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Medication during pregnancy is widespread, but there are few reports on its fetal safety. Recent studies suggest that medication during pregnancy can affect fetal morphological and functional development through multiple pathways, multiple organs, and multiple targets. Its mechanisms involve direct ways such as oxidative stress, epigenetic modification, and metabolic activation, and it may also be indirectly caused by placental dysfunction. Further studies have found that medication during pregnancy may also indirectly lead to multi-organ developmental programming, functional homeostasis changes, and susceptibility to related diseases in offspring by inducing fetal intrauterine exposure to too high or too low levels of maternal-derived glucocorticoids. The organ developmental toxicity and programming alterations caused by medication during pregnancy may also have gender differences and multi-generational genetic effects mediated by abnormal epigenetic modification. Combined with the latest research results of our laboratory, this paper reviews the latest research progress on the developmental toxicity and functional programming alterations of multiple organs in offspring induced by medication during pregnancy, which can provide a theoretical and experimental basis for rational medication during pregnancy and effective prevention and treatment of drug-related multiple fetal-originated diseases.
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OBJECTIVE@#To evaluate toxicity of raw extract of Panax notoginseng (rPN) and decocted extract of PN (dPN) by a toxicological assay using zebrafish larvae, and explore the mechanism by RNA sequencing assay.@*METHODS@#Zebrafish larvae was used to evaluate acute toxicity of PN in two forms: rPN and dPN. Three doses (0.5, 1.5, and 5.0 µ g/mL) of dPN were used to treat zebrafishes for evaluating the developmental toxicity. Behavior abnormalities, body weight, body length and number of vertebral roots were used as specific phenotypic endpoints. RNA sequencing (RNA-seq) assay was applied to clarify the mechanism of acute toxicity, followed by real time PCR (qPCR) for verification. High performance liquid chromatography analysis was performed to determine the chemoprofile of this herb.@*RESULTS@#The acute toxicity result showed that rPN exerted higher acute toxicity than dPN in inducing death of larval zebrafishes (P<0.01). After daily oral intake for 21 days, dPN at doses of 0.5, 1.5 and 5.0 µ g/mL decreased the body weight, body length, and vertebral number of larval zebrafishes, indicating developmental toxicity of dPN. No other adverse outcome was observed during the experimental period. RNA-seq data revealed 38 genes differentially expressed in dPN-treated zebrafishes, of which carboxypeptidase A1 (cpa1) and opioid growth factor receptor-like 2 (ogfrl2) were identified as functional genes in regulating body development of zebrafishes. qPCR data showed that dPN significantly down-regulated the mRNA expressions of cpa1 and ogfrl2 (both P<0.01), verifying cpa1 and ogfrl2 as target genes for dPN.@*CONCLUSION@#This report uncovers the developmental toxicity of dPN, suggesting potential risk of its clinical application in children.
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Animals , Zebrafish/genetics , Saponins/pharmacology , Panax notoginseng/chemistry , Larva , Sequence Analysis, RNAABSTRACT
Background Arsenic is recognized as a kind of developmental toxicant, which can pass through the placenta barrier and induce health defects in offspring. However, the effects of environmental levels of arsenic exposure during gestation on the reproductive system of adult male offspring remain unclear. Objective To investigate the impact of environmental levels of arsenic exposure during gestation on testosterone synthesis and sperm quality in F1 adult male rats. Methods Forty sexually mature Wistar female rats were randomly divided into four groups according to body weight, namely control group, low-dose sodium arsenite (NaAsO2) group, middle-dose NaAsO2 group, and high-dose NaAsO2 group. They were mated with sexually mature Wistar male rats in a ratio of 2:1, and the day with presence of a vaginal plug or spermatozoa in the vaginal smear was designated as gestational day 0 (GD0). Pregnant rats were provided drinking water containing 0, 1, 5,, or 25 mg·L−1 NaAsO2 until delivery. At postnatal day 70, the F1 male rats were euthanized. Anogenital distance was measured, testis and epididymis were weighed, and associated organ coefficients were calculated. Epididymal sperm quality was evaluated. The histological changes of testis were observed. The levels of testosterone and estradiol in serum were determined with ELISA kit. The testicular mRNA relative expression levels of key steroidogenic enzymes were determined by quantitative real-time PCR. The protein relative expression levels of key steroidogenic enzymes were determined by Western blotting. Results Compared with the control group, the testicular coefficients and epididymis coefficients were increased in the low- and middle-dose groups (P<0.05), and the epididymis coefficient was also increased in the high-dose group (P<0.05). As for the percentage of sperm motility, compared to the control group, grade Ⅰ sperm cells were increased in the low-dose group, but significantly decreased in the middle- and high-dose groups; grade Ⅱ and Ⅲ sperm cells were decreased in the low- and high-dose groups; grade Ⅳ sperm cells were significantly increased in the middle- and high-dose groups; all the differences above were statistically significant (P<0.05). Compared with the control group, there was a significant increase in serum testosterone levels in all treated groups (P<0.05), and the serum estradiol levels were significantly decreased in the high-dose group (P<0.05). Meanwhile, compared with the control group, the relative mRNA expression levels of Hsd3β1 and Cyp19a1 were decreased (P<0.05), while those of StAR and Cyp11a1 were increased in the high-dose group (P<0.05). In addition, the relative protein expression levels of CYP11A1 were significantly increased in all treated groups compared with the control group (P<0.05). Conclusion Environmental levels of arsenic exposure during gestation can up-regulate testosterone level and reduce sperm quality, and is a potential risk for reproductive dysfunction in adult male offspring.
