Decrease In Fetal Weight Research Articles

Impact of xylene exposure during organogenesis on foeto-placental efficiency and foetal viability: Exploring its association with oxidative stress-induced inflammation and apoptosis in utero.

The potential maternal and foetal toxicity resulting from exposure to xylene at or below the allowable limit of 100 ppm during gestation is not thoroughly studied. The aim of this study was to investigate maternal and foetal outcomes following prenatal exposure to xylene during organogenesis. Pregnant Sprague Dawley (SD) rats were administered intraperitoneal (IP) corn oil (vehicle), 100, 500, and 1000 parts per million (ppm) of xylene from gestational day (GD) 6 until GD17. Clinical signs, maternal weight gain, and food consumption were recorded daily. A caesarean hysterectomy was performed on GD21 to assess the reproductive and foetal outcomes. Exposure to 1000 ppm of xylene caused a significant decrease in the maternal body weight and food consumption, and an increase in intrauterine foetal deaths. Foetal assessment revealed a significant decrease in foetal weight in both male and female foetuses of female rats treated with 500 and 1000 ppm. Male placental weight was significantly decreased in all xylene-treated groups, while 1000 ppm xylene significantly decreased female placental weight. Histologically, marked uterine inflammatory lesions, fibrosis of the liver and renal tissues, as well as increased placental glycogen content were observed. Immunohistochemistry revealed a significant increase in lipid peroxidation and apoptotic markers. Thus, the foeto-maternal toxicities of xylene have been shown to be mediated by a systemic inflammatory response that exacerbates intrauterine oxidative stress and impairs foeto-placental transfer, leading to an increase in foetal mortality.

Abstract MP30: The Role of CD20+ B cells in Mediating Hypertension in Preeclampsia during Pregnancy

Pre-eclampsia (PE), new-onset hypertension after the 20 th week of pregnancy alongside other organ dysfunction, endothelial dysfunction, and immune activation. We have previously shown that CD19+ B cell adoptive transfer causes a PE phenotype in athymic nude rats. CD19 is present on all B cells including plasma cells. CD20 is absent from plasma cells but is present on mature B2 and memory B cells. The objective of this study was to determine if CD20+ B cells, excluding plasma cells, cause maternal hypertension, fetal growth restriction, and endothelial dysfunction. Three hundred thousand placental CD20+ B Cells from normal pregnant (NP) or PE patients were isolated by magnetic separation and injected i.p. into nude athymic rats on gestational day (GD) 12. On GD18, carotid catheters were inserted. On GD19, mean arterial pressure (MAP) was measured and blood and tissues were collected. Preproendothelin (PPET) expression was quantified in kidney and placental tissues using RT-PCR. A student’s t-test was used for statistical analysis. Participants whose placental B cells were used in this study had similar age, pre-pregnancy BMI, and diastolic BP on admission. PE participants had elevated systolic BP at admission (135±4 vs 120±4 mmHg) and delivery (139±6 vs 124±3 mmHg) as well as diastolic BP at delivery (79±4 vs 68±2 mmHg). PE participants also had trending decreases in fetal weight (2621±323 vs 3202±102 g) and gestational age (36±1 vs 39±0 weeks) at delivery. MAP increased from 107±4 mmHg (n=8) in the NP recipient rats to 123±2 mmHg (n=8, p<0.01) in the PE recipient rats. Pup and placental weights were unchanged following adoptive transfer. Renal PPET expression increased by 2.595±0.61 fold (ΔΔct) in PE recipient rats (n=7, p<0.05) compared to NP recipient rats (n=7). Placental PPET expression was unchanged following adoptive transfer. CD20+ B cells from women with PE contribute to hypertension and endothelial dysfunction during pregnancy. This data supports the important role of B cells in the development of PE and improves our understanding of the population of B cells responsible for contribution to the disease.

