Toxicology and toxicokinetics of oral pantoprazole in neonatal and juvenile dogs

BACKGROUND: Pantoprazole is an irreversible inhibitor of H⁺/K⁺ adenosine triphosphatase proton pump. This study encompassed the period of postnatal stomach development to determine whether immature animals are uniquely sensitive to progression of PPI‐induced enterochromaffin‐like cell hyperplasia. METHODS: Pantoprazole was administered to beagle dogs at 3, 10, or 30 mg/kg/day (10/sex/group) from PND 1 for 13 weeks, subsets of animals had a 13‐week recovery period. Clinical signs, body weights, growth, clinical chemistry, and neurobehavioral endpoints were assessed. Selected organs were weighed and histologically examined. RESULTS: There were no effects on body weights, growth, landmarks of physical and reproductive development, or sensory and neurobehavioral function. Cholesterol and triglyceride levels were increased at 10 and 30 mg/kg/day, but resolved during the recovery period. Stomach weight was increased at all doses, but after recovery the differences in stomach weights resolved for females although male stomach weights remained slightly increased. Pantoprazole‐related microscopic findings in the stomach consisted of increased mucosal height, glandular necrosis, and glandular dilation at all doses; and ECL cell hyperplasia, parietal cell vacuolation, and atrophy of chief cells are noted at 10 and/or 30 mg/kg/day. There was a partial recovery of these microscopic changes indicated by a decreased incidence and/or severity of increased mucosal height, glandular necrosis, ECL cell hyperplasia, and chief cell atrophy, and complete resolution of other microscopic observations. CONCLUSION: Pantoprazole administered to beagles from PND 1 for 13 weeks resulted in findings similar to those in adult dogs and juvenile dogs, which showed no increase in severity or progression of ECL hyperplasia. Birth Defects Res (Part B) 92:345–352, 2011. © 2011 Wiley‐Liss, Inc.     

Developmental toxicity evaluation of sodium thioglycolate administered topically to Sprague-Dawley (CD) rats and New Zealand White rabbits

BACKGROUND: Sodium thioglycolate, which has widespread occupational and consumer exposure to women from cosmetics and hair‐care products, was evaluated for developmental toxicity by topical exposure during the embryonic and fetal periods of pregnancy METHODS: Timed‐mated Sprague–Dawley rats (25/group) and New Zealand White (NZW) rabbits (24/group) were exposed to sodium thioglycolate in vehicle (95% ethanol:distilled water, 1:1) by unoccluded topical application on gestational days (GD) 6–19 (rats) or 6–29 (rabbits) for 6 hr/day, at 0, 50, 100, or 200 mg/kg body weight/day (rats) and 0, 10, 15, 25, or 65 mg/kg/day (rabbits). At termination (GD 20 rats; GD 30 rabbits), fetuses were examined for external, visceral, and skeletal malformations and variations. RESULTS: In rats, maternal topical exposure to sodium thioglycolate, at 200 mg/kg/day (the highest dose tested) on GD 6–19, resulted in maternal toxicity, including reduced body weights and weight gain, increased relative water consumption and one death. Treatment‐related increases in feed consumption and changes at the application site occurred at all doses, in the absence of increased body weights or body weight change. Fetal body weights/litter were decreased at 200 mg/kg/day, with no other embryo/fetal toxicity and no treatment‐related teratogenicity in any group. In rabbits, maternal topical exposure to sodium thioglycolate on GD 6–29 resulted in maternal dose‐related toxicity at the dosing site in all groups; no maternal systemic toxicity, embryo/fetal toxicity, or treatment‐related teratogenicity were observed in any group. CONCLUSIONS: A no observed adverse effect level (NOAEL) was not identified for maternal toxicity in either species with the dosages tested. The developmental toxicity NOAEL was 100 mg/kg/day (rats) and ≥65 mg/kg/day (rabbits; the highest dose tested). The clinical relevance of theses study results is uncertain because no data were available for levels, frequency, or duration of exposures in female workers or end users. Birth Defects Research Part B 68:144–161, 2003. © 2003 Wiley‐Liss, Inc.     

