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Individuals are exposed to a wide arrays of hazardous chemicals on a daily basis through various routes, many of which have not undergone comprehensive toxicity assessments. While traditional developmental toxicity tests involving pregnant animals are known for their reliability, they are also associated with high costs and time requirements. Consequently, there is an urgent demand for alternative, cost-efficient, and rapid in vitro testing methods. This study aims to address the challenges related to automating and streamlining the screening of early developmental toxicity of chemicals by introducing a mouse embryoid body test (EBT) model in a 384-ultra low attachment well format. Embryoid bodies (EBs) generated in this format were characterized by a spontaneous differentiation trajectory into cardiac mesoderm by as analyzed by RNA-seq. Assessing prediction accuracy using reference compounds suggested in the ICH S5(R3) guideline and prior studies resulted in the establishment of the acceptance criteria and applicability domain of the EBT model. The results indicated an 84.38% accuracy in predicting the developmental toxicity of 23 positive and 9 negative reference compounds, with an optimized cutoff threshold of 750 µM. Overall, the developed EBT model presents a promising approach for more rapid, high-throughput chemical screening, thereby facilitating well-informed decision-making in environmental management and safety assessments.
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Multicollinearity, characterized by significant co-expression patterns among genes, often occurs in high-throughput expression data, potentially impacting the predictive model's reliability. This study examined multicollinearity among closely related genes, particularly in RNA-Seq data obtained from embryoid bodies (EB) exposed to 5-fluorouracil perturbation to identify genes associated with embryotoxicity. Six genes-Dppa5a, Gdf3, Zfp42, Meis1, Hoxa2, and Hoxb1-emerged as candidates based on domain knowledge and were validated using qPCR in EBs perturbed by 39 test substances. We conducted correlation studies and utilized the variance inflation factor (VIF) to examine the existence of multicollinearity among the genes. Recursive feature elimination with cross-validation (RFECV) ranked Zfp42 and Hoxb1 as the top two among the seven features considered, identifying them as potential early embryotoxicity assessment biomarkers. As a result, a t test assessing the statistical significance of this two-feature prediction model yielded a p value of 0.0044, confirming the successful reduction of redundancies and multicollinearity through RFECV. Our study presents a systematic methodology for using machine learning techniques in transcriptomics data analysis, enhancing the discovery of potential reporter gene candidates for embryotoxicity screening research, and improving the predictive model's predictive accuracy and feasibility while reducing financial and time constraints.
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The incidence of thyroid cancer (TC) has increased considerably in the last few decades. Environmental factors, including plasticizers, are recognized as potential risks leading to thyroid cancer in humans. In this study, we used a transcriptome-metabolome-wide association study to find the unidentified carcinogenic mechanism of di-2-ethylhexyl phthalate (DEHP) in thyroid and biomarkers for non-invasive diagnosis. Rats were treated with different doses of DEHP (0, 0.3, 3, 30, 150 mg DEHP/kg bw/day) for 13 weeks. Then, the thyroids were processed for Ki67 staining and RNA-seq. Also, 17-h urine samples were collected for high-resolution metabolomics analysis. After a high dose of DEHP exposure, the terminal body weights and the thyroid and parathyroid glands weights were not altered. However, the liver weights and numbers of Ki67-positive cells were increased. Further, multivariate statistical analysis revealed that metabolic shifts were considerably altered above 30 mg DEHP/kg bw/day. In RNA-seq analysis, some cancer-related genes were altered, including 18 upregulated and 9 downregulated transcripts. These cancer transcripts and whole metabolome data were integrated to uncover thyroid cancer-related metabolic pathways, which revealed that cancer-related transcripts had a network structure linked to eicosanoids such as leukotriene D4 and prostaglandin. In brief, our study demonstrated that DEHP can induce thyroid hyperplasia through the eicosanoid-associated pathway, providing further insight into the mechanism of DEHP-associated thyroid cancer.
