The kidney plays an important role in iron homeostasis and mesangial cells (MCs) are phagocytic cells important for glomerular homeostasis. Sickle hemoglobin (HbS) modulators are promising clinical candidates for treatment of sickle cell disease. Although they prevent disease pathophysiology of HbS polymerization and red blood cell (RBC) sickling by increasing hemoglobin oxygen affinity, higher oxygen affinity can also cause transient tissue hypoxia with compensatory increases in erythropoiesis and subsequent increases in RBC turnover.
View Article and Find Full Text PDFAdministration of pediatric anesthetics with N-methyl D-aspartate (NMDA)-receptor antagonist and/or γ-aminobutyric acid (GABA) agonist activities may result in neuronal degeneration and/or neuronal cell death in neonatal rats. Evaluating pediatric drug candidates for this potential neurotoxicity is often part of overall preclinical new drug development strategy. This specialized assessment may require dosing neonatal rats at postnatal day 7 at the peak of the brain growth spurt and evaluating brain tissue 24 to 48 hours following dosing.
View Article and Find Full Text PDFBenzoic acid (BA) was administered in the diet to male and female Sprague Dawley Crl:CD(SD) rats in an OECD Test Guideline 443 Extended One-Generation Reproductive Toxicity (EOGRT) study to test for effects that may occur as a result of pre- and postnatal exposure. The study included cohorts of F offspring to evaluate potential effects of benzoic acid on reproduction, the developing immune system, and the developing neurological system with the inclusion of learning and memory assessments. Benzoic acid was incorporated in the diet at concentrations of 0, 7,500, 11,500, and 15,000 mg/kg diet (ppm).
View Article and Find Full Text PDFObjectives: Phage-gonadotropin-releasing hormone (GnRH) constructs with potential contraceptive properties were generated in our previous study via selection from a phage display library using neutralizing GnRH antibodies as selection targets. In mice, these constructs invoked the production of antibodies against GnRH and suppressed serum testosterone. The goal of this study was to evaluate this vaccine against GnRH for its potential to suppress reproductive characteristics in cats.
View Article and Find Full Text PDFFollowing publication of the original article.
View Article and Find Full Text PDFCertified LabDiet 5K96 Advanced Protocol™ Verified Casein Diet 10 IF (5K96) is a commercial diet low in soy isoflavones developed for use in developmental and reproductive toxicity (DART) studies, especially those designed to detect endocrine disruptors. The objective of this study was to determine the incidences and severities of 5K96-associated renal lesions in control F and F cohorts of rats fed the 5K96 diet. Kidneys from control animals of four DART studies involving Sprague-Dawley rats fed the 5K96 diet, were evaluated microscopically.
View Article and Find Full Text PDFAt elevated levels, fluoride (F) exposure has been associated with adverse human health effects. In rodents, F exposure has been reported to induce deficits in motor performance and learning and memory. In this study, we examined Long-Evans hooded male rats maintained on a standard diet (20.
View Article and Find Full Text PDFBirth Defects Res
February 2018
This review describes pre- and postnatal development of the male reproductive system in humans and laboratory animals, and highlights species differences in the timing and control of hormonal and morphologic events. Major differences are that the fetal testis is dependent on gonadotropins in humans, but is independent of such in rats; humans have an extended postnatal quiescent period, whereas rats exhibit no quiescence; and events such as secretion by the prostate and seminal vesicles, testicular descent, and the appearance of spermatogonia are all prenatal events in humans, but are postnatal events in rats. Major differences in the timing of the developmental sequence between rats and humans include: gonocyte transformation period (rat: postnatal day 0-9; human: includes gestational week 22 to 9 months of age); masculinization programming window (rat: gestational day 15.
View Article and Find Full Text PDFToxicol Pathol
January 2017
Age, and in particular young age, can significantly impact the response to toxicants in animals and can greatly influence the interpretation of tissue changes by the toxicologic pathologist. Although this applies to multiple organ systems, the current review focuses on the male reproductive system. When performing microscopic evaluation of male reproductive organs, the toxicologic pathologist must be aware of the dynamic changes in histomorphology, predominantly driven by timed hormonal alterations, at various life stages.
View Article and Find Full Text PDFThe distribution of monocarboxylate transporter (MCT) isoforms 1 and 4, which mediate the plasmalemmal transport of l-lactic and pyruvic acids, has been identified in the placentae of rats and rabbits at different ages of gestation. Groups of three pregnant Sprague-Dawley rats and New Zealand White rabbits were sacrificed on gestation days (GD) 11, 14, 18, or 20 and on GD 13, 18, or 28, respectively. Placentae were removed and processed for immunohistochemical detection of MCT1 and MCT4.
View Article and Find Full Text PDFToxicologic pathologists must evaluate tissues of immature animals from a number of types of nonclinical toxicity studies. The pathologist who is familiar with normal postnatal organ development is in a better position to appropriately detect and differentiate between abnormal, delayed, or precocious development. Vacuolation and apoptosis in multiple tissue types are normal components of development that could influence the interpretation of some tissues.