Toxicity study in juvenile rats with the α4β2 nicotinic acetylcholine receptor partial agonist CP-601,927

BACKGROUND: CP‐601927 is a selective α₄β₂ nicotinic acetylcholine receptor (nAChR) partial agonist. The objective of this study was to assess the potential effects persisting into adulthood when CP‐601,927 was administered to neonatal/juvenile rats. Since the juvenile toxicity study was being performed early in the development program and this study would represent the longest dosing period yet evaluated, the study design incorporated standard endpoints typically evaluated in a general toxicity screening study. METHODS: CP‐601,927 was administered to Sprague‐Dawley rats from postnatal day (PND) 7–70 by oral gavage at doses of 0.3, 1, or 3 mg/kg. During treatment animals were evaluated for growth, development, and sexual maturation. At the end of the treatment period general toxicity screening endpoints were collected (e.g., organ weights, histology, clinical chemistry). Following a 2‐week latency period, animals were evaluated for CNS function in a comprehensive behavioral training battery consisting of a functional observational battery, motor activity, acoustic startle response, and learning and memory evaluations. Reproductive competency was evaluated by mating treated rats and allowing pregnant dams to deliver and rear their litters until PND 10. RESULTS AND CONCLUSIONS: Treatment‐related findings included the death of 2 males receiving 3 mg/kg CP‐601,927, and transient reductions in body weight for both males and females during the third week of dosing which quickly recovered to control levels. The only treatment‐related alteration in behavior was decreased motor activity, which occurred only in females at the highest dose tested. CP‐601,927 had no effect on acoustic startle response, learning and memory, sexual maturation, reproductive capacity, or general toxicity endpoints. Birth Defects Res (Part B) 92:323–332, 2011. © 2011 Wiley‐Liss, Inc.     

Maternal exposure to multi-wall carbon nanotubes does not induce embryo-fetal developmental toxicity in rats

BACKGROUND: Although the potential risk of carbon nanotubes (CNTs) to humans has recently increased due to expanding production and widespread use, the potential adverse effects of CNTs on embryo–fetal development have not yet been determined. METHODS: This study investigated the potential effects of multi‐wall CNTs (MWCNTs) on pregnant dams and embryo–fetal development in rats. MWCNTs were administered to pregnant rats by gavage at 0, 40, 200, and 1,000 mg/kg/day. All dams were subjected to Cesarean section on day 20 of gestation, and the fetuses were examined for any morphological abnormalities. RESULTS: All animals survived to the end of the study. A decrease in thymus weight was observed in the high dose group in a dose‐dependent manner. However, maternal body weight, food consumption, and oxidant–antioxidant balance in the liver were not affected by treatment with MWCNTs. No treatment‐related differences in gestation index, fetal deaths, fetal and placental weights, or sex ratio were observed between the groups. Morphological examinations of the fetuses demonstrated no significant difference in incidences of abnormalities between the groups. CONCLUSIONS: The results show that repeated oral doses of MWCNTs during pregnancy induces minimal maternal toxicity and no embryo–fetal toxicity at 1,000 mg/kg/day in rats. The no‐observed‐adverse‐effect level of MWCNTs is considered to be 200 mg/kg/day for dams and 1,000 mg/kg/day for embryo–fetal development. In this study, the dosing formulation was not analyzed to determine the degree of reaggregation (or not), nor were blood levels of CNT's measured in the dosed animals to verify or characterize absorption. Birth Defects Res (Part B) 92:69–76, 2011. © 2011 Wiley‐Liss, Inc.     