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Drug use during pregnancy is unavoidable. Therefore, it is vitally important for medical workers to help pregnant women take drugs correctly to reduce the incidence of spontaneous abortion, premature birth, and low birth weight. In our study, drug screening model with induced pluripotent stem cells (iPSCs) was used to find some improper drugs which will result in woman's abortion. With 3D culture in vitro, iPSCs can form embryoid bodies (EBs) and cerebral organoids, which simulated in vitro development of early embryos, from inner cell mass to germ-layer differentiation. In the experiment, EBs were exposed to mifepristone (RU486), and three experimental groups were divided randomly. They were control group (without RU486), low-dose group (L-RU486, 10 μg·mL-1), and high-dose group (H-RU486, 20 μg·mL-1). After mifepristone exposure, EBs were observed at days 5, 8, and 11, including size of EB, cell apoptosis, and differentiation of germ layers, by using inverted optical microscope, TUNEL assay, and immunofluorescent staining. The results showed that through 3D culture, iPSCs could develop into embryoid bodies, neural rosettes, and finally cerebral organoids. After mifepristone exposure, EBs' sizes were decreased (P < 0.01); the levels of cell apoptosis in EBs were increased after mifepristone exposure (P < 0.01); the development of EBs' germ layer was affected. Mifepristone exposure could inhibit the proliferation of embryonic stem cells, reduce the differentiation of ectoderm (P < 0.01) and promote the development of mesoderm (P < 0.05). In conclusion, iPSCs can be used as a screening model for abortion drug, and EBs’ diameter, cell apoptosis, and differentiation changes of the germ layers can serve as criteria of abortion drug screening.
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Objective To evaluate the developmental toxicity and genotoxicity of leonurine. Methods Leonurine was given orally to SD pregnant rats on the 6th to 15th day of pregnancy at the dose of 500, 1 000 and 2 000 mg/kg body weight. The control group received 0.5% CMC-Na solution orally. Pregnant rats were sacrificed on the 20th day of pregnancy to analyze the reproductive toxicity. Ames test, in vitro chromosomal aberration test of CHO cell and in vivo micronucleus assay were performed to investigate the genotoxicity of leonurine. Results There was no difference statistically in weight gain of pregnant mice between two groups at the dose of 500, 1 000 and 2 000 mg/kg of motherwort alkaloids. In vitro CHO cell chromosomal aberration test indicated that there was no statistical difference between leonurine groups (doses of 250, 500 and 1 000 μg/ml) and the solvent control group with and without metabolic activation system S9. The number of micronuclei in ICR mice did not increase (P>0.05) in the mouse bone marrow micronucleus test at the doses of 100, 500 and 2 000 mg/kg. Conclusion No significant maternal toxicity, embryo toxicity, fetal toxicity and teratogenic effects were observed with leonurine at 500, 1 000 and 2 000 mg/kg doses. Leonurine was not genotoxic in Salmonella typhimurium reverse mutation test, in vitro CHO cells chromosome aberration test or mouse bone marrow micronucleus test. It showed that leonurine had no developmental toxicity and genotoxicity under the conditions of the experiment.
