Developmental Toxicity In Rodents Research Articles

Di(2-ethylhexyl) phthalate-induced toxicity and peroxisome proliferator-activated receptor alpha: a review

The plasticizer di(2-ethylhexyl) phthalate (DEHP) has been widely used in the manufacture of polyvinyl chloride-containing products such as medical and consumer goods. Humans can easily be exposed to it because DEHP is ubiquitous in the environment. Recent research on the adverse effects of DEHP has focused on reproductive and developmental toxicity in rodents and/or humans. DEHP is a representative of the peroxisome proliferators. Therefore, peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways are the expected mode of action of several kinds of DEHP-induced toxicities. In this review, we summarize DEHP kinetics and its mechanisms of carcinogenicity and reproductive and developmental toxicity in relation to PPARα. Additionally, we give an overview of the impacts of science policy on exposure sources.

Combining mouse embryonic stem cells and zebrafish embryos to evaluate developmental toxicity of chemical exposure

The assays in this study utilize mouse embryonic stem cells (mESCs) and zebrafish embryos to evaluate the potential developmental toxicity of industrial and pharmaceutical chemicals. A set of eleven chemicals of known mammalian in vivo teratogenicity were tested in the assays and correlations to mammalian data. Using mESCs, proliferation, differentiation, and cytotoxicity of the chemicals were measured. In zebrafish embryos, lethality and the lowest effect level concentrations for morphological malformations were determined. Clustering of the assays based on frequency of affected assays resulted in a ranking of the test compounds that correlated to in vivo rodent data (R = 0.88, P < 0.001). We conclude that the combination of ESC- and zebrafish-based assays provides a valuable platform for the prioritization of pharmaceutical and industrial chemicals for further testing of developmental toxicity in rodents.

In silico prediction of the developmental toxicity of diverse organic chemicals in rodents for regulatory purposes.

The experimental determination of the developmental toxicity potential (LEL) of chemicals is not only tedious, time and resource intensive, but it also involves unethical tests on animals. In this study, we have established quantitative structure activity relationship (QSAR) models for predicting the developmental toxicity potential of chemicals in rodents following the OECD guidelines. Accordingly, decision tree forest (DTF) and decision tree boost (DTB) based local (L-QSAR), global (G-QSAR) and interspecies quantitative structure activity-activity relationship (ISC QSAAR) models were developed for estimating the LEL (lowest effective level) dose of chemicals for developmental toxicity in rats and rabbits. The structural features of chemicals responsible for developmental toxicity in rodents were extracted and used in QSAR/QSAAR analysis. The external predictive power of the developed models was evaluated through the internal and external validation procedures. In test data, the L-QSAR models (DTF, DTB) yielded R2 values of >0.846 (rat) and >0.906 (rabbit), whereas in G-QSAR, the correlation value was >0.870 between the measured and predicted endpoint values. In ISC QSAAR models, the R2 values in test data were 0.830 (DTF) and 0.927 (DTB), respectively. Values of various statistical validation coefficients derived from the test data (except rm2 in DTF based rat L-QSAR and ISC QSAAR models) were above their respective threshold limits, thus putting a high confidence in this analysis. The prediction quality of the developed QSAR/QSAAR models was also assessed using the mean absolute error (MAE) criteria and found good. The applicability domains of the constructed models were defined using the descriptor range, leverage, and standardization approaches. The results suggest that the developed QSAR/QSAAR models can reliably predict the developmental toxicity potential of structurally diverse chemicals in rodents, generating useful toxicity data for risk assessment in humans.

