Prenatal prednisone exposure disturbs fetal kidney development and its characteristics.

Prednisone is a synthetic glucocorticoid that is commonly used in both human and veterinary medication. Now, it is also recognized as an emerging environmental contaminant. Pregnant women may be exposed to prednisone actively or passively through multiple pathways and cause developmental toxicity to the fetus. However, the impact of prenatal prednisone exposure (PPE) on fetal kidney development remains unclear. In this study, pregnant mice were administered prednisone intragastrically during full-term pregnancy with different doses (0.25, 0.5, or 1 mg/(kg·day)), or at the dose of 1 mg/(kg·day) in different gestational days (GD) (GD0-9, GD10-18, or GD0-18). The pregnant mice were euthanized on GD18. HE staining revealed fetal kidney dysplasia, with an enlarged glomerular Bowman's capsule space and a reduced capillary network in the PPE groups. The expression of the podocyte and the mesangial cell marker genes was significantly reduced in the PPE groups. However, overall gene expression in renal tubules and collecting ducts were markedly increased. All of the above effects were more pronounced in high-dose, full-term pregnancy, and female fetuses. Studies on the mechanism of the female fetal kidney have revealed that PPE reduced the expression of Six2, increased the expression of Hnf1ß, Hnf4α, and Wnt9b, and inhibited the expression of glial cell line-derived neurotrophic factor (GDNF) and Notch signaling pathways. In conclusion, this study demonstrated that there is a sex difference in the developmental toxicity of PPE to the fetal kidney, and the time effect is manifested as full-term pregnancy > early pregnancy > mid-late pregnancy.

Lack of effects on female fertility or pre- and postnatal development of offspring in rats after exposure to AS03-adjuvanted recombinant plant-derived virus-like particle vaccine candidate for COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulting in the coronavirus disease 2019 (COVID-19) has afflicted tens of millions of people in a worldwide pandemic. A recently developed recombinant Plant-Derived Virus-Like Particle Vaccine candidate for COVID-19 (CoVLP) formulated with AS03 has been shown to be well-tolerated and highly immunogenic in healthy adults. Since the target population for the vaccine includes women of childbearing potential, the objective of the study was to evaluate any untoward prenatal and postnatal effects of AS03-adjuvanted CoVLP administered intramuscularly to Sprague-Dawley female rats before cohabitation for mating (22 and 8 days prior) and during gestation (Gestation Days [GD] 6 and 19). The embryo-fetal development (EFD) cohort was subjected to cesarean on GD 21 and the pre/post-natal (PPN) cohort was allowed to naturally deliver. Effects of AS03-adjuvanted CoVLP was evaluated on pregnant rats, embryo-fetal development (EFD), during parturition, lactation and the development of the F1 offspring up to weaning Vaccination with AS03-adjuvanted CoVLP induced an antibody response in F0 females and anti-SARS-CoV-2 spike-specific maternal antibodies were detected in the offspring at the end of the gestation and lactation periods. Overall, there was no evidence of untoward effects of AS03-adjuvanted CoVLP on the fertility or reproductive performance of the vaccinated F0 females. There was no evidence of untoward effects on embryo-fetal development (including teratogenicity), or early (pre-weaning) development of the F1 offspring. These results support the acceptable safety profile of the AS03-adjuvanted CoVLP vaccine for administration to women of childbearing potential.

Investigation of teratogenic effects of letrozole on fetal bone development / Investigación de los efectos teratogénicos de letrozol en el desarrollo óseo fetal