Assuntos
Dietilexilftalato , Neoplasias da Glândula Tireoide , Animais , Dietilexilftalato/toxicidade , Eicosanoides , Humanos , Antígeno Ki-67 , Metaboloma , Plastificantes , Ratos , TranscriptomaRESUMO
Bisphenol F (BPF, 4,4'-methylenediphenol) has recently been selected as an alternative to bisphenol A (BPA), which is used in the manufacturing of polycarbonates and epoxy resins. This study aimed to investigate the general, and reproductive/developmental effects of BPF. Therefore, BPF at dose levels of 0, 1, 5, 20, and 100 mg/kg/day was administered daily by oral gavage to Sprague-Dawley rats during the pre-mating, mating, gestation, and early lactation periods, and reproductive and developmental toxicities including general systemic toxicities were investigated. A decrease in body weight and food consumption was observed in the female rats treated with BPF at 20 and 100 mg/kg/day during the pre-mating and gestation periods. Additionally, gamma glutamyl transpeptidase levels were increased in the female rats administered 100 mg/kg/day. At 100 mg/kg/day, ovarian weight decreased and vaginal mucification increased according to a necropsy and histopathological examination, respectively. Moreover, the number of implantation sites and litter size decreased at 100 mg/kg/day. However, no significant BPF-related changes were observed in the male rats. Based on the results of this study, the no-observed-adverse-effect levels (NOAELs) of BPF for general systemic and reproductive effects were 5 and 20 mg/kg/day, respectively.
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Reprodução , Ratos , Masculino , Feminino , Animais , Ratos Sprague-Dawley , Relação Dose-Resposta a Droga , Nível de Efeito Adverso não ObservadoRESUMO
Sore throat lozenges, which are over-the-counter drugs, contain 2,4-dichlorobenzyl alcohol (DCBA) as the primary ingredient. However, comprehensive data on the prenatal developmental toxicity of DCBA is limited. Therefore, this study was conducted to determine the effects of DCBA on pregnant rats and prenatal development. Sprague-Dawley rats were administered different doses of DCBA (0, 25, 100, 400, and 800 mg/kg/day) daily via an oral gavage from gestation day (GD) 6-19. Thereafter, all the live dams were sacrificed on GD 20, and caesarean sections were conducted. Live fetuses and their placenta were weighed and then examined for external, visceral, and skeletal malformations and variations. Based on the results obtained, dams at 800 mg/kg/day showed systemic toxicities, including a decrease in body weight and food consumption, and liver changes. Additionally, this treatment induced decreases in fetal and placental weights, as well as the increased incidence of retarded ossifications and full supernumery rib, and the decreased number of ossification centers. Therefore, based on these findings, the no-observed-adverse-effect level of DCBA was determined to be 400 mg/kg/day for dams and prenatal development.
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Anormalidades Induzidas por Medicamentos , Placenta , Anormalidades Induzidas por Medicamentos/etiologia , Animais , Álcoois Benzílicos , Peso Corporal , Feminino , Nível de Efeito Adverso não Observado , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Hypoxic-ischaemic encephalopathy (HIE) is a type of brain injury affecting approximately 1 million newborn babies per year worldwide, the only treatment for which is therapeutic hypothermia. Thrombin-preconditioned mesenchymal stem cells (MSCs) exert neuroprotective effects by enriching cargo contents and boosting exosome biogenesis, thus showing promise as a new therapeutic strategy for HIE. This study was conducted to evaluate the tissue distribution and potential toxicity of thrombin-preconditioned human Wharton's jelly-derived mesenchymal stem cells (th-hWJMSCs) in animal models before the initiation of clinical trials. We investigated the biodistribution, tumorigenicity and general toxicity of th-hWJMSCs. MSCs were administered the maximum feasible dose (1 × 105 cells/10 µL/head) once, or at lower doses into the cerebral ventricle. To support the clinical use of th-hWJMSCs for treating brain injury, preclinical safety studies were conducted in newborn Sprague-Dawley rats and BALB/c nude mice. In addition, growth parameters were evaluated to assess the impact of th-hWJMSCs on the growth of newborn babies. Our results suggest that th-hWJMSCs are non-toxic and non-tumorigenic in rodent models, survive for up to 7 days in the brain and hold potential for HIE therapy.
