Thirteen week toxicity study of dietary l-tryptophan in rats with a recovery period of 5 weeks.

Although l-tryptophan is nutritionally important and widely used in medical applications, toxicity data for its oral administration are limited. The purpose of this study was to evaluate the potential toxicity of an experimental diet containing added l-tryptophan at doses of 0 (basal diet), 1.25%, 2.

Exposure to MnCl2 · 4H2O during development induces activation of microglial and perivascular macrophage populations in the hippocampal dentate gyrus of rats.

Developmental exposure to Mn caused Mn accumulation in the brain tissue and transient disruption of granule cell neurogenesis, targeting the late stage differentiation of progenitor cells in the subgranular zone of the hippocampal dentate gyrus of rats. Because neurogenesis is influenced by proinflammatory responses, this study was performed to determine whether Mn exposure causes microglial activation in the dentate hilus, a region anatomically close to the subgranular zone of the dentate gyrus. Pregnant rats were treated with dietary MnCl2 · 4H2O at 32, 160 or 800 ppm from gestational day 10 to day 21 after delivery.

Transient suppression of late-stage neuronal progenitor cell differentiation in the hippocampal dentate gyrus of rat offspring after maternal exposure to nicotine.

To examine the developmental exposure effect of nicotine (NIC) on hippocampal neurogenesis, pregnant Sprague-Dawley rats were treated with (-)-NIC hydrogen tartrate salt through drinking water at 2, 10 or 50 ppm from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, immunohistochemically doublecortin (Dcx)(+) cells increased at ≥10 ppm in the dentate subgranular zone (SGZ) as examined in male offspring; however, dihydropyrimidinase-like 3 (TUC4)(+) cells decreased at 2 ppm, and T box brain 2 (Tbr2)(+) cells were unchanged at any dose. Double immunohistochemistry revealed decreases in TUC4(+)/Dcx(+) and TUC4(+)/Dcx(-) cells, an increase in TUC4(-)/Dcx(+) cells at 2 and 10 ppm and an increase in Tbr2(-)/Dcx(+) cells at 50 ppm, suggesting an increase in type-3 progenitor cells at ≥2 ppm and decrease in immature granule cells at 2 and 10 ppm.

Glycidol induces axonopathy by adult-stage exposure and aberration of hippocampal neurogenesis affecting late-stage differentiation by developmental exposure in rats.

To investigate the neurotoxicity profile of glycidol and its effect on developmental hippocampal neurogenesis, pregnant Sprague Dawley rats were given drinking water containing 0, 100, 300, or 1000 ppm glycidol from gestational day 6 until weaning on day 21 after delivery. At 1000 ppm, dams showed progressively worsening gait abnormalities, and histopathological examination showed generation of neurofilament-L(+) spheroids in the cerebellar granule layer and dorsal funiculus of the medulla oblongata, central chromatolysis in the trigeminal nerve ganglion cells, and axonal degeneration in the sciatic nerves. Decreased dihydropyrimidinase-like 3(+) immature granule cells in the subgranular zone (SGZ) and increased immature reelin(+) or calbindin-2(+) γ-aminobutyric acid-ergic interneurons and neuron-specific nuclear protein (NeuN)(+) mature neurons were found in the dentate hilus of the offspring of the 1000 ppm group on weaning.

Reversible effect of developmental exposure to chlorpyrifos on late-stage neurogenesis in the hippocampal dentate gyrus in mouse offspring.

The effect of developmental exposure to chlorpyrifos (CPF) on hippocampal neurogenesis was examined in male mice after maternal dietary exposure to CPF at 0, 4, 20, or 100ppm from gestation day 10 to postnatal day (PND) 21. Cholinesterase activity was dose-dependently decreased in red blood cells at ≥4ppm and in the brain at 100ppm both in dams and offspring on PND 21. Immunohistochemically, doublecortin(+) cells were decreased at ≥20ppm in the subgranular zone (SGZ) of the dentate gyrus, and NeuN(+)-expressing mature neurons were decreased at 100ppm in the hilus on PND 21.

Reversible effect of maternal exposure to chlorpyrifos on the intermediate granule cell progenitors in the hippocampal dentate gyrus of rat offspring.

To examine the effects of developmental exposure to chlorpyrifos (CPF) on neurogenesis in the hippocampal dentate gyrus, pregnant rats were treated with 2.8, 14 or 70 ppm CPF in the diet from gestational day 10 to day 21 after delivery. Dams had decreased cholinesterase (ChE) activities in red blood cells (RBC) at intakes of ≥2.

Disruptive cell cycle regulation involving epigenetic downregulation of Cdkn2a (p16(Ink4a)) in early-stage liver tumor-promotion facilitating liver cell regeneration in rats.