SUMMARY: Letrozole is mainly used for the treatment of unexplained infertility, breast cancer and polycystic ovarian syndrome, with secondary use in ovarian stimulation. In cases of unexpected or unknown pregnancy during the use of letrozole, letrozole may cause a teratogenic effect on the fetus. In this reason, in this study, we aimed to determine the effect of letrozole on fetal bone development. In this study, 32 pregnant Wistar albino rats were used. The rats were divided into four groups: Control (saline) and high; 0.3 mg/kg, medium; 0.03 mg/kg, low; 0.003 mg/ kg letrozole. Saline and letrozole were administered in 100 mL solutions by intraperitonaly from day 11 to day 15 of pregnancy. The skeletal system development of fetuses was examined with double skeletal staining, immunohistochemical staining methods and mineral density scanning electron microscopy. A total of 100 fetuses from female rats, 25 in each group, were included in the study. As a result of that, ossification rates were observed to decrease depending on the dose of letrozole in the forelimb limb (scapula, humerus, radius, ulna) and hindlimb (femur, tibia, fibula) limb bones. As a result of the statistical analysis, a statistically significant decrease was found in the ossification rates of all bones between the control group and low, medium, high letrozole groups (p<0.001). Exposure to letrozole during pregnancy adversely affected ossification and bone growth. However, the teratogenic effects of letrozole are unclear. Therefore, it needs to be investigated more extensively.

RESUMEN: Letrozol se usa principalmente para el tratamiento de la infertilidad inexplicable, el cáncer de mama y el síndrome de ovario poliquístico, con estimulación ovárica de uso secundario. En casos de embarazo inesperado o desconocido durante el uso de letrozol, puede causar un efecto teratogénico en el feto. Por esta razón, en este estudio, nuestro objetivo fue determinar el efecto de letrozol en el desarrollo óseo fetal. Se utilizaron 32 ratas albinas Wistar preñadas las cuales se distribuyeron en cuatro grupos: Control (solución salina) y alta; 0,3 mg/kg, medio; 0,03 mg/kg, bajo; 0,003 mg/kg de letrozol. Se administró solución salina y letrozol en soluciones de 100 mL por vía intraperitoneal desde el día 11 hasta el día 15 de la preñez. El desarrollo del sistema esquelético de los fetos se examinó con tinción esquelética doble, métodos de tinción inmunohistoquímica y microscopía electrónica de barrido de densidad mineral. Se incluyeron en el estudio un total de 100 fetos de ratas hembra, 25 en cada grupo. Como resultado, se observó que las tasas de osificación disminuían dependiendo de la dosis de letrozol en los huesos de los miembros torácicos (escápula, húmero, radio, ulna) y de las miembros pélvicos (fémur, tibia, fíbula). Se encontró una disminución estadísticamente significativa en las tasas de osificación de todos los huesos entre el grupo control y los grupos de letrozol bajo, medio y alto (p<0,001). La exposición a letrozol durante la preñez afectó negativamente la osificación y el crecimiento óseo. Sin embargo, los efectos teratogénicos del letrozol no están claros por lo que debe ser investigado más extensamente.

Thyroxine Supplementation in Pregnant Women After Thyroidectomy for Thyroid Cancer and Neonatal Birth Weight.

Patients are often supplemented with a sufficient dose of thyroxine after thyroidectomy for thyroid cancer. However, the influence of thyroxine supplementation on fetal growth in pregnant women after thyroidectomy for thyroid cancer remains unclear. The aim of this study was to investigate the effect of thyroxine supplementation on neonatal birth weight. This cohort study included 49,896 pregnant women (278 patients with a history of thyroidectomy for thyroid cancer and 39,363 control cases after exclusion). Thyroid parameters were examined in pregnant women and their newborns. The associations between maternal thyroid function and neonatal birth weight and small for gestational age were studied using regression analyses. In the levothyroxine supplementation group, free thyroxine (FT4) levels were significantly higher in both early pregnancy (P < 0.001) and late pregnancy (P < 0.001) groups than in the control group. Furthermore, levels of neonatal thyroid stimulating hormone (P = 0.032) and birth weight (P = 0.043) were significantly lower than those in the control group. We also observed a significant inverse association between maternal FT4 levels in early pregnancy and neonatal birth weight (P=0.028), especially in male newborns (P=0.036). In summary, after thyroidectomy for thyroid cancer, a sufficient dose of thyroxine supplementation in early pregnancy is significantly associated with reduced birth weight and may need to be monitored.

Mechanisms underlying cognitive impairment induced by prenatal nicotine exposure: a literature review.