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Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Trombina/metabolismo , Geleia de Wharton/citologia , Animais , Animais Recém-Nascidos , Biomarcadores , Transformação Celular Neoplásica , Gerenciamento Clínico , Modelos Animais de Doenças , Humanos , Hipóxia-Isquemia Encefálica/etiologia , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Ratos , Trombina/farmacologiaRESUMO
Serial blood sampling for toxicokinetics is generally conducted in regulatory embryo-fetal development (EFD) studies in rats. EFD studies are designed to detect the potential adverse effects of pharmaceuticals on pregnant females and their fetuses; this information is useful for understanding the relationships between systemic exposure levels and toxicity profiles. However, additional satellite pregnant females are needed for toxicokinetics because comprehensive information regarding the potential impact of serial blood sampling on pregnant females is scarce. Here, in this study, we investigated the potential impact of serial blood sampling in pregnant female rats using a typical EFD study design. Additionally, we investigated the additional endpoints (clinical pathology, organ weights, and histopathology) that were deemed likely to be sensitive to blood sampling. Results indicated that serial blood sampling in pregnant females induced physiological adaptive changes and did not affect the general endpoints in EFD studies. Nevertheless, inclusion of satellite groups in EFD studies may be a more prudent approach considering the physiological changes in pregnant females and potential off-target effects of candidate pharmaceuticals. These results provide background information on the impact of serial blood sampling in pregnant females and will be useful to design the regulatory EFD studies.
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Coleta de Amostras Sanguíneas/métodos , Toxicocinética , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Desenvolvimento Embrionário/fisiologia , Feminino , Desenvolvimento Fetal/fisiologia , Feto , Tamanho do Órgão , Gravidez , Ratos , Projetos de Pesquisa , Testes de Toxicidade/métodosRESUMO
Bisphenol A (BPA), a synthetic monomer commonly included in the daily products, has a structure similar to the estrogen receptor agonist. Therefore BPA has been anticipated to interfere with the hormone metabolisms and cause diverse pathological conditions. But the effects of BPA on the genetic landscapes of liver or hepatic cells have not been fully established. Gene expressional changes induced by low- or high-dose of BPA were evaluated in 3D cultured human hepatoma cells (HepG2 spheroids) in vitro at 0, 0.5, 5 and 200⯵M and liver of rats exposed to BPA at 0, 0.5 and 250â¯mg/kg for 90 days in vivo. Functional enrichment analysis, pathway activity measurement and network analysis were performed using BPA-responsive genes. Treatment with BPA changed a lot of gene expressions in both HepG2 spheroids and rat livers depending on doses of BPA. Functional enrichment and pathway analysis show that lipid or steroid metabolism-related functions were altered by BPA in both HepG2 spheroids and livers of rats. Lipid metabolism-related functions altered by BPA formed a large cluster encompassing lipid biosynthesis, steroid metabolic process and cholesterol regulation process. It was also observed that distribution of pathway activities was correlated between HepG2 spheroids and rat livers at low-dose of BPA. Distance distribution in protein-protein interaction network also evidenced the closeness of BPA-responsive genes to metabolism pathways which include lipid metabolism. Collectively, we demonstrated that BPA greatly influenced overall gene expression and biological functions in both human hepatoma spheroids and rat liver, in which lipid- or steroid metabolism-associated genes were significantly altered by the exposure to BPA.
