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1.
Comp Med ; 70(1): 35-44, 2020 02 01.
Article in English | MEDLINE | ID: mdl-31744593

ABSTRACT

Pregnant rabbits are a common nonrodent model for reproductive safety evaluation in preclinical drug development. During reproductive toxicology studies, rabbits are prone to decreased food consumption and anorexia. When persistent or severe, this condition can lead to hepatic lipidosis and pregnancy toxemia, which may confound the interpretation of study results. Non-Esterified Fatty Acids (NEFAs) have been used in veterinary production medicine to evaluate the impact of diet on the energy balance of pregnant animals. In the current study, sustained-release buprenorphine was used to suppress the appetite of pregnant New Zealand white rabbits, mimicking the clinical presentation of animals in reproductive toxicology studies. Sequential NEFA evaluations during gestation, along with other clinical endpoints, such as the necessity and duration of veterinary intervention, were used to evaluate the effects of feeding hay and a pelleted diet as compared with a pelleted diet alone. Elevated NEFA levels were directly correlated to litter size, the number of viable fetuses and the number of days on veterinary consult due to severely decreased consumption of pelleted diet. Animals with hay as part of their diet did not require additional diet supplementation as determined by qualitative evaluation of hay intake and adequate fecal output. These data suggest that including hay as a portion of the standard diet benefits pregnant rabbits in laboratory or production settings.


Subject(s)
Animal Feed , Fatty Acids, Nonesterified/administration & dosage , Feeding Behavior , Rabbits , Animals , Appetite/physiology , Disease Models, Animal , Eating/physiology , Female , Pregnancy
2.
Curr Protoc Mouse Biol ; 7(4): 306-325, 2017 Dec 20.
Article in English | MEDLINE | ID: mdl-29261233

ABSTRACT

Evaluation of the female reproductive system is an important part of basic reproductive biology research, toxicology testing, and mutant mouse phenotype assessment. The female reproductive system is dynamic and the onset of puberty and the normal changes observed during estrous cyclicity can create challenges for an investigator. Experimental work in the female mouse requires an understanding of the potential impact of the estrous cycle and tracking normal changes throughout the cycle allows for control of this key variable. The estrous cycle can be evaluated using vaginal cytology, which provides the researcher a daily assessment of the entire reproductive endocrine axis and allows for samples to be collected at precise times within the cycle. These protocols describe the basic approach to evaluating the onset of cyclicity, tracking the normal cycle, and collection and microscopic evaluation of the reproductive system and mammary gland in the mouse. © 2017 by John Wiley & Sons, Inc.


Subject(s)
Estrous Cycle/physiology , Genitalia, Female/physiology , Mammary Glands, Animal/physiology , Mice/physiology , Models, Animal , Animals , Female
3.
Toxicol Pathol ; 44(7): 1034-58, 2016 10.
Article in English | MEDLINE | ID: mdl-27613106

ABSTRACT

There are currently no reports describing mammary gland development in the Harlan Sprague-Dawley (HSD) rat, the current strain of choice for National Toxicology Program (NTP) testing. Our goals were to empower the NTP, contract labs, and other researchers in understanding and interpreting chemical effects in this rat strain. To delineate similarities/differences between the female and male mammary gland, data were compiled starting on embryonic day 15.5 through postnatal day 70. Mammary gland whole mounts, histology sections, and immunohistochemically stained tissues for estrogen, progesterone, and androgen receptors were evaluated in both sexes; qualitative and quantitative differences are highlighted using a comprehensive visual timeline. Research on endocrine disrupting chemicals in animal models has highlighted chemically induced mammary gland anomalies that may potentially impact human health. In order to investigate these effects within the HSD strain, 2,3,7,8-tetrachlorodibenzo-p-dioxin, diethylstilbestrol, or vehicle control was gavage dosed on gestation day 15 and 18 to demonstrate delayed, accelerated, and control mammary gland growth in offspring, respectively. We provide illustrations of normal and chemically altered mammary gland development in HSD male and female rats to help inform researchers unfamiliar with the tissue and may facilitate enhanced evaluation of both male and female mammary glands in juvenile toxicity studies.