Perfluorooctanoic Acid Effects on Steroid Hormone and Growth Factor Levels Mediate Stimulation of Peripubertal Mammary Gland Development in C57Bl/6 Mice

Perfluorooctanoic acid (PFOA) is a synthetic, widely used perfluorinated carboxylic acid and a persistent environmental pollutant. It is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha). Studies have shown that PFOA causes hepatocellular hypertrophy, tumorigenesis, and developmental toxicity in rodents, and some of its toxicity depends on the expression of PPARalpha. Our recent study revealed a stimulatory effect of peripubertal PFOA treatment (5 mg/kg) on mammary gland development in C57Bl/6 mice. The present study was designed to examine the underlying mechanism(s). It was found that mammary gland stimulation by PFOA was similarly observed in PPARalpha knockout and wild-type C57Bl/6 mice. The presence of ovaries was required for PFOA treatment (5 mg/kg) to stimulate mammary gland development with significant increases in the levels of enzymes involved in steroid hormone synthesis in both PFOA-treated wild-type and PPARalpha knockout mouse ovaries. PFOA treatment significantly increased serum progesterone (P) levels in ovary-intact mice and also enhanced mouse mammary gland responses to exogenous estradiol (E), P, and E + P. In addition, PFOA treatment resulted in elevated mammary gland levels of epidermal growth factor receptor (EGFR), estrogen receptor alpha, amphiregulin (Areg, a ligand of EGFR), hepatocyte growth factor, cyclin D1, and proliferating cell nuclear antigen (PCNA) in both wild-type and PPARalpha knockout mouse mammary glands. These results indicate that PFOA stimulates mammary gland development in C57Bl/6 mice by promoting steroid hormone production in ovaries and increasing the levels of a number of growth factors in mammary glands, which is independent of the expression of PPARalpha.

NTP‐CERHR Expert Panel Report on the reproductive and developmental toxicity of hydroxyurea

The National Toxicology Program (NTP) and the National Institute of Environmental Health Sciences (NIEHS) established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in June 1998. The purpose of CERHR is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects on reproduction and development caused by agents to which humans may be exposed. Hydroxyurea was selected for evaluation by a CERHR expert panel because of (1) its increasing use in the treatment of sickle cell disease in children and adults, (2) knowledge that it inhibits DNA synthesis and is cytotoxic, and (3) published evidence of its reproductive and developmental toxicity in rodents. Hydroxyurea is FDA-approved for reducing the frequency of painful crises and the need for blood transfusions in adults with sickle cell anemia who experience recurrent moderate-to-severe crises. Hydroxyurea is used in the treatment of cancer, sickle cell disease, and thalassemia. It is the only treatment for sickle cell disease aside from blood transfusion used in children. Hydroxyurea may be used in the treatment of children and adults with sickle cell disease for an extended period of time or for repeated cycles of therapy. Treatment with hydroxyurea may bemore » associated with cytotoxic and myelosuppressive effects, and hydroxyurea is mutagenic.« less

In Vivo Assessment of Prenatal Developmental Toxicity in Rodents

This unit presents two basic protocols for testing prenatal developmental toxicity in rodents. The standard protocol for assessing prenatal developmental toxicity, often referred to as a Segment II study, describes the methods used for performing cesarean sections and examining cesarean-delivered fetuses for external, skeletal, and visceral alterations. The protocol for the Chernoff/Kavlock assay, a developmental toxicity screen, describes methods for examining parturition, and postnatal growth and viability of prenatally exposed litters.