Cell cycle aberration was immunohistochemically examined in relation to preneoplastic liver cell foci expressing glutathione S-transferase placental form (GST-P) at early stages of tumor-promotion in rats with thioacetamide (TAA), a hepatocarcinogen facilitating liver cell regeneration. Immunoexpression of p16(Ink4a) following exposure to other hepatocarcinogens/promoters and its DNA methylation status were also analyzed during early and late tumor-promotion stages. GST-P(+) liver cell foci increased cell proliferation and decreased apoptosis when compared with surrounding liver cells.

Reversible aberration of neurogenesis affecting late-stage differentiation in the hippocampal dentate gyrus of rat offspring after maternal exposure to manganese chloride.

To examine the effects of developmental manganese (Mn)-exposure on hippocampal neurogenesis, pregnant rats were treated with MnCl(2)·4H(2)O in the diet at 32, 160 or 800 ppm from gestation day 10 to day 21 after delivery. Serum concentrations of thyroid-related hormones were examined in offspring exposed to MnCl(2)·4H(2)O at 800 or 1600 ppm. Immunohistochemical analysis revealed increased doublecortin-positive cells in the subgranular zone of the dentate gyrus on postnatal day (PND) 21 following exposure to MnCl(2)·4H(2)O at 800 ppm, indicating an increase of type-3 progenitor or immature granule cells.

Adolescent hyperactivity of offspring after maternal protein restriction during the second half of gestation and lactation periods in rats.

To clarify the effect of systemic growth retardation on behavior, pregnant rats were fed a synthetic diet with either a normal (20% casein) or low (10% casein) protein concentration from gestational day 10 to postnatal day (PND) 21 at weaning. Offspring were examined for sensory and reflex functions, detailed clinical observations, manipulative test, grip strength, motor activity and water-filled multiple T-maze test. Lowering trend in the air righting reflex index during lactation period and a decrease in grip strength on PND 72 were observed in the low protein diet group showing suppression of systemic growth.

Similar distribution changes of GABAergic interneuron subpopulations in contrast to the different impact on neurogenesis between developmental and adult-stage hypothyroidism in the hippocampal dentate gyrus in rats.

Hypothyroidism affects neurogenesis. The present study was performed to clarify the sensitivity of neurogenesis-related cellular responses in the hippocampal dentate gyrus between developmental and adult-stage hypothyroidism. An exposure study of methimazole (MMI) as an anti-thyroid agent at 0, 50, 200 ppm in the drinking water was performed using pregnant rats from gestation day 10 to postnatal day (PND) 21 (developmental hypothyroidism) and adult male rats by setting an identical exposure period from PND 46 through to PND 77 (adult-stage hypothyroidism).

Transient aberration of neuronal development in the hippocampal dentate gyrus after developmental exposure to brominated flame retardants in rats.

We immunohistochemically investigated the impact and reversibility of three brominated flame retardants (BFRs) known to be weak thyroid hormone disruptors on neuronal development in the hippocampal formation and apoptosis in the dentate subgranular zone. Pregnant Sprague-Dawley rats were exposed to 10, 100, or 1,000 ppm decabromodiphenyl ether (DBDE); 100, 1,000 or 10,000 ppm tetrabromobisphenol A (TBBPA) or 1,2,5,6,9,10-hexabromocyclododecane (HBCD) in the diet from gestational day 10 through to day 20 after delivery (weaning). On postnatal day (PND) 20, interneurons in the dentate hilus-expressing reelin increased with all chemicals, suggestive of aberration of neuronal migration.

Developmental exposure to manganese chloride induces sustained aberration of neurogenesis in the hippocampal dentate gyrus of mice.

The effect of exogenously administered manganese (Mn) on developmental neurogenesis in the hippocampal dentate gyrus was examined in male mice after maternal exposure to MnCl(2) (0, 32, 160, or 800 ppm as Mn in diet) from gestational day 10 to day 21 after delivery on weaning. Immunohistochemistry was performed to monitor neurogenesis and interneuron subpopulations on postnatal days (PNDs) 21 and 77 (adult stage). Reelin-synthesizing γ-aminobutyric acid (GABA)ergic interneurons increased in the hilus with ≥ 160 ppm on weaning to sustain to PND 77 at 800 ppm.

Reversible aberration of neurogenesis targeting late-stage progenitor cells in the hippocampal dentate gyrus of rat offspring after maternal exposure to acrylamide.

We have recently shown that maternal exposure to acrylamide (AA) impaired neurogenesis in rat offspring measured by the increase in interneurons producing reelin, a molecule regulating migration and correct positioning of developing neurons, in the hippocampal dentate gyrus. To clarify the cellular target of AA on hippocampal neurogenesis and its reversibility after maternal exposure, pregnant Sprague-Dawley rats were given drinking water containing AA at 0, 4, 20, 100 ppm on day 10 of pregnancy through day 21 after delivery on weaning. Male offspring were examined immunohistochemically on postnatal day (PND) 21 and PND 77.

Complex apocrine carcinoma with dominant myoepithelial proliferation in a dog.