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Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Transcriptoma , Animais , Células Hep G2 , Humanos , Fígado , RatosRESUMO
BACKGROUND: Titanium dioxide (TiO2) nanoparticles are among the most manufactured nanomaterials in the industry, and are used in food products, toothpastes, cosmetics and paints. Pregnant women as well as their conceptuses may be exposed to TiO2 nanoparticles; however, the potential effects of these nanoparticles during pregnancy are controversial, and their internal distribution has not been investigated. Therefore, in this study, we investigated the potential effects of oral exposure to TiO2 nanoparticles and their distribution during pregnancy. TiO2 nanoparticles were orally administered to pregnant Sprague-Dawley rats (12 females per group) from gestation days (GDs) 6 to 19 at dosage levels of 0, 100, 300 and 1000 mg/kg/day, and then cesarean sections were conducted on GD 20. RESULTS: In the maternal and embryo-fetal examinations, there were no marked toxicities in terms of general clinical signs, body weight, food consumption, organ weights, macroscopic findings, cesarean section parameters and fetal morphological examinations. In the distribution analysis, titanium contents were increased in the maternal liver, maternal brain and placenta after exposure to high doses of TiO2 nanoparticles. CONCLUSION: Oral exposure to TiO2 during pregnancy increased the titanium concentrations in the maternal liver, maternal brain and placenta, but these levels did not induce marked toxicities in maternal animals or affect embryo-fetal development. These results could be used to evaluate the human risk assessment of TiO2 nanoparticle oral exposure during pregnancy, and additional comprehensive toxicity studies are deemed necessary considering the possibility of complex exposure scenarios and the various sizes of TiO2 nanoparticles.
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Encéfalo/metabolismo , Fígado/metabolismo , Nanopartículas/análise , Placenta/metabolismo , Titânio/farmacocinética , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Exposição Materna , Nanopartículas/química , Especificidade de Órgãos , Gravidez , Ratos , Distribuição Tecidual , Titânio/químicaRESUMO
Polyhexamethylene guanidine phosphate (PHMG-P) has effective antimicrobial activity against various microorganisms and has been widely used as a biocide in commercial products. However, its use as a humidifier disinfectant has provoked fatal idiopathic lung disease in South Korea, especially in pregnant or postpartum women and their young children. PHMG-P-related toxicological studies of reproduction and development in experimental animals have not been identified, and thus, we investigated the potential effects of early-stage oral exposure to PHMG-P by assessing its toxicological properties. PHMG-P was repeatedly administered by oral gavage at dose levels of 0, 13, 40 and 120â¯mg/kg to Sprague-Dawley rats during the pre-mating, mating, gestation and early lactation periods, and then general systemic and reproductive/developmental toxicities were investigated. At 120â¯mg/kg, PHMG-P-related toxicities including subdued behavior, thin appearance, decreased body weight, decreased food consumption and decreased F1 pup body weight were observed. Based on the results of this study, the no-observed-adverse-effect levels (NOAELs) of PHMG-P for both general systemic effects and development are considered to be 40â¯mg/kg/day.
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Anti-Infecciosos/toxicidade , Guanidinas/toxicidade , Troca Materno-Fetal , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Fertilidade/efeitos dos fármacos , Masculino , Nível de Efeito Adverso não Observado , Gravidez , Ratos Sprague-Dawley , Reprodução/efeitos dos fármacosRESUMO
We produced an adaptive lens array composed of multiple flat lens arrays arranged in a curved shape with an adjustable radius of curvature, in order to overcome the hardware problem of the conventional flat or curved lens array-based systems. The manufactured adaptive lens array is applied to an integral imaging system. The gap mismatch that occurs when using a curved lens array is resolved by computing the exact display mapping position of element images through each lens. The results of the experiment demonstrate that the adaptive lens array-based integral imaging system successfully generated elemental images according to the curvature transformation of the adaptive lens array, and they were reconstructed as 3D images.
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A real-time interactive orthographic-view image display of integral imaging (II) microscopy that includes the generation of intermediate-view elemental images (IVEIs) for resolution enhancement is proposed. Unlike the conventional II microscopes, parallel processing through a graphics processing unit is required for real-time display that generates the IVEIs and interactive orthographic-view images in high speed, according to the user interactive input. The real-time directional-view display for the specimen for which 3D information is acquired through II microscopy is successfully demonstrated by using resolution-enhanced elemental image arrays. A user interactive feature is also satisfied in the proposed real-time interactive display for II microscopy.