Developmental Toxicity of Oral and Inhaled Vinyl Acetate in the Rat

Developmental Toxicity of Oral and Inhaled Vinyl Acetate in the Rat. Hurtt, M. E., Vinegar, M. B., Rickard, R. W., Cascieri, T. C., and Tyler, T. R. (1995). Fundam. Appl. Toxicol. 24, 198-205.Vinyl acetate (VA) is used almost exclusively as an industrial chemical in polymerization, copolymerization, or as a chemical intermediate. The present studies were undertaken as part of a collaborative effort by the VA producers of Western Europe, Japan, and the United States to provide animal toxicology data for risk assessment. To assess the potential of VA causing developmental toxicity in rodents, groups of 23 or 24 Crl:CD(SD)BR rats were given 0, 200, 1000, or 5000 ppm VA in drinking water or exposed 6 hr/day to 0, 50, 200, or 1000 ppm VA vapors on Days 6-15 of gestation (both routes approximating 0, 25, 100, or 500 mg/kg/day). Administration of VA in the drinking water produced no evidence of maternal or developmental toxicity. A significantly lowered water intake was observed in dams from the 5000 ppm VA group and probably reflected unpalatability of the VA water solution at the highest dose level. In the inhalation study, maternal toxicity was evident by a marked reduction in the weight gain of dams exposed to 1000 but not 200 or 50 ppm VA. Fetal toxicity was evident by a statistically significant decrease in mean fetal weight and mean crown-rump length in fetuses from the 1000-ppm VA group. In addition, there was a statistically significant increase in the incidence of minor skeletal alterations in fetuses from dams exposed to 1000 ppm VA. Delayed ossification was the main skeletal alteration. In summary, pregnant rats were relatively insensitive to the effects of VA administered in the drinking water at a concentration level as high as 5000 ppm. However, VA did adversely affect both the dam and the conceptus at an inhaled concentration of 1000 ppm, but not at lower exposure levels. These results indicate that VA is not uniquely toxic to the conceptus. The no-observed-effect level for the dam and conceptus under these experimental conditions was greater than 5000 ppm for the drinking water study and was 200 ppm for the inhalation study.

Developmental Toxicity of Oral and Inhaled Vinyl Acetate in the Rat

Vinyl acetate (VA) is used almost exclusively as an industrial chemical in polymerization, copolymerization, or as a chemical intermediate. The present studies were undertaken as part of a collaborative effort by the VA producers of Western Europe, Japan, and the United States to provide animal toxicology data for risk assessment. To assess the potential of VA causing developmental toxicity in rodents, groups of 23 or 24 Crl:CD(SD)BR rats were given 0, 200, 1000, or 5000 ppm VA in drinking water or exposed 6 hr/day to 0, 50, 200, or 1000 ppm VA vapors on Days 6–15 of gestation (both routes approximating 0, 25, 100, or 500 mg/kg/day). Administration of VA in the drinking water produced no evidence of maternal or developmental toxicity. A significantly lowered water intake was observed in dams from the 5000 ppm VA group and probably reflected unpalatability of the VA water solution at the highest dose level. In the inhalation study, maternal toxicity was evident by a marked reduction in weight gain of dams exposed to 1000 but not 200 or 50 ppm VA. Fetal toxicity was evident by a statistically significant decrease in mean fetal weight and mean crown-rump length in fetuses from the 1000-ppm VA group. In addition, there was a statistically significant increase in the incidence of minor skeletal alterations in fetuses from dams exposed to 1000 ppm VA. Delayed ossification was the main skeletal alteration. In summary, pregnant rats were relatively insensitive to the effects of VA administered in the drinking water at a concentration level as high as 5000 ppm. However, VA did adversely affect both the dam and the conceptus at an inhaled concentration of 1000 ppm, but not at lower exposure levels. These results indicate that VA is not uniquely toxic to the conceptus. The no-observed-effect level for the dam and conceptus under these experimental conditions was greater than 5000 ppm for the drinking water study and was 200 ppm for the inhalation study.

Toxicity and carcinogenicity of riddelliine following 13 weeks of treatment to rats and mice

Toxicity studies of riddelliine, a member of a class of pyrrolizidine alkaloids, were conducted because riddelliine has been found to contaminate human food sources. Groups of male and female Fischer rats were administered riddelliine by gavage in phosphate buffer at doses up to 10 mg/kg, and B 6C 3F 1 mice at doses up to 25 mg/kg, five times a week. The animals were necropsied after 13 weeks of treatment or after a 7 or 14 week recovery period. Body weight gains were inversely related to dose in both rats and mice. Body weight of the 1.0 and 3.3 mg/kg female rats and 10.0 and 25.0 mg/kg mice remained depressed during the 14 week recovery period. At 13 weeks, significant findings included dose-related hepatopathy and intravascular macrophage accumulation in rats and hepatocytomegaly in mice. During the 14 week recovery period these lesions persisted and hepatic foci of cellular alteration in male rats and bile duct proliferation in female rats and male and female mice increased in severity. In the 10 mg/kg group of female rats adenomas of the liver occurred in two of ten at 13 weeks and in one of five at the 14 week recovery period. In separate studies, the frequency of micronucleated erythrocytes in peripheral blood was increased in male mice administered a single dose (150 mg/kg) of riddelliine. Increases in unscheduled DNA and S-phase syntheses were detected in primary hepatocytes from rats and mice treated with riddelliine at doses up to 25.0 mg/kg for 5 or 30 days. In mating trials in rats and mice, pup weights from treated dams at birth and during suckling were lower than controls. Thus, riddelliine is genotoxic and carcinogenic and may cross the placenta and/or be found in milk, causing developmental toxicity in rodents.