Safety of embryo cryopreservation: insights from mid-term placental transcriptional changes

BackgroundIn recent years, with benefits from the continuous improvement of clinical technology and the advantage of fertility preservation, the application of embryo cryopreservation has been growing rapidly worldwide. However, amidst this growth, concerns about its safety persist. Numerous studies have highlighted the elevated risk of perinatal complications linked to frozen embryo transfer (FET), such as large for gestational age (LGA) and hypertensive disorders during pregnancy. Thus, it is imperative to explore the potential risk of embryo cryopreservation and its related mechanisms.MethodsGiven the strict ethical constraints on clinical samples, we employed mouse models in this study. Three experimental groups were established: the naturally conceived (NC) group, the fresh embryo transfer (Fresh-ET) group, and the FET group. Blastocyst formation rates and implantation rates were calculated post-embryo cryopreservation. The impact of FET on fetal growth was evaluated upon fetal and placental weight. Placental RNA-seq was conducted, encompassing comprehensive analyses of various comparisons (Fresh-ET vs. NC, FET vs. NC, and FET vs. Fresh-ET).ResultsReduced rates of blastocyst formation and implantation were observed post-embryo cryopreservation. Fresh-ET resulted in a significant decrease in fetal weight compared to NC group, whereas FET reversed this decline. RNA-seq analysis indicated that the majority of the expression changes in FET were inherited from Fresh-ET, and alterations solely attributed to embryo cryopreservation were moderate. Unexpectedly, certain genes that showed alterations in Fresh-ET tended to be restored in FET. Further analysis suggested that this regression may underlie the improvement of fetal growth restriction in FET. The expression of imprinted genes was disrupted in both FET and Fresh-ET groups.ConclusionBased on our experimental data on mouse models, the impact of embryo cryopreservation is less pronounced than other in vitro manipulations in Fresh-ET. However, the impairment of the embryonic developmental potential and the gene alterations in placenta still suggested it to be a risky operation.

Risk Factors for The Incident of Serotinus Pregnancy in The Lalowaru Health Center Area, North Moramo District

Background: Post-term pregnancy is one of the complications that can be detrimental to the mother and baby, one of which is a decrease in fetal weight which can cause death in the baby. Objective: To determine the risk factors for serotinus pregnancy in the Lalowaru Community Health Center area, North Moramo District. Methods: This type of quantitative analytical research uses a case-control design. The population in the study were all mothers with a history of serotinus pregnancy. The total sample was 66 respondents, using random sampling techniques Results: There were 32 respondents (48.5%) who were at risk of experiencing a serotinous pregnancy and 34 other respondents (51.5%) who were not at risk of experiencing a serotinous pregnancy. In addition, 31 respondents (47%) with parity were at risk of experiencing a serotinous pregnancy and 35 respondents (53%) were not at risk of experiencing a serotinous pregnancy. The results showed that respondents at risk age had a 31.006 times greater chance of experiencing a serotonin pregnancy and respondents in the risk category had a 17.031 times greater chance of experiencing a serotonin pregnancy. Based on the results of statistical tests, a ρ value of 0.003 (0.003<0.05) was obtained, indicating that age is a risk factor for serotinus pregnancy. The ρ value is 0.010 (0.010<0.05), which means that parity is also a risk factor for serotinus pregnancy. Conclusions: age and parity are risk factors for serotinous pregnancy in the Lalowaru Community Health Center Working Area, North Moramo District

Exposure to fine particulate matter 2.5 from wood combustion smoke causes vascular changes in placenta and reduce fetal size

During gestation, maternal blood flow to the umbilical cord and placenta increases, facilitating efficient nutrient absorption, waste elimination, and effective gas exchange for the developing fetus. However, the effects of exposure to wood smoke during this period on these processes are unknown. We hypothesize that exposure to PM2.5, primarily sourced from wood combustion for home heating, affects placental vascular morphophysiology and fetal size. We used exposure chambers that received either filtered or unfiltered air. Female rats were exposed to PM2.5 during pre-gestational and/or gestational stages. Twenty-one days post-fertilization, placentas were collected via cesarean section. In these placentas, oxygen diffusion capacity was measured, and the expression of angiogenic factors was analyzed using qPCR and immunohistochemistry. In groups exposed to PM2.5 during pre-gestational and/or gestational stages, a decrease in fetal weight, crown-rump length, theoretical and specific diffusion capacity, and an increase in HIF-1α expression were observed. In groups exposed exclusively to PM2.5 during the pre-gestational stage, there was an increase in the expression of placental genes Flt-1, Kdr, and PIGF. Additionally, in the placental labyrinth region, the expression of angiogenic factors was elevated. Changes in angiogenesis and angiogenic factors reflect adaptations to hypoxia, impacting fetal growth and oxygen supply. In conclusion, this study demonstrates that exposure to PM2.5, emitted from wood smoke, in both pre-gestational and gestational stages, affects fetal development and placental health. This underscores the importance of addressing air pollution in areas with high levels of wood smoke, which poses a significant health risk to pregnant women and their fetuses.