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Background: Korean red ginseng (KRG) is a product from ginseng roots, which is enriched with ginsenosides and has been utilized for a long time as an adaptogen to alleviate various physiological or disease conditions. While KRG is generally considered safe, conducting a thorough toxicological assessment of the spray-dried powder G1899 during the juvenile period is essential to establish its safety profile. This study aimed to assess the safety of G1899 during the juvenile period using Sprague-Dawley rats. Methods: Two studies were conducted separately: a juvenile toxicity study and a uterotrophic bioassay. To assess the potential toxicity at systemic, postnatal developmental, and reproductive levels, G1899 was orally gavaged once a day in post-weaning juvenile Sprague-Dawley (SD) rats at 0, 1250, 2500, or 5000 mg/kg/day. Estrogenicity was assessed by orally gavaging G1899 in immature female SD rats at 0, 2500, or 5000 mg/kg/day on postnatal days (PND) 19-21, followed by a uterotrophic bioassay. These studies were conducted in accordance with the Good Laboratory Practice (GLP) regulations and regulatory test guidelines. Results: Regarding juvenile toxicity, no abnormalities related to the G1899 treatment were observed in any group during the experiment. Moreover, no uterotrophic responses were observed in the dosed female group. Based on these results, the no observed adverse effect level (NOAEL) of G1899 was determined to be at least 5000 mg/kg/day for general systemic function, developmental/reproductive function, and estrogenic activity. Conclusion: Our results suggest that G1899 is not toxic to juveniles at doses of up to 5000 mg/kg/day.
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This paper proposes an open computer language (OpenCL) parallel processing method to generate the elemental image arrays (EIAs) for hexagonal lens array from a three-dimensional (3D) object such as a volume data. Hexagonal lens array has a higher fill factor compared to the rectangular lens array case; however, each pixel of an elemental image should be determined to belong to the single hexagonal lens. Therefore, generation for the entire EIA requires very large computations. The proposed method reduces processing time for the EIAs for a given hexagonal lens array. By using the proposed image space parallel processing (ISPP) method, it can enhance the processing speed that generates the 3D display of real-time interactive integral imaging for hexagonal lens array. In our experiment, we implemented the EIAs for hexagonal lens array in real-time and obtained a good processing time for a large of volume data for multiple cases of lens arrays.
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Algoritmos , Interpretação de Imagem Assistida por Computador/instrumentação , Interpretação de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/instrumentação , Imageamento Tridimensional/métodos , Armazenamento e Recuperação da Informação/métodos , Lentes , Sistemas Computacionais , Desenho de Equipamento , Análise de Falha de Equipamento , Aumento da Imagem/instrumentação , Aumento da Imagem/métodos , Análise Numérica Assistida por Computador , Processamento de Sinais Assistido por Computador/instrumentaçãoRESUMO
In an integral imaging display, the computer-generated integral imaging method has been widely used to create the elemental images from a given three-dimensional object data. Long processing time, however, has been problematic especially when the three-dimensional object data set or the number of the elemental lenses are large. In this paper, we propose an image space parallel processing method, which is implemented by using Open Computer Language (OpenCL) for rapid generation of the elemental images sets from large three-dimensional volume data. Using the proposed technique, it is possible to realize a real-time interactive integral imaging display system for 3D volume data constructed from computational tomography (CT) or magnetic resonance imaging (MRI) data.