Subject(s)
Mammary Glands, Animal/drug effects , Mammary Glands, Animal/embryology , Aging , Animals , Diethylstilbestrol/toxicity , Female , Male , Polychlorinated Dibenzodioxins/toxicity , Pregnancy , Prenatal Exposure Delayed Effects , Rats , Rats, Sprague-Dawley , Toxicity Tests
4.
Toxicol Pathol ; 43(4): 558-68, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25398757

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.


Subject(s)
Caprylates/toxicity , Fluorocarbons/toxicity , Liver Neoplasms, Experimental/chemically induced , Liver Neoplasms, Experimental/metabolism , Liver/drug effects , PPAR alpha/metabolism , Prenatal Exposure Delayed Effects/chemically induced , Animals , Female , Liver Neoplasms, Experimental/pathology , Male , Mice , Mice, Knockout , PPAR alpha/genetics , Pregnancy , Prenatal Exposure Delayed Effects/metabolism , Prenatal Exposure Delayed Effects/pathology
5.
Toxicol Pathol ; 43(4): 546-57, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25326589

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.


Subject(s)
Caprylates/toxicity , Fluorocarbons/toxicity , Mitochondria, Liver/drug effects , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/pathology , Animals , Body Weight/drug effects , Dose-Response Relationship, Drug , Female , Hepatocytes/drug effects , Hepatocytes/metabolism , Hepatocytes/pathology , Liver/cytology , Liver/drug effects , Liver/metabolism , Liver/pathology , Mice , Mitochondria, Liver/metabolism , Mitochondria, Liver/pathology , PPAR alpha/metabolism , Pregnancy , Prenatal Exposure Delayed Effects/metabolism
6.
Environ Mol Mutagen ; 55(6): 457-71, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24616037

ABSTRACT

A systems biology approach was applied to investigate the mechanisms of chromosomal instability in melanoma cell lines. Chromosomal instability was quantified using array comparative genomic hybridization to identify somatic copy number alterations (deletions and duplications). Primary human melanocytes displayed an average of 8.5 alterations per cell primarily representing known polymorphisms. Melanoma cell lines displayed 25 to 131 alterations per cell, with an average of 68, indicative of chromosomal instability. Copy number alterations included approximately equal numbers of deletions and duplications with greater numbers of hemizygous (-1,+1) alterations than homozygous (-2,+2). Melanoma oncogenes, such as BRAF and MITF, and tumor suppressor genes, such as CDKN2A/B and PTEN, were included in these alterations. Duplications and deletions were functional as there were significant correlations between DNA copy number and mRNA expression for these genes. Spectral karyotype analysis of three lines confirmed extensive chromosomal instability with polyploidy, aneuploidy, deletions, duplications, and chromosome rearrangements. Bioinformatic analysis identified a signature of gene expression that was correlated with chromosomal instability but this signature provided no clues to the mechanisms of instability. The signature failed to generate a significant (P = 0.105) prediction of melanoma progression in a separate dataset. Chromosomal instability was not correlated with elements of DNA damage response (DDR) such as radiosensitivity, nucleotide excision repair, expression of the DDR biomarkers γH2AX and P-CHEK2, nor G1 or G2 checkpoint function. Chromosomal instability in melanoma cell lines appears to influence gene function but it is not simply explained by alterations in the system of DDR.


Subject(s)
Chromosomal Instability/genetics , Melanoma/genetics , Systems Biology/methods , Cell Line, Tumor , Comparative Genomic Hybridization , Computational Biology , DNA Copy Number Variations/genetics , DNA Damage/genetics , DNA Damage/physiology , Humans , Karyotyping , Oncogenes/genetics
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