose of this study was to obtain more information about research misconduct policies across the globe. We found that twenty-two of the top forty research and development funding countries (55%) had a national misconduct policy. Four countries (18.2%) are in the process of developing a policy, and four (18.2%) have a national research ethics code but no misconduct policy. All twenty-two countries (100%) with national policies included fabrication, falsification, and plagiarism in the definition of misconduct, but beyond that there was considerable diversity. Unethical authorship was mentioned in 54.6% of the misconduct definitions, followed by unethical publication practices (36.4%), conflict of interest mismanagement (36.4%), unethical peer review (31.8%), misconduct related to misconduct investigations (27.3%), poor record keeping (27.3%), other deception (27.3%), serious deviations (22.7%), violating confidentiality (22.7%), and human or animal research violations (22.7%). Having a national policy was positively associated with research and development funding ranking and intensiveness. To promote integrity in international research collaborations, countries should seek to harmonize and clarify misconduct definitions and develop procedures for adjudicating conflicts when harmonization does not occur.
    Accountability in Research Policies and Quality Assurance 01/2015; 22(5):249-66. DOI:10.1080/08989621.2014.958218 · 0.72 Impact Factor
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    ABSTRACT: In 2000, the U.S. federal government adopted a uniform definition of research misconduct as fabrication, falsification, or plagiarism (FFP), which became effective in 2001. Institutions must apply this definition of misconduct to federally-funded research to receive funding. While institutions are free to adopt definitions of misconduct that go beyond the federal standard, it is not known how many do. We analyzed misconduct policies from 183 U.S. research institutions and coded them according to thirteen different types of behavior mentioned in the misconduct definition. We also obtained data on the institution's total research funding and public vs. private status, and the year it adopted the definition. We found that more than half (59%) of the institutions in our sample had misconduct policies that went beyond the federal standard. Other than FFP, the most common behaviors included in definitions were "other serious deviations" (45.4%), "significant or material violations of regulations" (23.0%), "misuse of confidential information" (15.8%), "misconduct related to misconduct" (14.8%), "unethical authorship other than plagiarism" (14.2%), "other deception involving data manipulation" (13.1%), and "misappropriation of property/theft" (10.4%). Significantly more definitions adopted in 2001 or later went beyond the federal standard than those adopted before 2001 (73.2% vs. 26.8%), and significantly more definitions adopted by institutions in the lower quartile of total research funding went beyond the federal standard than those adopted by institutions in the upper quartiles. Public vs. private status was not significantly associated with going beyond the federal standard.
    Accountability in Research 01/2015; 22(1):14-21. DOI:10.1080/08989621.2014.891943 · 0.72 Impact Factor
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    ABSTRACT: Tetrabromobisphenol A (TBBPA), a widely used flame retardant, caused uterine tumors in rats. In this study, TBBPA was administered to male and female Wistar Han rats and B6C3F1/N mice by oral gavage in corn oil for 2 years at doses up to 1,000 mg/kg. TBBPA induced uterine epithelial tumors including adenomas, adenocarcinomas, and malignant mixed Müllerian tumors (MMMTs). In addition, endometrial epithelial atypical hyperplasia occurred in TBBPA-treated rats. Also found to be related to TBBPA treatment, but at lower incidence and at a lower statistical significance, were testicular tumors in rats, and hepatic tumors, hemangiosarcomas (all organs), and intestinal tumors in male mice. It is hypothesized that the TBBPA uterine tumor carcinogenic mechanisms involve altered estrogen levels and/or oxidative damage. TBBPA treatment may affect hydroxysteroid-dehydrogenase-17β (HSD17β) and/or sulfotransferases, enzymes involved in estrogen homeostasis. Metabolism of TBBPA may also result in the formation of free radicals. The finding of TBBPA-mediated uterine cancer in rats is of concern because TBBPA exposure is widespread and endometrial tumors are a common malignancy in women. Further work is needed to understand TBBPA cancer mechanisms. © 2014 by The Author(s).