Human and animal studies have conclusively shown that prenatal nicotine exposure alters fetal brain development and causes persistent impairment in the cognitive function of offspring. However, the mechanisms underlying the effect of prenatal nicotine exposure on cognitive function in offspring are still unclear. The objective of this review is to discuss the published studies on the mechanisms underlying the effects of prenatal nicotine exposure on cognitive impairment and discuss the potential mechanisms of action. The findings of the reviewed studies show that the main mechanisms involved are alteration in the composition of nicotinic acetylcholine receptor subunits, increase in surface expression of the glutamate receptor subunit GluR2, a reduction in neurogenesis, alteration of Akt and ERK1/2 activity, and mitochondrial dysfunction in the hippocampus and cortex. These pathways could shed light on future molecular markers and therapeutic targets for the prevention and treatment of cognitive dysfunction induced by prenatal nicotine exposure.

Maternal magnolol supplementation alters placental morphology, promotes placental angiogenesis during mid-gestation and improves offspring growth in a pregnant mouse model.

The placenta is the organ that determines the growth of the fetus and the outcome of pregnancy. Magnolol is a multifunctional polyphenol with antioxidant, anti-inflammatory, anticancer and neuroprotective functions. However, there is less knowledge of the effects or complications in the placenta and the mechanism underlying the effect of magnolol when used during pregnancy. The aim of this study was to explore the effects of maternal magnolol supplementation on pregnancy outcomes and placental alterations in a pregnant mouse model. A total of 128 pregnant mice were randomly divided into 4 groups supplemented with 0, 40, 80 and 160 µM magnolol from gestational day 0 (GD0) to delivery. Our results revealed that the number of large-for-gestation-age fetuses on GD13 and the weaning weight of offspring were increased in the magnolol treatment groups. Moreover, maternal magnolol supplementation increased superoxide dismutase (SOD), decreased malondialdehyde (MDA) in maternal serum, and promoted the expression of heme oxygenase-1 (HO-1) in the placenta. Furthermore, magnolol significantly increased the area of the junctional zone and decidua in the placentas and increased the expression of interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), chemokine (CC Motif) Ligand 3 (CCL3), chemokine (CXC motif) ligand 10 (CXCL10), insulin-like growth factor-1 (IGF-1) and T-box transcription factor 21 (T-bet) in the placenta during GD13 in pregnant mice, while suppressor of cytokine signaling 1 (SOCS1) was reduced. Moreover, the ratio of blood space in the labyrinth area, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were all increased in the magnolol treatment groups on GD13. Taken together, these results indicate that magnolol can improve the growth of offspring, which might be due to the alteration of placental morphology and the promotion of placental angiogenesis during mid-gestation.

Transcriptomic, proteomic, and metabolomic analyses identify candidate pathways linking maternal cadmium exposure to altered neurodevelopment and behavior.

Cadmium (Cd) is a ubiquitous toxic heavy metal of major public concern. Despite inefficient placental transfer, maternal Cd exposure impairs fetal growth and development. Increasing evidence from animal models and humans suggests maternal Cd exposure negatively impacts neurodevelopment; however, the underlying molecular mechanisms are unclear. To address this, we utilized multiple -omics approaches in a mouse model of maternal Cd exposure to identify pathways altered in the developing brain. Offspring maternally exposed to Cd presented with enlarged brains proportional to body weights at birth and altered behavior at adulthood. RNA-seq in newborn brains identified exposure-associated increases in Hox gene and myelin marker expression and suggested perturbed retinoic acid (RA) signaling. Proteomic analysis showed altered levels of proteins involved in cellular energy pathways, hypoxic response, and RA signaling. Consistent with transcriptomic and proteomic analyses, we identified increased levels of retinoids in maternally-exposed newborn brains. Metabolomic analyses identified metabolites with significantly altered abundance, supportive of changes to cellular energy pathways and hypoxia. Finally, maternal Cd exposure reduced mitochondrial DNA levels in newborn brains. The identification of multiple pathways perturbed in the developing brain provides a basis for future studies determining the mechanistic links between maternal Cd exposure and altered neurodevelopment and behavior.