The Teratogenic Effect of Dimefluthrin-Based Mosquito Coils on Pregnant Mice (Mus musculus L.)

Dimefluthrin, a synthetic pyrethroid insecticide, claims to be safe and harmless to mammals. However, the potential risk of mosquito coils containing dimefluthrin to pregnant mice remains uncertain. This study aimed to examine the teratogenic effect of dimefluthrin when inhaled by pregnant mice at different stages of gestation. The study used mosquito coils with 0.031% dimefluthrin as the active ingredient and was exposed to pregnant mice at various pregnancy stages. The results revealed that mosquito coils with dimefluthrin had teratogenic effects, reducing the number of live fetuses and increasing the number of dead fetuses, especially from the seventh to the eighteenth day of pregnancy. Additionally, there was a decrease in fetal weight, length, and volume, particularly during the seventh to eighth day of gestation. Hemorrhages were observed as fetal abnormalities and were highest three hr after exposure every day during pregnancy. The conclusion of this research is pregnant mice exposed to mosquito coil smoke containing dimefluthrin experienced a decrease in the number of live fetuses and an increase in fetal mortality. While there was no significant impact on reabsorption, the fetuses showed reduced weight, and size, and an increased incidence of hemorrhages when exposed for three hr daily during pregnancy.

The adverse effects of vitrification on mouse embryo development and metabolic phenotype in offspring.

Embryo vitrification is a standard procedure in assisted reproductive technology. Previous studies have shown that frozen embryo transfer is associated with an elevated risk of adverse maternal and neonatal outcomes. This study aimed to explore the effects of mouse blastocyst vitrification on the phenotype of vitrified-warmed blastocysts, their intrauterine and postnatal development, and the long-term metabolic health of the derived offspring. The vitrified-warmed blastocysts (IVF + VT group) exhibited reduced mitochondrial activity, increased apoptotic levels, and decreased cell numbers when compared to the fresh blastocysts (IVF group). Implantation rates, live pup rates, and crown-rump length at E18.5 were not different between the two groups. However, there was a significant decrease in fetal weight and fetal/placental weight ratio in the IVF + VT group. Furthermore, the offspring of the IVF + VT group at an age of 36 weeks had reduced whole energy consumption, impaired glucose and lipid metabolism when compared with the IVF group. Notably, RNA-seq results unveiled disturbed hepatic gene expression in the offspring from vitrified-warmed blastocysts. This study revealed the short-term negative impacts of vitrification on embryo and fetal development and the long-term influence on glucose and lipid metabolism that persist from the prenatal stage into adulthood in mice.

SAT065 Developmental Programming: Sex-specific Programming Of Pancreas In A Sheep Model Of Polycystic Ovary Syndrome