Juvenile toxicity assessment of d,l-methylphenidate in rats

BACKGROUND: The oral administration of d,l‐methylphenidate (MPH) was designed to encompass the major part of postnatal development in the rat and to evaluate potential chronic effects. METHODS: Wistar Hannover rats were cross‐fostered on postpartum day 0 (day of birth) and were administered MPH at doses of 5, 50, and 100 mg/kg/day (mpkd) on postpartum days 7 to 70. Clinical signs, body weight, food consumption, developmental, behavioral, clinical/anatomic pathology, toxicokinetic, and fertility evaluations were conducted. RESULTS: MPH‐related effects on clinical signs, body weight, and behavior tests were noted. Increased locomotor activity and cage biting/chewing occurred at ≥5 mpkd (females) and ≥50 mpkd (males) and were absent after dosing ceased. Body weight parameters were decreased at ≥50 mpkd and were comparable to controls at 5 weeks' recovery. Open field motor activity tests conducted 2 weeks after dosing ceased revealed decreased peripheral beam breaks at ≥50 mpkd. Passive avoidance tests conducted 3 weeks after dosing ceased indicated decreased females reaching learning criterion at 100 mpkd. This is considered of nominal significance as there were no effects in the water maze test or retention in passive avoidance test. After multiple doses, females exhibited higher exposures than males and exposures were reduced in all groups in comparison to those after a single dose. CONCLUSIONS: These results suggest that MPH can produce enduring behavioral effects in rats. The no‐toxicologic‐effect‐level was 5 mpkd, associated with AUC_{(0–24 h)} racemate values in males and females, respectively, of 101 and 153 ng.h/mL after chronic dosing. Birth Defects Res (Part B) © 2008 Wiley‐Liss, Inc.     

Dose–Response Effects of Diphenylhydantoin on Pregnant Dams and Embryo‐Fetal Development in Rats

Despite the widespread use of diphenylhydantoin (DPH), there is a lack of reliable information on the teratogenic effects, correlation with maternal and developmental toxicity, and dose–response relationship of DPH. This study investigated the dose–response effects of DPH on pregnant dams and embryo‐fetal development as well as the relationship between maternal and developmental toxicity. DPHwas orally administered to pregnant rats from gestational days 6 through 15 at 0, 50, 150, and 300 mg/kg/day. At 300 mg/kg, maternal toxicity including increased clinical signs, suppressed body weight, decreased food intake, and increased weights of adrenal glands, liver, kidneys, and brain were observed in dams. Developmental toxicity, including a decrease in fetal and placental weights, increased incidence of morphological alterations, and a delay in fetal ossification delay also occurred. At 150 mg/kg, maternal toxicity manifested as an increased incidence of clinical signs, reduced body weight gain and food intake, and increased weights of adrenal glands and brain. Only minimal developmental toxicity, including decreased placental weight and an increased incidence of visceral and skeletal variations, was observed. No treatment‐related maternal or developmental effects were observed at 50 mg/kg. These results show that DPH is minimally embryotoxic at a minimal maternotoxic dose (150 mg/kg/day) but is embryotoxic and teratogenic at an overt maternotoxic dose (300 mg/kg/day). Under these experimental conditions, the no‐observed‐adverse‐effect level of DPH for pregnant dams and embryo‐fetal development is considered to be 50 mg/kg/day. These data indicate that DPH is not a selective developmental toxicant in the rat.     

Blood alcohol concentration and microencephaly: a dose-response study in the neonatal rat

The relationships among microencephaly, peak blood alcohol concentration (BAC), and dose of alcohol were examined in a rat model of third-trimester fetal alcohol effects. Ethyl alcohol was administered to neonatal rats from postnatal day 4 to day 10 during the brain growth spurt via an artificial rearing technique. Groups of rats received one of nine doses of alcohol (0.0, 2.5, 3.3, 4.0, 4.5, 5.3, 6.6, 7.5, or 8.5 g/kg body weight) administered in 8 hours each day. BACs were determined on postnatal days 6 and 7 at times corresponding to peak and trough BACs, respectively. On postnatal day 10, brains were removed, and total brain weights, cerebellar weights and brainstem weights were measured. Pups receiving 4.0 g/kg/day or less had mean peak BACs below 150 mg/dl and did not exhibit significant microencephaly when compared with controls. Higher dosages further increased the peak BAC and produced significant microencephaly. While a dose of 4.5 g/kg/day was sufficient to decrease significantly both total brain weight and cerebellar weight, a minimum dose of 6.6 g/kg/day was required for significant restriction of brainstem weight. The dose of 7.5 g/kg/day yielded a mean peak BAC of 420 mg/dl and reduced total brain weight, cerebellar weight, and brainstem weight by 33%, 52%, and 22%, respectively, relative to controls. Exposure to 8.5 g/kg/day was uniformly lethal. Peak BAC and total brain weight were highly correlated (r = -.916). As peak BAC increased, total brain weight decreased linearly. Comparisons with previous studies indicate that condensing the daily dose of alcohol effectively reduced the threshold doses for microencephaly and lethality.     