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OBJECTIVE To investigate the embryo-fetal developmental toxicity (EFDT) of careno?prazan hydrochloride (KFP-H008) in rabbits. METHODS Pregnant rabbits were given by gavage KFP-H008 at 5, 15 and 50 mg·kg-1 during the organogenetic period (gestation days 6-18, GD 6-18). Rabbits in positive control group were treated with cyclophosphamide (CP) 10 mg·kg-1 by iv. Maternal body mass and food consumption during gestation were recorded. Pregnant dams were euthanized on GD 29. The numbers of live/dead fetuses, resorptions, implantations, corpora lutea, and gravid uterus mass, placenta mass, fetal gender ratios, body mass, and skeletal development were evaluated. Moreover, the toxicokinetic parameters including AUC and C0-t, and tissue distributions were determined. RESULTS From GD 13, the maternal body mass and the food consumption in KFP-H00815 and 50 mg · kg-1 groups were lower than in the normal control group (P<0.05). Also, the reduced fetal crown rump length and mass, skeletal malformations/variations were observed in KFP-H00815 and 50 mg · kg-1 groups (P<0.05). KFP-H008 was rapidly eliminated, and became undetectable in the maternal plasma after a single administration. Following multiple KFP-H00850 mg · kg-1 treatment, both KFP-H008 and its metabolites were detectable in various tissues of the maternal and fetus, which might be the evidence for carenoprazan-induced developmental toxicity. In KFP-H00815 mg · kg-1 group, KFP-H008 and its metabolites were undetectable in most of maternal and fetal tissues. CONCLUSION The no observed adverse effect level (NOAEL) of KFP-H008 for maternal and fetal rabbits is about 5 mg·kg-1.
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OBJECTIVE: To obtain information on the toxicity of lufenuron on the reproduction ability and the growth and development of offspring in female and male rats through two-generation reproduction toxicity study. METHODS: The specific pathogen free healthy SD rats were randomly divided into control group and low-, medium-and high-dose lufenuron groups, with 60 rats in each group, half females and half males. Rats in the low-, medium-and high-dose lufenuron groups were respectively fed with lufenuron at the dose of 5.0, 20.0 and 80.0 mg/(kg body weight·day) for 8 weeks before mating. The control group was fed with standard foot. The reproductive index, brain and reproductive organ coefficients and pathological changes were observed in P and F1 parents. The birth and growth indexes of the offspring were measured. RESULTS: i) P generation: from the 14 th day, the female rats in the medium-dose group had lower body weight than that of the female control group(P<0.05); from the 35 th day, the body weight was lower than that of the female low-dose group(P<0.05). From the 14 th day, the female rats in the high-dose group had lower body weight than that of the other three female groups(P<0.05). From the 14 th day, the male rats in the medium-and high-dose groups had lower body weight than that of the male control group and low-dose group(P<0.05). The body weight of pregnant rats in the parental high-dose group was lower than that of the control group, low-dose group, and medium-dose group at day 0, 7, 14, 19 of the pregnancy duration(P<0.05). The body weight of pregnant rats in the parental medium-dose group was lower than that of the low-dose group on day 0 of the pregnancy duration, and lower than that of the control and low-dose groups on day 7 and 14(P<0.05). The conception rate, the new-borne survival rates and the feeding survival rate of female rats in the high-dose group was lower than that of the other three female groups(P<0.008). The new-borne feeding survival rate of female rats in the medium-dose group was lower than that of the control group and low-dose group(P<0.008). The organ coefficients of brain in female rats in the medium-and high-dose groups were higher than that of the female control group and low-dose group(P<0.05). The organ coefficients of brain and testis in male rats in the medium-and high-dose groups were higher than that of the control group and low-dose group(P<0.05). The organ coefficient of epididymis in male rats in the high dose group was lower than that of the other three male groups(P<0.05). ii) F1 generation: the body weight of female rats in the low-and medium-dose group was higher than that of the female control group on the 42 th day(P<0.05). The body weight of male rats in the low-dose group was higher than that of the male control group on the 42 th, 49 th, and 56 th days(P<0.05). The body weight of male rats in the medium-dose group was higher than that of the male control group on the 14 th, 21 th, 42 th, 49 th, and 56 th days(P<0.05). The new-borne survival rate in the low-dose group was lower than that of the control group(P<0.017). The body weight of new-borne rats in the high-dose group on day 4 of birth was lower than that in the other three female groups(P<0.05). iii) F2 generation: the body weight of male rats in the male medium-dose group was lower than that in the control group on day 21 of birth(P<0.05). CONCLUSION: The reproductive and developmental toxicity of lufenuron is found in rats in the medium-and high-dose groups. Toxicities including low body weight, conception rate, new-borne survival rate and feeding survival rate are found in P generation; low body weight and feeding survival rate are found in F1 generation; low body weight is found in male F2 generation. The no-observed-adverse-effects levels of lufenuron in two-generation reproductive study are 5.87 mg/(kg·d) for females and 5.09 mg/(kg·d) for males in SD rats.