    Toxicologic Pathology 12/2014; DOI:10.1177/0192623314557335 · 1.92 Impact Factor
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    ABSTRACT: Perfluorooctanoic acid (PFOA) is a ubiquitous pollutant that causes liver toxicity in rodents, a process believed to be dependent on peroxisome proliferator-activated receptor-alpha (PPARα) activation. Differences between humans and rodents have made the human relevance of some health effects caused by PFOA controversial. We analyzed liver toxicity at 18 months following gestational PFOA exposure in CD-1 and 129/Sv strains of mice and compared PFOA-induced effects between strains and in wild type (WT) and PPARα-knockout (KO) 129/Sv mice. Pregnant mice were exposed daily to doses (0.01-5 mg/kg/BW) of PFOA from gestation days 1 to 17. The female offspring were necropsied at 18 months, and liver sections underwent a full pathology review. Hepatocellular adenomas formed in PFOA-exposed PPARα-KO 129/Sv and CD-1 mice and were absent in untreated controls from those groups and WT 129/Sv. Hepatocellular hypertrophy was significantly increased by PFOA exposure in CD-1, and an increased severity was found in WT 129/Sv mice. PFOA significantly increased nonneoplastic liver lesions in PPARα-KO mice (hepatocyte hypertrophy, bile duct hyperplasia, and hematopoietic cell proliferation). Low-dose gestational exposures to PFOA induced latent PPARα-independent liver toxicity that was observed in aged mice. Evidence of liver toxicity in PPARα-KO mice warrants further investigation into PPARα-independent pathways.
    Toxicologic Pathology 11/2014; DOI:10.1177/0192623314558463 · 1.92 Impact Factor
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    ABSTRACT: Inhalation of benzene at levels below the current exposure limit values leads to hematotoxicity in occupationally exposed workers.
    Environmental Health Perspectives 11/2014; DOI:10.1289/ehp.1408202 · 7.03 Impact Factor
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    ABSTRACT: It is proposed that cadmium (Cd) is an environmental "metalloestrogen" and its action is mediated via the estrogen receptor (ER). Cd mimics the effects of estrogen in the rat uterus, and blood Cd concentrations positively correlate with ER levels in uteri of women with fibroids.
    Environmental Health Perspectives 10/2014; DOI:10.1289/ehp.1408234 · 7.03 Impact Factor
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    ABSTRACT: Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPARs), PFOA exposure can induce defects in fatty acid oxidation, lipid transport, and inflammation. Here, pregnant CD-1 mice were orally gavaged with 0, 0.01, 0.1, 0.3, and 1 mg/kg of PFOA from gestation days (GD) 1 through 17. On postnatal day (PND) 21, histopathologic changes in the livers of offspring included hepatocellular hypertrophy and periportal inflammation that increased in severity by PND 91 in an apparent dose-dependent response. Transmission electron microscopy (TEM) of selected liver sections from PND 91 mice revealed PFOA-induced cellular damage and mitochondrial abnormalities with no evidence of peroxisome proliferation. Within hypertrophied hepatocytes, mitochondria were not only increased in number but also exhibited altered morphologies suggestive of increased and/or uncontrolled fission and fusion reactions. These findings suggest that peroxisome proliferation is not a component of PFOA-induced hepatic toxicity in animals that are prenatally exposed to low doses of PFOA.
    Toxicologic Pathology 10/2014; DOI:10.1177/0192623314551841 · 1.92 Impact Factor
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    ABSTRACT: Sorbitol dehydrogenase (SDH) is a liver-specific enzyme sensitive to the detection of acute hepatocellular injury in rats; however, its usefulness has been questioned as being a highly labile enzyme. The purpose of this study was to determine the stability of serum and plasma SDH activity from both untreated rats and those treated with a single low dose injection of d-(+)-galactosamine hydrochloride, a known hepatotoxicant. After collection and initial SDH activity analysis, aliquots of serum and plasma were stored at 21°C, 4°C, and -80°C and analyzed at various time points. Serum SDH activity was stable for 4 hr at 21°C. At 4°C, serum SDH activity was stable for 24 hr, after which it significantly increased; it was not stable at -80°C. Plasma SDH activity was significantly increased by 4 hr at 21°C and 4°C, and by 48 hr at -80°C. Analysis of plasma SDH activity should occur shortly after blood collection. Analysis of serum SDH activity should occur within 4 hr of collection or stored at 4°C and measured within 24 hr. Extended storage at 4°C or -80°C for the measurement of serum or plasma SDH activity cannot be recommended due to the observed substantial elevations in SDH activity.