Disruption of behavior and brain metabolism in artificially reared rats

Early adverse life stress has been associated to behavioral disorders that can manifest as inappropriate or aggressive responses to social challenges. In this study, we analyzed the effects of artificial rearing on the open field and burial behavioral tests and on GFAP, c‐Fos immunoreactivity, and glucose metabolism measured in anxiety‐related brain areas. Artificial rearing of male rats was performed by supplying artificial milk through a cheek cannula and tactile stimulation, mimicking the mother's licking to rat pups from the fourth postnatal day until weaning. Tactile stimulation was applied twice a day, at morning and at night, by means of a camel brush on the rat anogenital area. As compared to mother reared rats, greater aggressiveness, and boldness, stereotyped behavior (burial conduct) was observed in artificially reared rats which occurred in parallel to a reduction of GFAP immunoreactivity in somatosensory cortex, c‐Fos immunoreactivity at the amygdala and primary somatosensory cortex, and lower metabolism in amygdala (as measured by 2‐deoxi‐2‐[¹⁸fluoro]‐d ‐glucose uptake, assessed by microPET imaging). These results could suggest that tactile and/or chemical stimuli from the mother and littermates carry relevant information for the proper development of the central nervous system, particularly in brain areas involved with emotions and social relationships of the rat. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1413–1429, 2017     

Impaired myelin formation in experimental hyperphenylalaninaemia

Abstract— From the 5th to the 20th postnatal day, rats were injected with saline (controls) or phenylalanine (3 mg/g daily). The quantities of cholesterol and glycolipids were significantly lower in the phenylalanine-injected rats, but brain DNA and protein contents were the same in both groups. As a result of the reduced formation of lipids, the hyperphenylalaninaemic brains contained significantly less myelin than control brains, but the gross composition [ratio of protein: cholesterol: galactolipid: phospholipid) of the myelin was unchanged. We suggest that in hyperphenylalaninaemic brains the reduced availability of cholesterol may cause a reduction in the formation of cholesterol-phospholipid-protein complexes in brain, which in turn may limit the formation of myelin.     

Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols

AY-9944 (AY) exacerbates chronic recurrent seizures in rats that are analogous to atypical absence epilepsy in humans. The mechanism by which AY affects the slow spike-and-wave discharges associated with these seizures is not known, but is thought to involve inhibition of cholesterol synthesis. We tested the hypothesis that seizures seen with AY are due to significant reduction in brain cholesterol and/or elevated brain 7-dehydrocholesterol by assessing whether three other cholesterol synthesis inhibitors mimic AY seizures in rats. Effects of AY on brain sterols and spike-and-wave discharge duration were compared with those of two other late-stage cholesterol inhibitors [BM 15.766 (BM) and U18666A (UA)] and to an HMG-CoA reductase (early-stage cholesterol) inhibitor, lovastatin. With BM or UA, prolongation of seizure duration and brain sterol changes was similar to that caused by AY. AY effects on both brain sterols and seizure duration were dose-related. Lovastatin, with or without concurrent AY, mimicked AY seizures but reduced brain cholesterol by <10% and did not significantly change brain 7-dehydrocholesterol. Either lovastatin has a different mechanism of action than these late-stage cholesterol inhibitors or the brain sterol changes are not directly responsible for seizures in this model.     