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Objective:To take zebrafish embryo as the research object, in order to investigate the development toxicity, cardiotoxicity, liver toxicity and kidney toxicity of water extract of Jiaotaiwan (JTW) on zebrafish embryo. Method:Zebrafish embryos with normal development at 12 h (hpf) after fertilization were selected as model animals for the growth and cardiotoxicity experiments. The embryos were treated with 125, 250, 500 mg·L-1 of JTW water extracts, and the effects of the drugs on the heart rate and morphology of the embryos and LD50 were observed at 72 h (hpf) after fertilization. Zebrafish embryos with normal development at 72 h (hpf) after fertilization were used as model animals for the liver and kidney toxicity experiments. The embryos were treated with 125，250，500 mg·L-1 of JTW water extracts, and the effect of the drugs on morphological changes, Alanine aminotransferase(ALT), Aspartate aminotransferase (AST) activity, and creatinine content of the larvae and LD50 were observed at 72 d (dpf) after fertilization. Result:The zebrafish embryos in control group developed normally, the heart was well developed, and the heartbeat was even and powerful. The LD50 of JTW water extract on zebrafish embryos for 72 h was 1 023 mg·L-1. Compared with the embryos in the control group, 250，500 mg·L-1 treatment groups in the development toxicity had a smaller head, shorter body lengths (P<0.05), and decreased eye size (P<0.05). Compared with the control group embryos, the pericardial edema was observed in the 500 mg·L-1 group, the heart rate was significantly decreased in the 250，500 mg·L-1 JTW water extract groups (P<0.01), the atrial and ventricular areas were significantly reduced (P<0.05), the distance of SV-BA became significantly larger (P<0.05), the distance of AV channel became significantly larger (P<0.01), and the in-flow distance was significantly shorter (P<0.01). In the acute toxicity experiment, the LD50 of JTW water extract for zebrafish larvae for 72 h was 1 067 mg·L-1. Compared with control group, JTW water extract significantly reduced ALT activity in zebrafish larvae (P<0.05). Conclusion:This experiment found that JTW has an obvious toxicity in embryonic development, which is mainly manifested as delayed growth and severe cardiotoxicity. Great attention shall be paid to clinical administration to pregnant women, lactating women and patients with heart disease.
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Reproductive toxicity is the toxicity of reproductive system caused due to environmental factors such as chemicals, heavy metals etc. They interfere in some way with normal reproduction, such substances are called reprotoxic. It includes hazardous effects on fertility and sexual function in adult males and females as well as developmental toxicity in the offspring. Developmental toxicity is abnormal structure or functional development following exposure of pregnant or lactating females. In environment there are various factors which are responsible for causing adverse effect on reproductive system. Heavy metals like cadmium, lead, mercury, Industrial chemicals like phthalates, BPA, Agricultural chemicals, radiations, some of the narcotics drugs like morphine, ethanol, psychotropic drugs like diazepam, chlorpromazine, hypotensives like methyldopa, reserpine. All these factors acts as reproductive toxicants and affects male and female reproductive system causing spontaneous abortion, miscarriage, reduced fertility, preterm delivery, LBW, affect sertoli cells in the testis, affect leydig cell function etc. In ancient Ayurvedic texts also it is described that the heavy metal such as mercury, copper affects the reproductive system. Metals and metallic compounds, pesticides, some food additives have a nature of accumulations within the living body when it exposed since prolonged period. These factors accumulate in the body day by day. This is nothing but Dushivisha (cumulative toxins). Dushivishas vitiates the Dhatus after the laps of a long time on obtaining a favorable condition. It also affects the Shukradhatu causing Shukrashaya (diminish semen). People should be aware of all these factors to take adequate precaution.
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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.