A rare case of complex apocrine carcinoma displaying dominant myoepithelial proliferation developed in the right leg subcutis of a 10-year-old male dog. The major cell population consisted of diffusely proliferating p63-expressing neoplastic cells that were largely myoepithelial in origin co-expressing α-smooth muscle actin. A small portion of the cell population consisted of concomitant basal epithelial cells lacking α-smooth muscle actin expression.

Disruptive neuronal development by acrylamide in the hippocampal dentate hilus after developmental exposure in rats.

To examine whether developmental exposure to acrylamide (AA) impairs neuronal development, pregnant Sprague-Dawley rats were treated with AA at 0, 25, 50 or 100 ppm in drinking water from gestational day 6 until weaning on postnatal day 21. Offspring were immunohistochemically examined at the end of exposure. We investigated the expression of Reelin (a molecule regulating neuronal migration and positioning) in the hilus of the hippocampal dentate gyrus.

No effect of sustained systemic growth retardation on the distribution of Reelin-expressing interneurons in the neuron-producing hippocampal dentate gyrus in rats.

Reelin signaling plays a role in neuronal migration and positioning during brain development. To clarify the effect of systemic growth retardation on the distribution of Reelin-expressing interneurons in the hilus of the hippocampal dentate gyrus, pregnant rats were fed a synthetic diet with either a normal (20% casein) or low (10% casein) protein concentration from gestational day 10 to postnatal day (PND) 21 at weaning. Male offspring were immunohistochemically examined at PND 21 and on PND 77.

Studies of the toxicological potential of capsinoids XIV: a 26-week gavage toxicity study of dihydrocapsiate in rats.

To further evaluate the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate, CAS No. 205687-03-2), a 26-week gavage toxicity study was conducted in Sprague-Dawley rats (20/sex/group). Test animals received either dihydrocapsiate, 100, 300, or 1000 mg/kg/day, or vehicle (medium-chain triglyceride) by gavage and were observed for antemortem and postmortem signs of toxicity including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights.

Effects of pregnancy and lactation on warfarin-induced changes in blood coagulation-related parameters in rats.

Effects of pregnancy and lactation on warfarin-induced changes in blood coagulation-related parameters were examined in rats. Warfarin (0.5 mg/kg/day) was given orally to pregnant and non-pregnant rats for 3 days from gestation day (GD) 17 to 19 or to lactating and non-pregnant rats for 3 days from post partum day (PPD) 10 to 12.

Induction of GST-P-positive proliferative lesions facilitating lipid peroxidation with possible involvement of transferrin receptor up-regulation and ceruloplasmin down-regulation from the early stage of liver tumor promotion in rats.

To elucidate the role of metal-related molecules in hepatocarcinogenesis, we examined immunolocalization of transferrin receptor (Tfrc), ceruloplasmin (Cp) and metallothionein (MT)-1/2 in relation to liver cell foci positive for glutathione-S-transferase placental form (GST-P) in the early stage of tumor promotion by fenbendazole (FB), phenobarbital, piperonyl butoxide or thioacetamide in a rat two-stage hepatocarcinogenesis model. To estimate the involvement of oxidative stress responses to the promotion, immunolocalization of 4-hydroxy-2-nonenal, malondialdehyde and acrolein was similarly examined. Our findings showed that MT-1/2 immunoreactivity was not associated with the cellular distribution of GST-P and proliferating cell nuclear antigen, suggesting no role of MT-1/2 in hepatocarcinogenesis.

Phenobarbital (PB)-induced changes in blood coagulationrelated parameters in pregnant rats, lactating rats and pups.

Effects of repeated administration of phenobarbital (PB) on blood coagulation-related parameters were examined in non-pregnant, pregnant and lactating rats, and also in pups born to PB-treated lactating dams. PB was orally administered at a dose level of 80 mg/kg/day to pregnant (from gestation day (GD) 13), postpartum (from postpartum day (PPD) 7) and non-pregnant rats (from 13 weeks of age) for 7 days. Blood was collected on GD20 or PPD14 to perform blood coagulation examination.

Carbon tetrachloride-induced hepatotoxicity in pregnant and lactating rats.

Carbon tetrachloride (CCl4) is well known to induce hepatotoxicity after being metabolized to trichloromethyl free radical ((.)CCl3) by CYP2E1. In the present study, the hepatotoxicity induced by a single oral dose (2,000 mg/kg) of CCl4 was compared between pregnant (gestation days (GD) 13 and 19) or postpartum (postpartum days (PPD) 1, 13 and 27) and non-pregnant rats.

Unexpected sudden deaths of F344 rats in long-term toxicity studies: relationship between sudden deaths and stomach tube material or feed type.

Sudden deaths of F344 rats (F344/Du Crj (Fischer)) have occurred frequently in the late stage of carcinogenicity studies using stomach tubes. To reduce the sudden deaths, the incidence of sudden deaths was compared in the control groups from 104-week carcinogenicity studies using two different stomach tubes (metal and Teflon) and feeds (pellet and powder). The results indicate that replacing metal tubes with Teflon tubes from the first administration or after week 41 of administration was not effective in reducing the sudden deaths.