Prenatal developmental toxicity of decabromodiphenyl ethane in the rat and rabbit

BACKGROUND: The potential embryotoxic and teratogenic effects of decabromodiphenyl ethane (DBDPEthane; CASRN 84852–53–9) were evaluated in prenatal developmental studies using rats and rabbits and performed in accordance with international guidelines and Good Laboratory Practice standards. Preliminary dose‐range‐finding studies were conducted, which indicated doses up to 1,250 mg/kg‐day were well tolerated by both rats and rabbits. METHODS: For the developmental studies, animals were administered DBDPEthane via gavage at dosage levels of 0, 125, 400, or 1,250 mg/kg‐day from gestation day (GD) 6 through 15 for rats and GDs 6 through 18 for rabbits. All female rats and rabbits were sacrificed on GD 20 or GD 29, respectively, and subjected to cesarean section. Fetuses were individually weighed, sexed, and examined for external, visceral and skeletal abnormalities. RESULTS: No treatment‐related mortality, abortions, or clinical signs of toxicity were observed during the study. Body weights, body weight gain, and food consumption were not affected by treatment. No significant internal abnormalities were observed in either species on necropsy. Cesarean section parameters were comparable between control and treated groups. No treatment‐induced malformations or developmental variations occurred. CONCLUSIONS: Based on these results, no evidence of maternal toxicity, developmental toxicity, or teratogenicity was observed in rats or rabbits treated with DBDPEthane at dosage levels up to 1,250 mg/kg‐day. Birth Defects Res (Part B) 89:139–146, 2010. © 2010 Wiley‐Liss, Inc.     

An oral developmental neurotoxicity study of decabromodiphenyl ether (DecaBDE) in rats

BACKGROUND: Decabromodiphenyl ether (DecaBDE; CASRN 1163‐19‐5) is a flame retardant used in a variety of manufactured products. A single oral dose of 20.1 mg/kg administered to mice on postnatal day 3 has been reported to alter motor activity at 2, 4, and 6 months of age. METHODS: To further evaluate these results, a developmental neurotoxicity study was conducted in the most commonly used species for studies of this type, the rat, according to international validated testing guidelines and Good Laboratory Practice Standards. DecaBDE was administered orally via gavage in corn oil to dams from gestation day 6 to weaning at doses of 0, 1, 10, 100, or 1,000 mg/kg/day. Standard measures of growth, development, and neurological endpoints were evaluated in the offspring. Motor activity was assessed at 2 months of age. Additional motor activity assessments were conducted at 4 and 6 months of age. Neuropathology and morphometry evaluations of the offspring were performed at weaning and adulthood. RESULTS: No treatment‐related neurobehavioral changes were observed in detailed clinical observations, startle response, or learning and memory tests. No test substance‐related changes were noted in motor activity assessments performed at 2, 4, or 6 months of age. Finally, no treatment‐related neuropathological or morphometric alterations were found. CONCLUSIONS: Under the conditions of this study, the no‐observed‐adverse‐effect level for developmental neurotoxicity of DecaBDE was 1,000 mg/kg/day, the highest dose tested. Birth Defects Res (Part B) 92:17–35, 2011.© 2011 Wiley‐Liss, Inc.     

Effects of Melamine and Cyanuric Acid on Embryo‐Fetal Development in Rats

After the outbreak of acute renal failure associated with melamine‐contaminated pet food, melamine and melamine‐related compounds have become of great interest from a toxicologic perspective. We investigated the potential effects of melamine in combination with cyanuric acid (M + CA, 1:1) on pregnant dams and embryo‐fetal development in rats. M + CA was orally administered to pregnant rats from gestational days 6 through 19 at doses of 0, 3, 10, and 30 mg/kg/day of both melamine and cyanuric acid. Maternal toxicity of rats administered 30 mg/kg/day M + CA was manifested as increased incidences of clinical signs and death; gross pathologic findings; higher blood urea nitrogen and creatinine levels; lower body weight gain and food intake; decreased thymus weight; and increased heart, lung, and kidney weights. Histopathological examinations revealed an increase in the incidence of congestion, tubular necrosis/degeneration, crystals, casts, mineralization, inflammatory cells in tubules, tubular dilation, and atrophy of glomeruli in maternal kidneys, whereas fetal kidneys did not show any histopathological changes. Developmental toxicity included a decrease in fetal (28%) and placental weights and a delay in fetal ossification (n = 7). Increased incidence of gross and histopathological changes in the maternal kidney was also found in the middle dose group (n = 12). No treatment‐related maternal or developmental effects were observed in the low dose group (n = 12). Under these experimental conditions, M + CA is embryotoxic at an overt maternotoxic dose in rats and the no‐observed‐adverse‐effect level of M + CA is considered to be 3 mg/kg/day for pregnant dams and 10 mg/kg/day for embryo‐fetal development.     