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Animals , Humans , Mice , Rats , Diethylhexyl Phthalate , Toxicity , Environmental Pollutants , Toxicity , Haplorhini , PPAR alpha , Genetics , Metabolism , Plasticizers , ToxicityABSTRACT
Objective To examine the effect of niclosamide on thyroid endocrine disruption in larval zebrafish. Methods Zebrafish embryos (2 hours post-fertilization) were exposed to niclosamide at concentrations of 0, 5, 10, 20, 40 μg/L and 80 μg/L until 120 hours post-fertilization, and the body weight, hatching rate, malformation rate and survival rate of zebrafish embryos/larvae were measured. In addition, the triiodothyronine (T3) and thyroxin (T4) activities were determined in zebrafish, and the expression of tshβ and ttr genes that were associated with the regulation of thyroid hormones was quantified using a quantitative real-time PCR (qPCR) assay. Results Following exposure to niclosamide, there was no concentration-dependent hatching rate (F = 0.947, P = 0.924) or body weight of larval zebrafish (F = 1.042, P = 0.409); however, there were concentration-dependent survival rate (F = 9.309, P = 0.005) and malformation rate (F = 14.900, P = 0.001). As compared to controls, exposure to niclosamide at concentrations of 40 μg/L and 80 μg/L resulted in a significant reduction in the survival rate (both P values < 0.05), and a marked rise in the malformation rate of larval zebrafish (both P values < 0.05). In addition, the T4 activity increased (R2 = 0.927, F = 6.858, P = 0.003) and T3 activity decreased (R2 = 0.925, F = 8.212, P = 0.001) in larval zebrafish with the concentration of niclosamide. qPCR assay determined up-regulation of tshβ gene expression (R2 = 0.840, F = 9.032, P = 0.002) and down-regulation of ttr gene expression (R2 = 0.952, F = 9.130, P = 0.002). Conclusions Niclosamide exposure at environmental related concentrations may cause thyroid endocrine disruption of larval zebrafish.
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Domestic and foreign studies have shown that fine particulate matter (PM2.5) pollution is a major factor affecting human health. In addition to the direct impact on the respiratory and cardiovascular systems, PM2.5 exposure during pregnancy can directly affect the growth and development of offspring, manifested as cardiopulmonary dysfunction and cognitive disorder, various adverse pregnancy outcomes, abnormal organ development, and congenital defects. However, the mechanism underlying the developmental toxicity of PM2.5 is still unclear. This article reviews PM2.5-induced developmental toxicity based on epidemiological investigation and toxicological studies, which will provide references for further studies.
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Objective@#To investigate the reproductive and developmental toxicity of 2- (2H-1, 2, 3-benzotriazol-2-yl) -4-methyl-6- (2-methylpropen-2-yl) phenol in mice and to provide a basis for its risk assessment.@*Methods@#The reproductive and developmental toxicity of 2- (2H-1, 2, 3-benzotriazol-2-yl) -4-methyl-6- (2-methylpropen-2-yl) phenol was tested using the screening method of chemicals with reproductive and developmental toxicity in "Chemical Testing Method" (SEPA). After five days of adaptive feeding, 120 specific pathogen-free healthy Kunming mice (male/female ratio=1:1) were orally administered 0 (control) , 146, 292, and 584 mg/kg 2- (2H-1, 2, 3-benzotriazol-2-yl) -4-methyl-6- (2-methylpropen-2-yl) phenol for two weeks. One male mouse was mated with one female mouse in a single cage. The day on which a vaginal plug was observed was defined as gestation day 0 (GD0). The exposure for female mice was sustained to four days postpartum and the exposure for male mice was sustained for two weeks after mating. The body weight, food intake, body length, tail length, and sex ratio were recorded and the reproductive index was calculated. The reproductive organs were weighed and subjected to histopathological examination.@*Results@#The 584 mg/kg group had significantly lower body weight at weeks 5 and 6 and food intake at week 6 in male mice, uterus weight and uterus/body weight ratio in female mice, and body weight, body length, and tail length on day 0 in offspring compared with the control group (all P<0.05). The 292 mg/kg group had significantly lower testis weight of male mice and food intake of female mice at gestational week 2 than the control group (both P<0.05). The 146 mg/kg group had significantly lower food intake of female mice at gestational week 2 than the control group (P<0.05) .@*Conclusion@#For male and female Kunming mice, the no observed adverse effect levels of 2- (2H-1, 2, 3, -benzotriazol-2-yl) -4-methyl-6- (2-methylpropen-2-yl) phenol are both 146 mg/kg.