Abstract Disclosure: K.M. Halloran: None. A.K. Vyas: None. N. Saadat: None. V. Padmanabhan: None. Prenatal testosterone (T) treatment from gestational days (GD) 30-90 (sexually dimorphic window of fetal development where male fetuses naturally see elevated T) leads to reproductive and metabolic disruptions in female sheep that includes dyslipidemia, insulin resistance, and compensatory hyperinsulinemia similar to that seen in women with PCOS. The effects of excess T are seen as decreased pancreatic/fetal weight in female fetuses as opposed to an increase in beta cell size and lipid/collagen accumulation in adult females. We addressed the prenatal T-induced gene expression changes contributing to pancreatic compromise to determine if 1) the programmed event persists after cessation of T treatment, 2) T females (TF) are similar to control males (CM), and 3) it is exacerbated in the T males (TM). Time-mated pregnant sheep were administered T propionate (100 mg in 2 ml corn oil) or vehicle between GD 30-90 to obtain control female (CF), TF, CM, and TM fetuses (n=6/group). On ∼GD 120 (term: 147), fetuses were weighed and pancreas was collected, weighed, and the tail portion stored at -80°C until next-generation sequencing for gene expression profiling to identify potential pathways influenced by T and fetal sex. After removal of outliers (determined by Principal Component Analysis-PCA using SIMCA), 3D PCA plots showed clear separation of the treatment groups after stratifying by fetal sex. DESeq2 R package was used to identify differentially expressed genes (DEGs) between the comparisons of interest (CF vs TF, TF vs CM, and CM vs TM). Overall, T fetuses weighed less (P<0.05). Cohen’s effect size analysis found a large magnitude (Cohen’s d>0.8) decrease in fetal weight for TF vs CF, TM vs CM, and TF vs CM and a medium magnitude (d=0.5) decrease in pancreas weight for TF vs CM. Pancreatic:fetal weight ratios did not differ by treatment or fetal sex. 16 DEGS (1 up, 15 down) were identified between TF and CF, 7 DEGs (2 up, 4 down) between TF and CM, and 2 DEGs (up) between TM and CM (Adj P<0.1) with no overlap amongst them, suggesting that the effect of T in females is distinct from males and that TF are more similar to CM. Preliminary analysis indicates that the majority of the DEGs affected in TF are related to immune-signaling pathways, including c-type lectin domain family 4 member G (CLEC4G), cluster of differentiation 52 (CD52), and interleukin 21 receptor (IL21R); CD52, IL21R, and members of the CLEC4 family are implicated in autoimmune pathways linked to Type 1 diabetes. The 2 DEGs affected in TM are involved in plasma membrane dynamics: fer-1 like family member 6 (FER1L6) and chloride voltage gated channel 2 (CLCN2). These changes evident at the gene expression level a month after the cessation of T treatment is suggestive of sexually dimorphic reprogramming of fetal pancreas by exposure to excess T. Further, the endogenous increases in T seen in males may at least in part be responsible for sexually dimorphic programming. Presentation: Saturday, June 17, 2023

Exploration of Maternal and Fetal Toxicity Risks for Metronidazole-Related Teratogenicity and Hepatotoxicity through an Assessment in Albino Rats.

Metronidazole is the primary antimicrobial drug for treating acute and chronic vaginal pathogens during pregnancy; however, there has been insufficient research on placental disorders, early pregnancy loss, and preterm birth. Here, the potential activity of metronidazole on pregnancy outcomes was investigated. 130 mg/kg body weight of metronidazole was orally given individually to pregnant rats on gestation days 0-7, 7-14, and 0-20. Pregnancy outcome evaluations were carried out on gestation day 20. It was demonstrated that metronidazole could induce maternal and fetal hepatotoxicity. There is a significant increase in the activities of maternal hepatic enzymes (ALT, AST, and ALP), total cholesterol, and triglycerides compared with the control. These biochemical findings were evidenced by maternal and fetal liver histopathological alterations. Furthermore, metronidazole caused a significant decrease in the number of implantation sites and fetal viability, whereas it caused an increase in fetal lethality and the number of fetal resorptions. In addition, a significant decrease in fetal weight, placental weight, and placental diameter was estimated. Macroscopical examination revealed placental discoloration and hypotrophy in the labyrinth zone and the degeneration of the basal zone. The fetal defects are related to exencephaly, visceral hernias, and tail defects. These findings suggest that the administration of metroniazole during gestation interferes with embryonic implantation and fetal organogenesis and enhances placental pathology. We can also conclude that metronidazole has potential maternal and fetal risks and is unsafe during pregnancy. Additionally, it should be strictly advised and prescribed, and further consideration should be given to the associated health risks.