转运蛋白ABCG1/4 和ABCA1对脑胆固醇的调节作用

脑是富含胆固醇的器官,机体大约有25%的胆固醇集中在脑组织中.ATP结合盒超家族转运蛋白对脑组织中胆固醇的膜外转运和动态平衡起着重要的调节作用.研究发现,ATP结合盒超家族转运蛋白亚体ABCG1、ABCG4和ABCA1在成体脑组织中存在不同程度的表达,一种或多种亚体的缺失可以导致神经退行性病变.然而,ATP结合盒超家族转运蛋白亚体对脑发育过程中脑胆固醇动态变化的调节缺乏相关性的报道.在本研究中,从低胆固醇饮食喂养的C57BL/6J小鼠中获取出生后不同发育时期的脑组织,对ABCG1、ABCG4和ABCA1的mRNA与蛋白质表达水平进行测定,并对脑组织和血清中ATP结合盒超家族转运蛋白的表达水平与胆固醇水平的相关性进行研究.同时,使用ABCG1、ABCG4单一基因敲除鼠和ABCG1、ABCG4双基因敲除鼠,研究ATP结合盒超家族转运蛋白对与胆固醇合成的相关基因表达的影响以及对脑组织胆固醇代谢的调节作用.结果发现,ABCG1、ABCG4和ABCA1在机体多个器官中均有表达,但ABCG1和ABCG4在小鼠脑组织中表达量最高.在脑组织发育过程中,ABCG1和ABCG4mRNA水平呈现明显的表达时效性,小鼠于出生后42天达到峰值,而ABCA1 mRNA的表达水平无明显变化.血清和脑组织中中酯化型胆固醇水平呈双高峰分布,也于出生后42天达到最高.基因敲除鼠模型显示,单一敲除ABCG1或者ABCG4基因对脑组织胆固醇水平无明显影响,而ABCG1和ABCG4基因的同时缺失导致脑胆固醇水平显著升高,并明显降低胆固醇合成相关基因的表达水平.本研究表明,在脑发育成熟过程中,ATP结合盒超家族转运蛋白亚体ABCG1和ABCG4,而非ABCA1,以调节脑胆固醇的膜外转运;ABCG1和ABCG4互补调控脑胆固醇的动态平衡.     

Lovastatin attenuates nerve injury in an animal model of Guillain-Barré syndrome

Statins, widely used as clinically effective inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, exhibit anti-inflammatory properties that may be of therapeutic benefit for the management of some neurological disorders. In this study, a short-term course of lovastatin treatment is shown to markedly inhibit the development of experimental autoimmune neuritis (EAN) in the absence of hepatotoxic or myotoxic complications. Independent of cholesterol reduction, lovastatin treatment prevented EAN-induced peripheral nerve conduction deficits and morphologic nerve injury. Co-administration with mevalonate neutralized the prophylactic effects of lovastatin. When administered therapeutically, lovastatin significantly shortened the disease course. Autoreactive immunity, measured in vitro by myelin-stimulated proliferation of splenocytes, was significantly diminished by in vivo lovastatin treatment. Th1-dominant immune responses, measured by cytokine profiling, however, were not affected by lovastatin. Sciatic nerves of lovastatin-treated immunized rats showed markedly reduced levels of cellular infiltrates. Treating peripheral nerve endothelial monolayers with lovastatin significantly inhibited the in vitro migration of autoreactive splenocytes. Together, these data demonstrate that a short-term course of lovastatin attenuates the development and progression of EAN in Lewis rats by limiting the proliferation and migration of autoreactive leukocytes.     