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Objective To investigate the effects of gefitinib on early embryonic development and expression of abcb4 tumor resistance genes in zebrafish.Methods Zebrafish were adopted as experimental animals and divided into gefitinib group,mixture of doxorubicin and gefitinib group and blank group.Zebrafish embryos of 0.5-1.5 hours after fertilization(0.5-1.5 hpf) were exposed to different concentrations of gefitinib,and then embryo development of zebrafish in 24-120 hpf was observed and the number of death,hatch and malformation was recorded.The embryo mortality was calculated under different concentrations of gefitinib at different time points,and the numerical value of IC50 was calculated;Hatching rates of zebrafish embryo in 48 hpf and 72 hpf and malformation rates of zebrafish embryo in 120 hpf were calculated.The zebrafish embryos exposed to different concentrations of gefitinib in different groups were collected,and the expressionof abcb4 gene in zebrafish embryos was detected by real-time quantitative PCR.Results Gefitinib IC50 in zebrafish embryos was 16.18 μmol/L.Compared with the control group,higher dosage (20 μmol/L) of gefitinib in other two groups significantly decreased hatching rates of embryos,and had obvious embryonic lethal effects and teratogenic effects.Moreover,the mRNA levels of the abcb4 gene in the zebrafish embryos of gefitinib group were not significantly changed,whereas the mRNA levels of the abcb4 gene in mixture of doxorubicin and gefitinib group were significantly different(P＜0.05).Conclusion Gefitinib has no significant effects on the expression of abcb4 tumor resistance gene in early development of zebrafish embryos(P＞0.05),but it can reverse the drug resistant effects of doxorubicin,suggesting that zebrafish can construct tumor resistance model.
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Objective Herbal medicines containing toxic herbs or minerals such as Compound Danshen Tablet (CDT), Angong Niuhuang Pill (ANP), and Lidan Paishi Tablet (LPT) are avoided or used with caution for pregnant women because of potential teratogenicity. To understand their mechanism, they were chosen as model subjects for the research. Methods Zebrafish embryos were used to evaluate their potential teratogenic risk in vitro. Results All of them showed teratogenic and lethal effects in zebrafish embryos, with the EC50 values at 351, 793, and 220 μg/mL, and LC50 values at 417, 596, and 380 μg/mL, respectively. CDT and LPT, displaying week potential teratogenicity as their teratogenicity indexes were greater than 1, induced tail malformation and cardiac edema mainly in zebrafish embryos, respectively. Conclusion The results provide the significant guidance of clinical safety of medication.
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There is an increasing demand for neonatal and juvenile animal toxicity studies during the research and development of new drugs. In this paper,we discussed general evaluation parameters of pediatric non-clinical safety with pediatric drugs,such as growth and development and food intake,and paramenters of other organs and systems, such as the central nervous system,reproductive system, behavior evaluation in combination with our own experience. In addition,the characteristics of non-clin?ical safety evaluation of new traditional Chinese medicine materia medica used for juvenile animals were analyzed. This paper is intended reference for non-clinical safety evaluation of pediatric drugs and to gain some experience related to formulation of new guidelines.
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In current research and development of new drugs,the demand for toxicological study using neonatal and juvenile animals is becoming increasingly urgent. In this paper,we discussed the characteristics,importance and necessity of nonclinical safety evaluation for pediatric drugs,considerations for research design,selection of animal species and age,route and duration of drug administration and evaluation indexes. In addition,the characteristics of nonclinical safety evaluation of new traditional Chinese materia medica used for children were analyzed. It is hoped that these studies will not only provide support and reference for nonclinical safety evaluation of pediatric drugs but help accumulate material in formulating relevant guidelines.