Effect of monosodium glutamate on fetal development and progesterone level in pregnant Wistar Albino rats

Monosodium glutamate (MSG) is a widespread flavor enhancer and stabilizer in manufactured or packaged foods that possess myriad adverse effects. This study aimed to evaluate the effect of MSG on placental progesterone receptors and fetal development. Thirty pregnant Wistar Albino rats were divided into three groups (ten/each). The control group (G1) gavaged distilled water only, low-dose treated group (G2) gavaged 3 g/kg MSG, and high-dose treated group (G3) gavaged 6 g/kg MSG from 1st to 18th days of gestation, and all pregnant rats were sacrificed on the 19th day of gestation. The effect of MSG on fetal weights, crown vertebral length (CVL), placental weight, placental ghrelin expression, and fetal skeleton examination were estimated. MSG induced a significant decrease in fetal weights, CVL lengths, placental weight, and ghrelin expression in both treatment groups compared to the control group. Several parts of the fetal skeleton showed incomplete ossification and delayed chondrification in which high-dose maternally treated fetuses were more affected. Many degenerative changes were detected in both maternal and fetal liver and kidney tissues in MSG-treated groups. Moreover, MSG caused a significant increase in serum ALT, ALP, and creatinine levels in pregnant rats’ blood. Serum progesterone was only elevated in G3 on the 19th day of gestation. This study showed that the administration of MSG during pregnancy adversely influences fetal growth and skeletal development and caused several biochemical and histological changes in the maternal and fetal liver and kidney tissues which assure the toxic and teratogenic effects of MSG.

Retinoic acid as a teratogen: IX-Induction of fetal skeletal anomalies and alteration in the utero-placental expression pattern of EGFR during mice development

ABSTRACT Retinoic acid (RA), an active metabolite of vitamin A, plays essential signaling roles in mammalian embryogenesis. Nevertheless, it has long been recognized that overexposure to vitamin A or retinoic acid causes widespread teratogenesis in rodents as well as humans. However, the mechanism of its teratogenic effect is not yet understood. Here, we examined the effects of RA on the fetal and placental development as an attempt to find the mechanism of its teratogenicity through inhibition of utero-placental development. The pregnant mice were divided into three groups: RA treated group, control treated with dimethyl sulfoxide (DMSO) group and control non-treated group. The RA treated group received 15 mg/kg RA by intraperitoneal injection from 8.5 to 11.5 gestation days. The pregnant mice were sacrificed by cervical dislocation on days 9.5, 10.5, 12.5, 13.5 and 18.5 of gestation. The uteri were isolated, and the fetuses have been exposed to morphological examination and skeletal staining. Moreover, histological and immunohistochemical studies on placenta have been done. Morphologically, we recorded a reduction in the number of implanted fetuses besides hematoma in different parts of the uteri of the RA treated animals. Furthermore, RA was found to induce decreases in fetal weight and length, as well as malformations in the tail, forelimbs and hindlimbs, which were confirmed by skeletal examination. Interestingly, RA treatment showed a decrease in the expression level of epidermal growth factor receptor (EGFR) during placenta development, especially in junctional and labyrinth zones. We concluded that high dose of RA may have a direct teratogenic effect on the fetus besides an indirect effect through modulating EGFR signal during the placenta development.

Thermal skin burn in a late gestation period in experimental animals: state of the system “mother-fetus”

Objective. To study the effect of thermal skin burns in experimental animals (rats) on the state of the system “mother-fetus” in a late gestation period.Materials and methods. An experimental study was carried out on 18 female outbred white rats weighing 300–350 g (per 9 rats in the control and experimental groups), which were exposed to third-degree thermal burns with an area of 12 cм2 in a late gestation period. The oxygen transport function and the main blood biochemical markers were studied. The effect of thermal injury on the course of pregnancy was studied.Results. The thermal skin burn in the rats in the late gestation period leads to the development of hypoxia, a decrease in the affinity of hemoglobin for oxygen and metabolic acidosis in the mother’s body. Changes in the blood biochemical markers indicate the presence of endogenous intoxication. In the experimental animal group, a decrease in fetal weight was observed, an increase in the post-implantation fetal death rate was noted.Conclusion. Impaired oxygen homeostasis and endogenous intoxication in skin burns in rats in late gestation periods lead to fetal malnutrition and a qualitative increase in the post-implantation fetal death rate.