    Toxicologic Pathology 10/2014; DOI:10.1177/0192623314552853 · 1.92 Impact Factor
  • Archive für Toxikologie 09/2014; 88(11). DOI:10.1007/s00204-014-1369-5 · 5.08 Impact Factor
  • Grace E Kissling, Joseph K Haseman, Errol Zeiger
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    ABSTRACT: A recent article by Gaus (2014) demonstrates a serious misunderstanding of the NTP's statistical analysis and interpretation of rodent carcinogenicity data as reported in Technical Report 578 (Ginkgo biloba) (NTP 2013), as well as a failure to acknowledge the abundant literature on false positive rates in rodent carcinogenicity studies. The NTP reported Ginkgo biloba extract to be carcinogenic in mice and rats. Gaus claims that, in this study, 4800 statistical comparisons were possible, and that 209 of them were statistically significant (p<0.05) compared with 240 (4800×0.05) expected by chance alone; thus, the carcinogenicity of Ginkgo biloba extract cannot be definitively established. However, his assumptions and calculations are flawed since he incorrectly assumes that the NTP uses no correction for multiple comparisons, and that significance tests for discrete data operate at exactly the nominal level. He also misrepresents the NTP's decision making process, overstates the number of statistical comparisons made, and ignores that fact that that the mouse liver tumor effects were so striking (e.g., p<0.0000000000001) that it is virtually impossible that they could be false positive outcomes. Gaus' conclusion that such obvious responses merely "generate a hypothesis" rather than demonstrate a real carcinogenic effect has no scientific credibility. Moreover, his claims regarding the high frequency of false positive outcomes in carcinogenicity studies are misleading because of his methodological misconceptions and errors.
    Toxicology Letters 09/2014; DOI:10.1016/j.toxlet.2014.09.016 · 3.36 Impact Factor
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    ABSTRACT: Visualizing the interior (lumen) of a tubular structure within tissue can provide a unique perspective on anatomical organization of the tissue. Portal tracts of the liver contain several vessels and ducts in various patterns of intertwining branches and are an example of such spaces. An inexpensive method, using light microscopy and a sample of conventionally stained canine livers, was used to colorize and allow visualization of the lumens of vessels within the portal tract in three dimensions. When the colour of the background was digitally cleared and the lumen filled with a solid colour, it was possible to measure areas and volumes of the portal vein, arteries, bile ducts and lymphatics. Significant differences between vessels and ducts across lobes and gender in control samples are discussed. Differences were also found between control and mixed breed dogs and between controls and a dog that died of accidental traumatic haemorrhage. These differences are discussed in relation to visualizing lumens using images generated from a light microscope. Vessels in plants such as xylem and continuously formed spaces resulting from ice formation are other examples where this technique could be applied.
    Journal of Microscopy 09/2014; 256(3). DOI:10.1111/jmi.12171 · 2.15 Impact Factor
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    ABSTRACT: In mice, inorganic arsenic in the drinking water in the parts per million range via the dam during in utero life or with whole-life exposure is a multi-site carcinogen in the offspring. However, human arsenic exposure is typically in the parts per billion (ppb) range. Thus, we studied "whole-life" inorganic arsenic carcinogenesis in mice at levels more relevant to humans. Breeder male and female CD1 mice were exposed to 0, 50, 500 or 5,000 ppb arsenic (as sodium arsenite) in the drinking water for 3 weeks prior to breeding, during pregnancy and lactation, and after weaning (at week 3) groups of male and female offspring (initial n = 40) were exposed for up to 2 years. Tumors were assessed in these offspring. Arsenic exposure had no effect on pregnant dam weights or water consumption, litter size, offspring birthweight or weight at weaning compared to control. In male offspring mice, arsenic exposure increased (p < 0.05) bronchiolo-alveolar tumor (adenoma or carcinoma) incidence at 50-ppb group (51 %) and 500-ppb group (54 %), but not at 5,000-ppb group (28 %) compared to control (22 %). These arsenic-induced bronchiolo-alveolar tumors included increased (p < 0.05) carcinoma at 50-ppb group (27 %) compared to controls (8 %). An increase (p < 0.05) in lung adenoma (25 %) in the 50-ppb group compared to control (11 %) occurred in female offspring. Thus, in CD1 mice whole-life arsenic exposure induced lung tumors at human-relevant doses (i.e., 50 and 500 ppb).