Developmental Toxicity Evaluations of Whole Mixtures of Disinfection By‐products using Concentrated Drinking Water in Rats: Gestational and Lactational Effects of Sulfate and Sodium

A developmental toxicity bioassay was used in three experiments to evaluate water concentrates for suitability in multigenerational studies. First, chlorinated water was concentrated 135‐fold by reverse osmosis; select lost disinfection by‐products were spiked back. Concentrate was provided as drinking water to Sprague–Dawley and F344 rats from gestation day 6 to postnatal day 6. Maternal serum levels of luteinizing hormone on gestation day 10 were unaffected by treatment for both strains. Treated dams had increased water consumption, and increased incidences of polyuria, diarrhea, and (in Sprague–Dawley rats) red perinasal staining. Pup weights were reduced. An increased incidence of eye defects was seen in F344 litters. Chemical analysis of the concentrate revealed high sodium (6.6 g/l) and sulfate (10.4 g/l) levels. To confirm that these chemicals caused polyuria and osmotic diarrhea, respectively, Na₂SO₄ (5–20 g/l) or NaCl (16.5 g/l) was provided to rats in drinking water. Water consumption was increased at 5‐ and 10‐g Na₂SO₄/l and with NaCl. Pup weights were reduced at 20‐g Na₂SO₄/l. Dose‐related incidences and severity of polyuria and diarrhea occurred in Na₂SO₄‐treated rats; perinasal staining was seen at 20 g/l. NaCl caused polyuria and perinasal staining, but not diarrhea. Subsequently, water was concentrated ～120‐fold and sulfate levels were reduced by barium hydroxide before chlorination, yielding lower sodium (≤1.5 g/l) and sulfate (≤2.1 g/l) levels. Treatment resulted in increased water consumption, but pup weight and survival were unaffected. There were no treatment‐related clinical findings, indicating that mixtures produced by the second method are suitable for multigenerational testing. Birth Defects Res (Part B) 00:1–11, 2012. Published 2012 by Wiley Periodicals, Inc.     

Postnatal development of rat pups after maternal exposure to diethanolamine

BACKGROUND: Diethanolamine (DEA), a widely used surfactant, was administered to pregnant mice at the oral LD10 resulting in failure of pups to grow and thrive through postnatal day (PND) 3 [National Toxicology Program, 1987; York et al., Teratology 37:503-504, 1988]. The toxicity profile for DEA differs among rodent species. This study investigated DEA-induced postnatal toxicity in a second species. METHODS: Timed-mated Sprague-Dawley rats were dosed (0, 50, 125, 200, 250, or 300 mg DEA/kg/day, p.o.) on gestational days (GD) 6-19. Dams and pups were monitored for body weight, feed/water intake, clinical signs, litter size, and sex ratio. At necropsy (PND 21), maternal liver and kidney weights and number of uterine implantation sites were recorded. RESULTS: The high-dose group was terminated early due to excessive toxicity. The estimated maternal LD10 was 218 mg/kg/day. Maternal effects included decreased body weight and relative feed intake (>or=200 mg/kg/day), transiently reduced relative water intake (125 and 250 mg/kg/day), and increased absolute kidney weight (>or=125 mg/kg/day). Postimplantation loss (PND 0) and pup mortality (PND 0-4) were increased (>or=200 and >or=125 mg/kg/day, respectively). Pup body weight was reduced (>or=200 mg/kg/day) as late as PND 21. CONCLUSIONS: This study demonstrates reduced postnatal growth and survival in a second species after gestational exposure to DEA, persistence of toxic effects through the end of lactation, possibly due to long elimination half-life, and maternal and developmental toxicity no-observed-adverse-effect level (NOAELs) (50 mg/kg/day) and lowest-observed-adverse-effect level (LOAELs) (125 mg/kg/day) for oral DEA exposure during embryo/fetal development in the rat.     

Effect of hormonal environment on sterol concentrations of rat aorta and plasma.