Developmental toxicity of inhaled methyl ethyl ketone in Swiss mice

Methyl ethyl ketone (MEK) is a widely used industrial solvent to which there is considerable human exposure. To assess the potential for MEK to cause developmental toxicity in rodents, groups of Swiss (CD-1) mice were exposed to 0, 400, 1000, or 3000 ppm MEK vapors 7 hr/day on Days 6–15 of gestation. Groups consisted of about 30 bred females each. Exposure of pregnant mice to these concentrations of MEK did not result in overt maternal toxicity although there was a slight, treatment-related increase in relative liver weight which was statistically significant in the 3000 ppm group. Mild developmental toxicity was observed in the 3000 ppm group in the form of a reduction in mean fetal body weight. This reduction was statistically significant for the males only, although the relative decrease from the control values was the same for both sexes. There was no increase in the incidence of resorptions or the number of litters with resorptions among mice exposed to MEK. There was no significant increase in the incidence of any single malformation, but several malformations which were not observed in the concurrent control group or the controls of contemporary studies were present at a low incidence—cleft palate, fused ribs, missing vertebrae, and syndactyly. There was also a significant trend for increased incidence of misaligned sternebrae, a developmental variation. In summary, pregnant Swiss (CD-1) mice were relatively insensitive to the toxic effects of MEK at the inhaled concentrations used in this study. However, the offspring of the mice exhibited significant signs of developmental toxicity at the 3000 ppm exposure level. Neither maternal nor developmental toxicity was observed at 1000 ppm MEK or below.

Developmental Toxicity of Inhaled Methyl Ethyl Ketone in Swiss Mice

Developmental Toxicity of Inhaled Methyl Ethyl Ketone in Swiss Mice. Schwetz, B. A., Mast, T. J., Weigel, R. J., Dill, J. A., and Morrissey, R. E. (1991). Fundam. Appl. Toxicol. 16, 742–748. Methyl ethyl ketone (MEK) is a widely used industrial solvent to which there is considerable human exposure. To assess the potential for MEK to cause developmental toxicity in rodents, groups of Swiss (CD-1) mice were exposed to 0, 400, 1000, or 3000 ppm MEK vapors 7 hr/day on Days 6–15 of gestation. Groups consisted of about 30 bred females each. Exposure of pregnant mice to these concentrations of MEK did not result in overt maternal toxicity although there was a slight, treatment-related increase in relative liver weight which was statistically significant in the 3000 ppm group. Mild developmental toxicity was observed in the 3000 ppm group in the form of a reduction in mean fetal body weight. This reduction was statistically significant for the males only, although the relative decrease from the control values was the same for both sexes. There was no increase in the incidence of resorptions or the number of litters with resorptions among mice exposed to MEK. There was no significant increase in the incidence of any single malformation, but several malformations which were not observed in the concurrent control group or the controls of contemporary studies were present at a low incidence—cleft palate, fused ribs, missing vertebrae, and syndactyly. There was also a significant trend for increased incidence of misaligned sternebrae, a developmental variation. In summary, pregnant Swiss (CD-1) mice were relatively insensitive to the toxic effects of MEK at the inhaled concentrations used in this study. However, the offspring of the mice exhibited significant signs of developmental toxicity at the 3000 ppm exposure level. Neither maternal nor developmental toxicity was observed at 1000 ppm MEK or below.