Intergenerational genetic programming mechanism and sex differences of the adrenal corticosterone synthesis dysfunction in offspring induced by prenatal ethanol exposure.

We previously found that prenatal ethanol exposure (PEE) induced adrenal dysplasia in offspring, which was related to intrauterine maternal glucocorticoid overexposure. This study investigated the intergenerational genetic effect and sex differences of PEE-induced changes in the synthetic function of adrenal corticosterone in offspring, and to clarify the intrauterine origin programming mechanism. Wistar pregnant rats were gavaged with ethanol (4 g/kg bw/d) from gestation day (GD) 9-20, and F1 generation was born naturally. The F1 generation female rats in the PEE group were mated with normal male rats to produce F2 generation. Serum and adrenal glands of fetal rats and F1/F2 adult rats were collected at GD20 and postnatal week 28. PEE increased the serum corticosterone level, while diminishing the expression of adrenal steroid synthases of fetal rats. Moreover, PEE enhanced the mRNA expression of GR and HDAC1, but inhibited the mRNA expression of SF1 and reduced the H3K9ac level of P450scc in the fetal adrenal gland. In PEE adult offspring of F1 and F2 generation the serum corticosterone level, the H3K9ac level of P450scc and its expression were decreased in males but were increased in females. In NCI-H295R cells, cortisol reduced the production of endogenous cortisol, down-regulated SF1, and up-regulated HDAC1 expression by activating GR, and decreased H3K9ac level and expression of P450scc. In conclusion, PEE could induce adrenal dysplasia in offspring with sex differences and intergenerational genetic effects, and the adrenal insufficiency in male offspring was related to the induction of low functional genetic programming of P450scc by intrauterine high corticosterone through the GR/SF1/HDAC1 pathway.

Effects of bis(2-butoxyethyl) phthalate exposure in utero on the development of fetal Leydig cells in rats.

Phthalates are plasticizers widely found in the environment. They are potential endocrine disruptors. Bis(2-butoxyethyl) phthalate (BBOP) is a unique phthalate that contains oxygen atoms in the carbon backbone. Little is known about its reproductive and developmental toxicity. The objective of this study was to determine the effect of BBOP on fetal Leydig cell development after in utero exposure to rats. Sprague Dawley pregnant dams were randomly allocated into 6 groups, and were gavaged with BBOP (0, 10, 100, 250, 500, and 1000 mg/kg body weight/day) from gestational day (GD) 14-21. Seven of the 8 dams in the 1000 mg/kg BBOP group died before giving birth. Twelve of the 20 dams in the 500 mg/kg BBOP group had whole litter loss. BBOP significantly reduced the body weight of dams and male offspring and serum testosterone level and anogenital distance of male fetus on GD 21 at 500 mg/kg. BBOP markedly increased fetal Leydig cell proliferation and number at 500 mg/kg while inducing their abnormal aggregation at 250 and 500 mg/kg. BBOP down-regulated the expression of Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Insl3, and Nr5a1 at various doses while up-regulating the expression of Sertoli cell gene Fshr and Sox9. The phosphorylation of AKT1, AKT2, and ERK1/2 was also markedly reduced by BBOP. In conclusion, BBOP in utero exposure can disrupt fetal Leydig cell development, possibly via the mechanism that may include inhibiting the phosphorylation of AKT1, AKT2, and ERK1/2.

Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth.

Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.

Bisphenol a Interferes with Uterine Artery Features and Impairs Rat Feto-Placental Growth.