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Objective To explore the growth and developmental parameters and behavioral characteristics of rhesus monkeys during the first year of birth and to establish the background data.Methods A total of 18 (♂=11,♀=7 ) infant rhesus monkeys born from individually caged mothers and with known genetic background and postnatal days were monitored monthly for body weight, body height, head circumference, chest circumference, forelimb length, hind limb length, crown-rump length, tail length and anal-genital distance from postnatal day ( PND) 1 to 360, while hematology, blood chemistry and lymphocyte subsets were examined on PND 28, 175 and 360, and finger maze test was carried out on PND 208.Results The body weight showed linear growth with no significant difference between genders (P>0.05). Except for the anal-genital distance of male infants was significantly greater than that of female infants ( P0.05).Compared with that at PND28, TP and BUN were significantly increased (P0.05) at PND 175 and 360.Compared with that at PND28, CD4 +and CD4 +/CD8 +were significantly decreased ( P<0.01) while CD8+significantly increased ( P<0.01) at PND175 and 360.The number of sessions to solve task 2 in learning test was significantly greater than other tasks with females significantly less than males ( P<0.05) .The females had higher correct rate than males in the 2-day random memory test (P<0.05).Conclusions Body weight and morphological parameters show a linear growth.The PND.The RBC, HGB, LYMPH, TP, BUN, ALP, CD4 +, CD8 +and CD4 +/CD8+in hematology, blood chemistry and lymphocyte subsets show relevant changes to the growth and development of organs and systems in infants, which should be highly concerned in drug evaluation.The finger maze test indicates that female infants have better reversal learning and long-term memory than male infants.Background data and behavioral characteristics of infant rhesus monkeys during the first 12 months of birth are established in this study, which provide useful reference and support the evaluation of developmental and reproductive toxicity of drugs in rhesus monkeys.
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Aim To explore the toxicity and safety of five kinds of known positive drugs, cyclophosphamide, acetyl salicylic acid, tetracycline hydrochloride, dexa-methasone acetate and azacitidine, using zebrafish em-bryos. Methods We selected normally developed 4 hpf zygote, and used water bath infecting method to add the drug to the artificial seawater. Each drug had five concentrating groups, a separate control group and solvent control group. We observed the dead zebrafish embryos after 120 hpf drugs, counted the number of deaths and deformities of zebrafish embryos, and cal-culated mortality abnormal rate, the median lethal con-centration (LC50 ), concentration for 50% of maximal effect (EC50 ), therapeutic index (TI) under 120 hpf condition. We also used the formula TI = LC50 / EC50 to calculate positive drug therapeutic index. Based on measured LC50 we calculated most nonlethal concentra-tion (MNLC) of each drug setting, namely 1 / 10 MN-LC, 1 / 3 MNLC, MNLC,LC10 four concentration, tha-lidomide as a positive control, vitamin C as a negative control, artificial seawater as control, 0. 5% DMSO as solvent control. Put in 28. 5 ℃ environment for 120 hours,embryo development was observed daily for de-velopmental state,mortality,deforming rate and abnor-mal condition. Results The result of five drugs LC50 in descending order: cyclophosphamide > azacitidine> tetracycline hydrochloride > acetylsalicylic acid >dexamethasone acetate. EC50 in descending order: cy-clophosphamide > tetracycline hydrochloride > azaciti-dine > acetylsalicylic acid > dexamethasone acetate. The TI values of cyclophosphamide, acetyl salicylic acid, tetracycline hydrochloride, dexamethasone ace-tate, azacitidine were 1. 92, 1. 11, 1. 05, 1. 44, 2. 99, respectively. Conclusion Zebrafish embryo model can be used in the preliminary evaluation of drugs, and the study of early developmental toxicity and safety.
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<p><b>OBJECTIVE</b>To evaluate the bio-safety of graphene quantum dots (GQDs), we studied its effects on the embryonic development of zebrafish.</p><p><b>METHODS</b>In vivo, biodistribution and the developmental toxicity of GQDs were investigated in embryonic zebrafish at exposure concentrations ranging from 12.5-200 μg/mL for 4-96 h post-fertilization (hpf). The mortality, hatch rate, malformation, heart rate, GQDs uptake, spontaneous movement, and larval behavior were examined.</p><p><b>RESULTS</b>The fluorescence of GQDs was mainly localized in the intestines and heart. As the exposure concentration increased, the hatch and heart rate decreased, accompanied by an increase in mortality. Exposure to a high level of GQDs (200 μg/mL) resulted in various embryonic malformations including pericardial edema, vitelline cyst, bent spine, and bent tail. The spontaneous movement significantly decreased after exposure to GQDs at concentrations of 50, 100, and 200 μg/mL. The larval behavior testing (visible light test) showed that the total swimming distance and speed decreased dose-dependently. Embryos exposed to 12.5 μg/mL showed hyperactivity while exposure to higher concentrations (25, 50, 100, and 200 μg/mL) caused remarkable hypoactivity in the light-dark test.</p><p><b>CONCLUSION</b>Low concentrations of GQDs were relatively non-toxic. However, GQDs disrupt the progression of embryonic development at concentrations exceeding 50 μg/mL.</p>