Cholesterol and cholesterol esters were measured on day 90 in the plasma and aortas of rats treated on day 4 as follows: control, gonadectomy, testosterone propionate (TP), estradiol-17beta (E). Sex differences were observed in sterol concentrations of control animals but were abolished by castration. TP and E significantly altered sex gland weights, aorta cholesterol and plasma cholesterol esters of both sexes. Little effect on plasma cholesterol or esterified cholesterol of the aorta was noted in any treatment group. A dose effect of E was observed in organ weights and sterols of male rats.     

Postnatal thyroxine modifies effects of early androgen on lordosis

The sensitivity of female rats to the organizational effects of postnatal androgen was examined after néonatal manipulations known to affect the rate of brain development: thyroxine (T₄) administration and handling at birth. Testosterone propionate (TP) was injected subcutaneously in oil on postnatal day 6 to littermates that (i) had been undisturbed at birth; (ii) had received saline injections (S) and associated handling (H) on the day of birth (postnatal day 1) and the following day; and (iii) had received T₄ in saline (1 μg/g body wt) and H on postnatal days 1 and 2. Estrous cycles at 45 and 90 days of age, ovulation at Day 100 and sexual receptivity (lordosis score) at Days 115 and 125 were used to evaluate changes in TP effects. The majority of animals treated with 100 μg TP on postnatal day 6 exhibited persistent estrus (PE) at 45 and 90 days of age as expected. Neither T₄ nor S pretreatment on postnatal days 1 and 2 changed the incidence of PE. A reduction in ovarian weights and incidence of ovulation at 100 days of age supported cycle data in that only one out of 25 androgenized rats showed ovulation, compared with 16 of 22 controls. At approximately 115 days of age 2 μg of estradiol benzoate were administered for 3 days and 0.5 mg progesterone given on the 4th day 4 hr prior to placing females with sexually vigorous males. T₄-TP females exhibited higher (< .01) median lordosis scores than their S-TP littermates. The latter results were replicated in a second test conducted 10 days later (p = .002). In addition, the second test indicated that the S-TP group had lower (p = .005) lordosis scores than littermates given only TP neonatally. The results of these studies demonstrate that pretreatment with T₄ and handling, which are known, respectively, to hasten and retard the chronology of brain maturation, can exert differential effects on behavioral manifestations of postnatal TP without modifying androgen-induced sterility.     

A diet of somatic cell nuclear transfer cloned-cattle meat produced no toxic effects on behavioral or reproductive characteristics of F1 rats derived from dams fed on cloned-cattle meat

Background: The composition and nutritional value of meat and milk derived from cloned animals and their progeny has not been demonstrated to be different from normal animals, but possible food consumption risks that might arise from unidentified hazards remain. In this study, we investigated the effects of somatic cell nuclear transfer cloned‐cattle meat diet on the behavioral and reproductive characteristics of F1 rats derived from dams that were also fed on cloned‐cattle meat. Methods and results: F1 rats were divided into five diet groups with their dams: commercial pellets (control), pellets containing 5% (N‐5) and 10% (N‐10) of normal‐cattle meat, and diets containing 5% (C‐5) and 10% (C‐10) of cloned‐cattle meat. In most cases, the cloned‐cattle meat diet did not affect body weight and food consumption in both male and female F1 rats during 11 weeks, except for significantly higher body weight in both N‐5 and N‐10 (3–5 weeks, p<0.05 or p<0.01) and significantly higher food consumption in the both normal‐ and cloned‐cattle meat groups (7–9 weeks, p<0.05 or p<0.01), as compared with the controls, respectively. We detected no signs of test substance‐related toxicities on organ weights and behavioral characteristics (sensory reflex, motor function, and spatial learning and memory tests). Reproductive functions did not significantly differ among all examined rats (mating, fertility, and implantation). Conclusions: These behavioral and reproductive toxicity results suggest that there are no obvious food safety concerns related to cloned‐cattle meat in these parameters. Birth Defects Res (Part B) 92:224–230, 2011. © 2011 Wiley‐Liss, Inc.