Pregnancy Outcomes in A Group Egyptian Patients with Systemic Lupus Erythematosus: A Cohort Study

Abstract Background Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age thus pregnancy in lupus patients is a common clinical scenario. SLE adversely affects pregnancy outcomes and pregnancy leads to SLE flares Aim of the work Determining the frequencies and predictors of maternal and fetal pregnancy outcomes in women with SLE by a prospective cohort study Patients and methods seventy-one pregnant lupus patients were followed prospectively, and their data compared to age-matched pregnant healthy controls attending Ain Shams University Hospital clinics Results Thirteen Patients had activity at conception. Sixty-six(93%) Where on treatment. Flares occurred in 51 patients (72%) during pregnancy with nephritis being the most common occurring in 78%. The prevalence of anemia, AKI and hypertension (HTN) during pregnancy were higher in SLE group than control group (P < 0.01). The rate of delivery by Cesarean section (CS), PTL, postpartum hemorrhage, preeclampsia (PE), severe PE and HELLP were higher in SLE group then control group (P < 0.01) as well as an increase in rate of postpartum infection (P < 0.05). There was an increase in rate of fetal loss, prematurity, intrauterine growth restriction (IUGR), NICU admission, still birth/intrauterine fetal death and highly significant decrease in fetal weight in SLE group than control group (P < 0.01). Pregestational HTN was independently associated with PE (OR 91.228; CI 6.791-1225.538). Proteinuria and HTN during pregnancy were independently associated with prematurity (OR 14.162 CI 1.029-194.958 & OR 10.596, CI 1.460-76.894). Conclusion Pregnancy in lupus patients carries a higher risk of pregnancy morbidity and worse fetal outcomes than the controls.

Maternal Exposure to Oxidized Soybean Oil Impairs Placental Development by Modulating Nutrient Transporters in a Rat Model.

As an exogenous food contaminant, dietary oxidized lipid impairs growth and development, and triggers chronic diseases in humans or animals. This study explores the effects of soybean oil with different oxidative degree on the placental injury of gestational rats. Thirty-two female adult rats are randomly assigned to four groups. The control group is fed the purified diet with fresh soybean oil (FSO), and the treatment groups are fed purified diets with lipid content replaced by oxidized soybean oil (OSO) at 200, 400, and 800 mEqO2 kg-1 from conception until delivery. On day 20 of gestation, OSO decreased placental and embryonic weights as the oxidative degree increased linearly and quadratically. The expression of Bax showed a linear increase, and Bcl-2 decreased as the oxidative degree increased. The expression of Fosl1 and Esx1 is linearly and quadratically decreased in OSO-treated groups than FSO group. OSO decreased the level of IL-10 but increased expression of IL-1β in placenta and plasma. OSO remarkably upregulates levels of Fatp1 and Glut1 and decreases expression of Snat2 and Glut3. OSO aggravates placental injury by modulating nutrient transporters and apoptosis-related genes, impedes placental growth and development, and ultimately leads to the decrease of fetal weight.

Alternariol exerts embryotoxic and immunotoxic effects on mouse blastocysts through ROS-mediated apoptotic processes.

Alternariol (AOH), a mycotoxin belonging to the genus Alternaria, has been shown to induce cytotoxicity, including apoptosis and cell cycle arrest, in several mammalian cell types. However, its effects on early-stage embryonic development require further investigation. Here, we have shown that AOH exerts embryotoxic effects on mouse blastocyst-stage embryos and long-term adverse effects on immunity in one-day-old newborn mice of the next generation. Significant apoptosis and decrease in total cell number, predominantly through loss of inner cell mass (ICM), and to a minor extent, trophectoderm (TE) cells, were observed in AOH-treated blastocysts. Moreover, AOH exerted detrimental effects on pre- and post-implantation embryo development potential and induced a decrease in fetal weight in in vitro development and embryo transfer assays. Injection of pregnant mice with AOH (1, 3 and 5mg/kg body weight/day) for 4days resulted in apoptosis of blastocyst-stage embryos and injurious effects on embryonic development from the zygote to blastocyst stage or embryo degradation and a further decrease in fetal weight. Furthermore, AOH exerted a long-term impact on the next generation, triggering a significant increase in total oxidative stress content and expression of genes encoding antioxidant proteins. Lower expression of CXCL1, IL-1β and IL-8 related to innate immunity was detected in liver tissue extracts obtained from one-day-old newborns of AOH-injected pregnant mice (5mg/kg body weight/day) relative to their non-treated counterparts. In addition, ROS served as an upstream regulator of AOH-triggered apoptotic processes and impairment of embryonic development. Our collective results highlight the potential of AOH as an embryotoxic and immunotoxic risk factor during embryo and infant development stages in mice.