    Archive für Toxikologie 07/2014; DOI:10.1007/s00204-014-1305-8 · 5.08 Impact Factor
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    Sherry A Ferguson, C Delbert Law, Grace E Kissling
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    ABSTRACT: The developing central nervous system may be particularly sensitive to Bisphenol A (BPA)-induced alterations. Here, pregnant Sprague-Dawley rats (n = 11-12/group) were gavaged daily with vehicle, 2.5 or 25.0 μg/kg BPA, or 5.0 or 10.0 μg/kg ethinyl estradiol (EE2) on gestational days 6-21. The BPA doses were selected to be below the no-observed-adverse-effect level of 5 mg/kg/day. On postnatal days 1-21, all offspring/litter were orally treated with the same dose. A naïve control group was not gavaged. Body weight, pubertal age, estrous cyclicity, and adult serum hormone levels were measured. Adolescent play, running wheel activity, flavored solution intake, female sex behavior, and manually-elicited lordosis were assessed. No significant differences existed between the vehicle and naïve control groups. Vehicle controls exhibited significant sexual dimorphism for most behaviors, indicating these evaluations were sensitive to sex differences. However, only EE2 treatment caused significant effects. Relative to female controls, EE2-treated females were heavier, exhibited delayed vaginal opening, aberrant estrous cyclicity, increased play behavior, decreased running wheel activity, and increased aggression toward the stimulus male during sexual behavior assessments. Relative to male controls, EE2-treated males were older at testes descent and preputial separation and had lower testosterone levels. These results suggest EE2-induced masculinization/defeminization of females and are consistent with increased SDN-POA volume at weaning in female siblings of these subjects (He et al., 2012). Although EE2 treatment caused pubertal delays and decreased testosterone levels in males, their behaviors were within the range of control males. Conversely, BPA treatment did not alter any measured endpoint. Similar to our previous reports (Ferguson et al., 2012, 2011), the BPA doses and design used here produced few alterations.
    Toxicological Sciences 05/2014; DOI:10.1093/toxsci/kfu077 · 4.48 Impact Factor
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    ABSTRACT: Trimethylolpropane triacrylate (TMPTA) is a multifunctional monomer with industrial applications. To determine the carcinogenic potential, male and female F344/N rats and B6C3F1/N mice were administered TMPTA (0, 0.3, 1.0, or 3.0 mg/kg) in acetone dermally for 2 years. There were no differences in the body weights and survival in the treated animals compared to controls. Nonneoplastic skin lesions at the site of application included epidermal hyperplasia and hyperkeratosis in both rats and mice. There were no incidences of tumors at the site of application in rats and mice. Rare malignant liver neoplasms were observed in female mice that included hepatoblastoma in the 0.3 and 3.0 mg/kg groups, and hepatocholangiocarcinoma in the 1.0 and 3.0 mg/kg groups. The incidences of uterine stromal polyp and stromal polyp or stromal sarcoma (combined) in female mice occurred with positive trends and the incidences were significantly increased in the 3.0 mg/kg group. A marginal increase in the incidences of malignant mesothelioma in male rats may have been related to TMPTA treatment. In conclusion, our studies show that TMPTA is dermal irritant in both rats and mice of either sex. Increased incidences of tumor formation were observed in female mice and male rats.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 04/2014; 66. DOI:10.1016/j.fct.2014.01.048 · 2.61 Impact Factor
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    ABSTRACT: Female ESR2 null-mice (betaERKO) display defects in ovarian function and are subfertile. Follicular maturation is impaired and explains smaller litters, but betaERKO also produce fewer litters which may be partially due to inadequate ovulatory signals. To test this, the amplitude and timing of the naturally occurring LH surge was measured in individual intact betaERKO and WT mice. Vaginal cytology was evaluated daily and blood samples were taken from mice in proestrus. The amplitude of the LH surge was severely blunted in betaERKO mice compared to WT, but pituitary LH levels revealed no differences. betaERKO mice did not produce a preovulatory estradiol surge. To determine if the smaller LH surges and the reduced number of litters in betaERKO were due to the lack of ESR2 in the hypothalamic-pituitary axis or due to the absence of ESR2 in the ovary, ovaries were transplanted from WT into betaERKO mice and vice versa. The size of the LH surge was only reduced in mice lacking ESR2 within the ovary and these mice had fewer litters. Fertility and size of the LH surge were rescued in betaERKO mice receiving a WT ovary. These data provide the first experimental evidence that the LH surge is impaired in betaERKO females, and may contribute to their reduced fertility. ESR2 is not necessary within the pituitary and hypothalamus for the generation of a normal LH surge and for normal fertility, but ESR2 is essential within the ovary to provide proper signals.