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Técnicas de Imagem Cardíaca/métodos , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X/métodos , Computadores , Coração/anatomia & histologia , Humanos , Crânio/anatomia & histologia , Design de SoftwareRESUMO
BACKGROUND: Bis-diamine was developed as amebicidal and male contraceptive agents; however, it is also reported to induce characteristic congenital heart defects especially in the cardiac conotruncal area of rats. Because of its characteristic congenital heart defects, bis-diamine-induced animal models can be used for studying congenital heart defects. However, comprehensive toxicological information regarding bis-diamine-induced congenital heart defects in this animal model is not available. METHODS: In this study, we investigated and characterized an animal model for bis-diamine-induced congenital heart defects. A single dose of 200-mg bis-diamine was administered by oral gavage to pregnant rats on gestation day 10, and then observed the representative toxicological endpoints for general systemic health of pregnant rats, embryo-fetal development, and parturition. RESULTS: Characteristic congenital heart defects and other birth defects similar to DiGeorge syndrome were observed in bis-diamine-administered pregnant rats. In addition, developmental and reproductive toxicity findings, including increased postimplantation loss, decreased fetal weight, increased perinatal death, and increased gestation period, were observed in bis-diamine-administered pregnant rats. In particular, these developmental and reproductive toxicities were observed without maternal toxicity findings. CONCLUSION: These results will be useful to use this animal model for further studies in congenital heart defects, cardiovascular defects, and understanding their mechanisms.
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Cardiopatias Congênitas , Coração , Animais , Diaminas/toxicidade , Modelos Animais de Doenças , Feminino , Masculino , Gravidez , Ratos , ReproduçãoRESUMO
Inhalation exposure to polyhexamethylene guanidine phosphate (PHMG-P), one of the primary biocides used in humidifier disinfectants, caused a fatal pulmonary disease in Korea. Pregnant women were also exposed to PHMG-P, and subsequent studies showed that PHMG-P inhalation during pregnancy adversely affects their health and embryo-fetal development. However, the postnatal developmental effects after birth on prenatally PHMG-P-exposed offspring have not yet been investigated. Therefore, in this study, we aimed to examine the postnatal development of prenatally PHMG-P-exposed offspring. Pregnant rats (22 or 24 females per group) were exposed to PHMG-P during pregnancy in a whole-body inhalation chamber at the target concentrations of 0, 0.14, 1.60, and 3.20 mg/m3. After parturition, the prenatally exposed offspring were transferred to non-exposed surrogate mothers to minimize the secondary effects of severe maternal toxicities. Postnatal development of offspring was then examined with a modified extended one-generation reproductive toxicity study design. At 3.20 mg/m3 PHMG-P, increased perinatal death rates and decreased viability index (postnatal survival of offspring between birth and postnatal day 4) were observed. In addition, F1 offspring had lower body weight at birth that persisted throughout the study. PHMG-P-exposed pregnant rats also had severe systemic toxicities and increased gestation period. At 1.60 mg/m3 PHMG-P, a decreased viability index was also observed with systemic toxicities of PHMG-P-exposed pregnant rats. These results indicate that prenatal PHMG-P exposure adversely affects the offspring's future health and could be used for human risk assessment.
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Desinfetantes , Umidificadores , Animais , Desinfetantes/análise , Desinfetantes/toxicidade , Feminino , Guanidinas , Humanos , Exposição por Inalação/análise , Pulmão/química , Gravidez , Ratos , ReproduçãoRESUMO
Biocides are widely used for their effective antiseptic and disinfectant properties, including polyhexamethylene guanidine phosphate (PHMG-P), which is also used as a biocide as it selectively disrupts bacterial cell membrane. It is used to clean humidifiers commonly used in the dry winter season in South Korea, which exposes people to PHMG-P inhalation. However, comprehensive toxicological data on PHMG-P inhalation exposure, including in pregnant women, and the potential occurrence of lung disease is lacking. Therefore, in this study, we investigated PHMG-P inhalation exposure-induced toxicities in pregnant rats and prenatal development of their conceptus. Pregnant rats were exposed to PHMG-P via inhalation at target concentrations of 0, 0.14, 1.60, and 3.20â¯mg/m3 from implantation to nearly parturition (from gestation day 6-20) and then analyzed for relevant abnormalities. Results showed systemic toxicities in the pregnant rats including respiratory function abnormalities, decreased body weight gain, and decreased food consumption at ≥1.60â¯mg/m3. Prenatal development toxicities, including decreased fetal weight with ossification retardations of fetal bones, were observed at 3.20â¯mg/m3. These results will contribute to clarifying the PHMG-P inhalation exposure-induced toxicities during pregnancy and support its risk assessment in humans.