Prenatal developmental toxicity evaluation of Verbena officinalis during gestation period in female Sprague-Dawley rats

Verbena officinalis is widely used by women for maintaining general health and treating various gynaecological disorders during pregnancy. A case report has indicated that the consumption of V. officinalis induced an abortifacient effect. Hence, this study aimed to investigate the prenatal developmental toxicity of this plant according to OECD guideline (no. 414). A total of 50 pregnant female rats (dams) were distributed into five groups (n = 10); 500 mg/kg 1000 mg/2000 mg/kg and 3000 mg/kg of V. offcinalis extracts and the fifth group served as a normal control. All dams received their respective oral single daily treatment from the 6th to the 20th day of gestation. Maternal clinical toxicity signs, body weight and weight gain were recorded. Caesarean sections were performed on day 21 to evaluate embryo–foetal developmental toxicity. For dams, ovaries were harvested and weighed. The number of corpora lutea, implantation sites, and resorptions were recorded. No mortality was observed in dams, but their body weight gain was significantly reduced particularly in dams treated with 2000 and 3000 mg/kg V. officinalis. Asymmetrical distribution of implantation sites and embryos were observed. Embryo-fetotoxicity retardation was observed as evident by the decrease in foetal weight, head cranium, tail length, and higher incidence in the pre-and post-implantation loss. Some foetal skeleton abnormalities such as incomplete ossification of skull, sternebrae, and metatarsal bones were observed in foetuses of the 2000 and 3000 mg/kg V. officinalis-treated dams. LC/MS analysis identified the major constituents including geniposidic acid, tuberonic acid glucoside, luteolin 7, 3′-digalacturonide, iridotrial and apigenin. The glycosylated flavonoids such as apigenin and luteolin could be responsible for the reported prenatal developmental toxicity. In conclusion, the use of V. officinalis during pregnancy is not safe indicating evidence-based toxic effects on the reproductive performance of dams and dose-dependent risk potentials to the foetuses.

Aspirin Ameliorates Preeclampsia Induced by a Peroxisome Proliferator-Activated Receptor Antagonist.

Reduced expression of peroxisome proliferator-activated receptor γ (PPARγ) in the placenta was found in women with severe preeclampsia. Aspirin is currently used as the only recommended intervention in pregnancies for prevention of preeclampsia. In this study, we aimed to investigate whether aspirin could attenuate PPARγ inhibitor (T0070907)-induced preeclampsia and its impact on expression of PPARγ. Sixty Sprague-Dawley rats were used and treated with different doses of aspirin (0, 1, and 1.5 mg/kg) in presence or absence of PPARγ antagonist, T0070907. We found that mean arterial blood pressure was significantly reduced by aspirin treatment in T0070907-exposed rats. T0070907 exposure also led to significant decrease in fetal weight and increase in placental weights. However, 1.5 mg/kg of aspirin reversed these effects of T0070907. Additionally, aspirin also reversed T0070907-induced changes in the levels of thromboxane B2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, and matrix metalloproteinase 2 in both maternal blood and placental tissue. The increased messenger RNA and protein levels of Cox1 and Cox2 induced by T0070907 were markedly reduced by aspirin treatment. Importantly, T0070907 repressed both transcriptional and translational levels of PPARγ, which were reversed by aspirin. In conclusion, this study suggests that aspirin prevented the occurrence of preeclampsia, which is possibly through enhancing both transcriptional and translational levels of PPARγ.

Enniatin B1 exerts embryotoxic effects on mouse blastocysts and induces oxidative stress and immunotoxicity during embryo development.