View Article and Find Full Text PDFThe hallmark of the extended one-generation reproductive toxicity study (EOGRTS) is that, based on certain criteria or triggers, selected offspring are assigned at weaning to different cohorts for further investigation of sexual maturation, reproductive organ integrity and function, neuropathological and behavioral endpoints, and/or immune function. The triggers allow for a more customizable design based directly on the data, while minimizing animal usage. Compared to the two-generation reproductive toxicity study, the EOGRTS design increases the number, extent, and duration of F1-offspring assessments resulting in more thorough and efficient utilization of the first generation while excluding the second generation of offspring unless triggered.
View Article and Find Full Text PDFGroups of Crl:CD-1 (ICR) mice (60/group/sex) were fed 0 (2 control groups), 5000, 20,000, or 40,000 ppm of enzymatically sourced (2R,4R)-monatin salt ("R,R-monatin") in the diet for up to two years. There were no adverse effects on survival, incidence of palpable masses and tumors, feed consumption, hematology or serum chemistry parameters, organ weights, or ophthalmic, macroscopic, and microscopic examinations. The only notable effect was statistically significantly lower mean body weights and body weight gains in all treated groups, which generally occurred throughout the study and were most likely a result of caloric dilution of the test diets and not considered adverse.
View Article and Find Full Text PDFThe U.S. Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP) is a multitiered approach to determine the potential for environmental chemicals to alter the endocrine system.
View Article and Find Full Text PDFThe immune system of the rat undergoes substantial functional and morphological development during the postnatal period. Some aspects of this development are genetically predetermined, while other aspects depend on environmental influences. Detailed information on postnatal development is important in the interpretation of histopathologic findings in juvenile toxicology and pubertal assay studies, as well as other studies conducted in juvenile rats.
View Article and Find Full Text PDFMethyl eugenol induces neuroendocrine (NE) cell hyperplasia and tumors in F344/N rat stomach. Detailed histopathological and immunohistochemical (IHC) characterization of these tumors has not been previously reported. The objective of this study was to fill that data gap.
View Article and Find Full Text PDFHistopathologic examination of the testis from juvenile rats is often necessary to characterize the safety of new drugs for pediatric use and is a required end point in male pubertal development and thyroid function assays. To aid in evaluation and interpretation of the immature testis, the characteristic histologic features of the developing rat testis throughout postnatal development are described and correlated with published neuroendocrine parameter changes. During the neonatal period (postnatal day [PND] 3-7), seminiferous tubules contained gonocytes and mitotically active immature Sertoli cells.
View Article and Find Full Text PDFHistopathologic examination of the immature ovary is a required end point on juvenile toxicity studies and female pubertal and thyroid function assays. To aid in this evaluation and interpretation of the immature ovary, the characteristic histologic features of rat ovary through the developmental periods are described. These histologic features are correlated with published changes in neuroendocrine profiles as the hypothalamic-pituitary-gonadal axis matures.
View Article and Find Full Text PDFIn response to growing concerns that environmental chemicals may have adverse effects on human health by altering the endocrine system, the Endocrine Disruptor Screening Program (EDSP), under the auspices of the United States Environmental Protection Agency (U.S. EPA), recently instituted a Tier I battery of tests including a female pubertal assay.
View Article and Find Full Text PDFAn acute, whole-body inhalation study for allyl alcohol in Sprague-Dawley rats was designed to support derivation of AEGL values, with emphasis on establishing NOAELs for irreversible effects of different exposure concentrations and durations. Groups of 10 rats were exposed for 1 hour (0, 50, 200, or 400 ppm), 4 hours (0, 20, 50, or 100 ppm), or 8 hours (0, 10, 20, or 50 ppm). Clinical evaluations were performed during exposure and in an open field within 22-71 minutes after termination of exposure.
View Article and Find Full Text PDFThe liver is the primary hematopoietic organ of the mammalian body during the fetal stage. The postnatal liver retains immunologically important functions and contains a substantial population of immunologically active cells, including T and B lymphocytes, Kupffer cells, liver-adapted natural killer (NK) cells (pit cells), natural killer cells expressing T cell receptor (NKT cells), stellate cells, and dendritic cells. The liver is the major site of production of the acute phase proteins that are associated with acute inflammatory reactions.
View Article and Find Full Text PDFMetrial glands are normal structures located in the mesometrial triangle of the pregnant rat uterus from gestational day (GD) 8 through termination of pregnancy. Metrial glands are composed of a dynamic mixed cell population of granulated metrial gland (GMG) cells, endometrial stromal cells, trophoblasts, blood vessels, and fibroblasts. Collections of similar cells may be seen in association with pseudopregnancy and other hormonal disturbances.
View Article and Find Full Text PDFHibernomas are rare neoplasms originating in brown adipose tissue of humans and other animal species, including laboratory animals. Background incidence values for these tumors in all common strains of laboratory rats are generally accepted as being <0.1%.
View Article and Find Full Text PDFOvarian follicle counting is a method to assess ovarian toxicity in reproductive toxicity studies in rats. Although ovarian follicle counting has been traditionally performed manually on hematoxylin and eosin (H&E)-stained sections, the use of immunohistochemical methods, including human cytochrome P450 1B1 (CYP1B1) and proliferating cell nuclear antigen (PCNA), have been used to enhance the visibility of the primordial and primary follicles to facilitate manual counting. In this study, serial sections from both ovaries from ten 3-month-old female Sprague Dawley rats were stained using routine H&E and immunohistochemistry for PCNA.
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