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Desinfetantes , Umidificadores , Animais , Desinfetantes/análise , Desinfetantes/toxicidade , Feminino , Guanidinas , Humanos , Exposição por Inalação/análise , Pulmão , Gravidez , Ratos , República da CoreiaRESUMO
Cerium oxide nanoparticles (CeO2 NPs) are widely used in various commercial applications because of their characteristic properties. People can be easily exposed to CeO2 NPs in real life, but the safety assessment of CeO2 NPs has not been fully investigated. Therefore, in this study, we conducted a combined repeated-dose and reproductive/developmental toxicity screening study (OECD testing guideline 422) to investigate the potential hazards on human health, including reproductive/developmental functions, after repeated daily CeO2 NPs oral gavage administration to both males and females. In addition, tissues from parental animals and their pups were collected to analyze the internal accumulation of cerium. CeO2 NPs were orally administered to Sprague-Dawley rats at doses of 0, 100, 300 and 1000 mg/kg during their pre-mating, mating, gestation and early lactation periods. In the general systemic and reproductive/developmental examinations, no marked toxicities were observed in any in-life and terminal observation parameters in this study. In the biodistribution analysis, cerium was not detected in either parental or pup tissues (blood, liver, lungs and kidneys). Repeated oral exposure of CeO2 NPs did not induce marked toxicities affecting general systemic and reproductive/developmental functions up to the dose level of 1000 mg/kg and the CeO2 NPs were not systemically absorbed in parental animals or their pups. This result could be used in risk assessment for humans, and additional toxicity studies with CeO2 NPs will be necessary considering various physicochemical properties and exposure probabilities of these nanoparticles.
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Cério/toxicidade , Nanopartículas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Reprodução/efeitos dos fármacos , Administração Oral , Animais , Cério/química , Cério/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Exposição Materna/efeitos adversos , Nanopartículas/química , Nanopartículas/metabolismo , Tamanho da Partícula , Exposição Paterna/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície , Distribuição TecidualRESUMO
BACKGROUND: Korean Red Ginseng has been widely used in traditional oriental medicine for a prolonged period, and its pharmacological effects have been extensively investigated. In addition, Angelica gigas and deer antlers were also used as a tonic medicine with Korean Red Ginseng as the oriental herbal therapy. METHODS: This study was conducted to evaluate the potential toxicological effect of KGC-HJ3, Korean Red Ginseng with angelica gigas and deer antlers, on reproductive and developmental functions including fertility, early embryonic development, maternal function, and embryo-fetal development. KGC-HJ3 was administered by oral gavage to Sprague-Dawley rats (22 animals per sex per group) at dose levels of 0 mg/kg (control), 500 mg/kg, 1000 mg/kg, and 2000 mg/kg to evaluate the potential toxicological effect on fertility and early embryonic development. In addition, KGC-HJ3 was also administered by oral gavage to mating-proven Sprague-Dawley rats (22 females per group) during the major organogenesis period at dose levels of 0 mg/kg (control), 500 mg/kg, 1000 mg/kg, and 2000 mg/kg to evaluate the potential toxicological effect on maternal function and embryo-fetal development. RESULTS AND CONCLUSION: No test item-related changes in parameters for fertility, early embryonic development, maternal function, and embryo-fetal development were observed during the study period. On the basis of these results, it was concluded that KGC-HJ3 did not have toxicological potential on developmental and reproductive functions. Therefore, no observed adverse effect levels of KGC-HJ3 for fertility, early embryonic development, maternal function, and embryo-fetal development is considered to be at least 2000 mg/kg/day.