Enniatins are mycotoxins of Fusarium fungi that naturally exist as mixtures of cyclic depsipeptides. Previous reports have documented hazardous effects of enniatins on cells, such as apoptosis. However, their effects on pre- and post-implantation embryonic development require further clarification. Here, we showed for the first time that enniatin B1 (ENN B1) exerts cytotoxic effects on mouse blastocyst-stage embryos and induces intracellular oxidative stress and immunotoxicity in mouse fetuses. Co-incubation of blastocysts with ENN B1 triggered significant apoptosis and led to a decrease in total cell number predominantly through loss of inner cell mass. In addition, ENN B1 appeared to exert hazardous effects on pre and postimplantation embryo development potential in an in vitro development assay. Treatment of blastocysts with 1-10 μM ENN B1 led to increased resorption of post-implantation embryos and decreased fetal weight in the embryo transfer assay in a dose-dependent manner. Importantly, in an in vivo model, intravenous injection with ENN B1 (1, 3, and 5 mg/kg body weight/d) for 4 days resulted in apoptosis of blastocyst-stage embryos and impairment of embryonic development from the zygote to blastocyst stage, subsequent degradation of embryos, and further decrease in fetal weight. Intravenous injection with 5 mg/kg body weight/d ENN B1 additionally induced a significant increase in total reactive oxygen species (ROS) content and transcription levels of genes encoding antioxidant proteins in mouse fetal liver. Moreover, ENN B1 triggered apoptosis through ROS generation and strategies to prevent apoptotic processes effectively rescued ENN B1-mediated hazardous effects on embryonic development. Transcription levels of CXCL1, IL-1β, and IL-8 related to innate immunity were downregulated after intravenous injection of ENN B1. These results collectively highlight the potential of ENN B1 to exert cytotoxic effects on embryos as well as oxidative stress and immunotoxicity during mouse embryo development.

Hydroxyurea embryotoxicity is enhanced in P53-deficient mice

Hydroxyurea, a ribonucleotide reductase inhibitor, is a potent teratogen in mice, causing severe limb and skeletal defects. The exposure of gestation day nine murine embryos to hydroxyurea elicits an early embryonic stress response that involves activation of the P53 transcription factor. The impact of this P53 activation on the embryotoxicity of hydroxyurea- is not known. The goal of this study was to test the hypothesis that P53 acts to suppress hydroxyurea embryotoxicity. Trp53+/− timed pregnant mice were treated with saline or hydroxyurea (200 or 400 mg/kg) on gestation day nine; fetuses were examined for viability and external and skeletal malformations on gestation day eighteen. Neither the deletion of Trp53 nor hydroxyurea treatment significantly affected fetal growth although a trend towards a decrease in fetal weights was observed in Trp53-/- fetuses. However, hydroxyurea induced a significantly higher incidence of malformations and resorptions in Trp53-/- fetuses compared to their wildtype littermates. Thus, fetal P53 genotype is an important determinant of the effects of hydroxyurea on organogenesis-stage embryos.

Protective Effects of Liquiritigenin against Citrinin-Triggered, Oxidative-Stress-Mediated Apoptosis and Disruption of Embryonic Development in Mouse Blastocysts.

The mycotoxin citrinin (CTN), a natural contaminant in foodstuffs and animal feeds, exerts cytotoxic and genotoxic effects on various mammalian cells and embryos. A previous investigation by our group revealed potentially hazardous effects of CTN on mouse oocyte maturation and pre- and post-implantation embryo development via the induction of apoptosis. The present study showed that CTN induces apoptosis and inhibits cell proliferation in the inner cell mass of mouse blastocysts. Notably, we observed for the first time that both these effects are suppressed by liquiritigenin (LQ). LQ is a type of flavonoid isolated from Glycyrrhiza radix with several biochemical and pharmacological activities, including antioxidant and anti-inflammatory properties. The preincubation of blastocysts with LQ clearly prevented CTN-induced disruption of pre- and post-implantation embryonic development and fetal weight loss, both in vitro and in vivo. CTN-induced damage processes directly promoted reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential (MMP) and activation of caspase-9 and caspase-3, which were effectively blocked by LQ. Moreover, in an animal model, intravenous injection of dams with CTN (3 mg/kg/day) triggered apoptosis of blastocysts, disruption of embryonic development from the zygote to the blastocyst stage and a decrease in fetal weight. Pre-injection with LQ (5 mg/kg/day) effectively reduced apoptosis and impaired the cytotoxic effects of CTN on development. Our in vivo findings further confirm that CTN exposure via injection has the potential to impair pre- and post-implantation development, leading to apoptosis and the suppression of sequent embryonic development, which can be effectively prevented by LQ.