    Biology of Reproduction 12/2013; 90(2). DOI:10.1095/biolreprod.113.113316 · 3.45 Impact Factor
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    ABSTRACT: Arachidonic acid stimulates cell adhesion by activating α2β1 integrins in a process that depends on protein kinases, including p38 mitogen activated protein kinase. Here, we describe the interaction of cytoskeletal components with key signaling molecules that contribute to the spreading of, and morphological changes in, arachidonic acid-treated MDA-MB-435 human breast carcinoma cells. Arachidonic acid-treated cells showed increased attachment and spreading on collagen type IV, as measured by electric cell-substrate impedance sensing. Fatty acid-treated cells displayed short cortical actin filaments associated with an increased number of β1 integrin-containing pseudopodia, whereas untreated cells displayed elongated stress fibers and fewer clusters of β1 integrins. Confocal microscopy of arachidonic acid-treated cells showed that vinculin and phospho-p38 both appeared enriched in pseudopodia and at the tips of actin filaments, and fluorescence ratio imaging indicated the increase was specific for the phospho-(active) form of p38. Immunoprecipitates of phospho-p38 from extracts of arachidonic acid-treated cells contained vinculin, and GST-vinculin fusion proteins carrying the central region of vinculin bound phospho-p38, whereas fusion proteins expressing the terminal portions of vinculin did not. These data suggest that phospho-p38 associates with particular domains on critical focal adhesion proteins that are involved in tumor cell adhesion and spreading, and that this association can be regulated by factors in the tumor microenvironment.
    Biochemistry and Cell Biology 12/2013; 91(6):404-18. DOI:10.1139/bcb-2013-0013 · 2.35 Impact Factor
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    ABSTRACT: We propose, and offer evidence to support, the concept that many uterine leiomyomas pursue a self-limited life cycle. This cycle can be arbitrarily divided on the basis of morphologic assessment of the collagen content into 4 phases: (1) proliferation, (2) proliferation and synthesis of collagen, (3) proliferation, synthesis of collagen, and early senescence, and (4) involution. Involution occurs as a result of both vascular and interstitial ischemia. Interstitial ischemia is the consequence of the excessive elaboration of collagen, resulting in reduced microvascular density, increased distance between myocytes and capillaries, nutritional deprivation, and myocyte atrophy. The end stage of this process is an involuted tumor with a predominance of collagen, little to no proliferative activity, myocyte atrophy, and myocyte cell death. Since many of the dying cells exhibit light microscopic and ultrastructural features that appear distinct from either necrosis or apoptosis, we refer to this process as inanosis, because it appears that nutritional deprivation, or inanition, is the underlying cause of cell death. The disposal of myocytes dying by inanosis also differs in that there is no phagocytic reaction, but rather an apparent dissolution of the cell, which might be viewed as a process of reclamation as the molecular contents are reclaimed and recycled.
    Obstetrics and Gynecology International 11/2013; 2013:528376. DOI:10.1155/2013/528376
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    ABSTRACT: In urine specimens that were collected from pregnant women in a large cohort, 24% contained more than 10ng/ml of total bisphenol A (BPA), suggesting external contamination. Therefore, we conducted an investigation of the source(s) of extraneous BPA in the specimens. We found that under the conditions used to collect urine specimens in the epidemiologic study, contamination with BPA occurred, and by two separate mechanisms.
    Environmental Research 10/2013; DOI:10.1016/j.envres.2013.07.002 · 3.95 Impact Factor
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    ABSTRACT: Based upon our morphologic observations, we hypothesize and also provide morphometric evidence for the occurrence of progressive developmental changes in many uterine fibroids, which can be arbitrarily divided into 4 phases. These developmental phases are related to the ongoing production of extracellular collagenous matrix, which eventually exceeds the degree of angiogenesis, resulting in the progressive separation of myocytes from their blood supply and a condition of interstitial ischemia. The consequence of this process of slow ischemia with nutritional and oxygen deprivation is a progressive myocyte atrophy (or inanition), culminating in cell death, a process that we refer to as inanosis. The studies presented here provide quantitative and semiquantitative evidence to support the concept of the declining proliferative activity as the collagenous matrix increases and the microvascular density decreases.
    Obstetrics and Gynecology International 09/2013; 2013:285103. DOI:10.1155/2013/285103

Publication Stats

2k Citations
509.81 Total Impact Points


  • 2004–2015
    • National Institutes of Health
      • Branch of Bio-statistics
      Maryland, United States
  • 2004–2014
    • National Institute of Environmental Health Sciences
      • • Biostatistics Branch
      • • Cellular & Molecular Pathology Branch
      Durham, North Carolina, United States
  • 2008–2013
    • Northern Inyo Hospital
      BIH, California, United States
    • University of Cincinnati
      • Department of Biological Sciences
      Cincinnati, Ohio, United States
  • 2011
    • North Carolina Department of Health and Human Services
      Raleigh, North Carolina, United States
  • 2006
    • Research Triangle Park Laboratories, Inc.
      Raleigh, North Carolina, United States
    • University of Southern Mississippi
      • Gulf Coast Research Laboratory
      HBG, Mississippi, United States