Bisphenol A (BPA) is a widespread environmental contaminant, found in human fluids and tissues. Maternal BPA exposure is associated with alterations in pregnancy outcomes. Because maternal uterine circulation plays a crucial role in normal placenta and fetal growth, we hypothesized that BPA compromises the function of uterine arteries (UAs) and fetoplacental development. Female rats were orally administered with BPA (2.5, 25 and 250 µg/kg/day) or with its vehicle (ethanol) for 30 days before pregnancy and during the first 20 days of pregnancy. To compare the effect of BPA in the reproductive vs. systemic circulation, it was tested on UAs and mesenteric arteries (MAs). Arteries were isolated and examined by pressure myography. Moreover, fetuses and placentas were weighed to provide an index of reproductive performance. In UAs of BPA-treated rats, lumen diameter, acetylcholine-relaxation and expressions of endothelial nitric oxide synthase 3 (NOS3), estrogen receptor α (ERα) and peroxisome proliferator-activated receptor É£ (PPARÉ£) were reduced. Conversely, no changes were observed in MAs. BPA treatment also reduced placental weights, while fetal weights were increased. For the first time, our results indicate that UAs represent a specific target of BPA during pregnancy and provide insight into the molecular mechanisms that underlie its negative effects on pregnancy outcomes.

Effects of inorganic copper injection in beef cows at late gestation on fetal and postnatal growth, hematology and immune function of their progeny.

To determine if Cu injection during late gestation can affect fetal and postnatal growth, hematology and immune function of progeny, 70 multiparous pregnant Angus cows, at 219 ± 15 d of gestation, were ranked by BW and BCS and randomly assigned to one of two treatments: Cu + (n = 35) in total 160 mg of Cu were administered subcutaneously in two moments (80 mg per moment) at 64 ± 15 d and 54 ± 15 d prepartum; and Cu- (n = 35), in total of 16 ml of sterile NaCl solution (9 g / l) were administered subcutaneously in two moments (8 ml per moment) at 64 ± 15 d and 54 ± 15 d prepartum. Calves from both treatments were weaned at 260 ± 15 d of age, male calves were separated from female calves and stockered on natural pastures until 690 ± 15 d of age, then placed into a feedlot for 104 d before slaughter. At the beginning of the experiment, cows Cu serum concentration was similar (P = 0.34) between treatments and these reflected a severe Cu deficiency (Cu + = 24.2 ± 1.5 µg/dl; Cu- = 22.2 ± 1.4 µg/dl). At calving, Cu serum concentration was greater (P < 0.01) in Cu + cows than Cu- cows. Copper serum concentration in calves from Cu + cows was greater at birth (P = 0.02) and 75 ± 15 d of age (P < 0.01) and tended (P = 0.07) to be greater at 160 ± 15 d of age compared to calves from Cu- cows. Calf BW at birth did not differ (P > 0.10) between treatments, however, calf BW adjusted at 75 d of age tended to be greater (P = 0.10) in calves from Cu + cows compared to calves from Cu- cows. Calf ADG from birth to 75 d of age was greater (P = 0.04) in calves from Cu + cows compared to calves from Cu- cows. Calf hematological parameters and titers of neutralizing antibodies against BHV-1 after primary and secondary vaccination against respiratory diseases did not differ (P > 0.10) between treatments. During finishing period, steers BW, 12th rib fat thickness and LM area were not affected (P > 0.10) by treatments. In summary, inorganic Cu injection during late gestation in Cu deficient beef cows allows to increase Cu serum concentration in calves from birth to 160 d of age. This event was associated with an increase in ADG and a tendency to increase BW during the first 75 days of life. After 75 days of age, any effect on the offspring performance was not observed.

Does maternal exposure to nicotine affect the oocyte quality and reproductive capacity in adult offspring?

Gonadal development begins in the intrauterine phase and females from most species are born with an established oocyte reserve. Exposure to drugs during gestation can compromise the offspring health, also affecting the gametes quality. Nicotine, the main component of cigarettes, is an oxidant agent capable of altering the fertility in men and women. As female gametes are susceptible to oxidative stress, this drug can damage the oolemma and affect oocyte maturation, induce errors during chromosomal segregation and DNA fragmentation. Oocyte mitochondria are particularly susceptible to injuries, contributing to the oocyte quality loss and embryonic development disruption. Thus, considering the high number of women who smoke during pregnancy, while significant events are occurring in the embryo for future fertility of offspring, we seek to verify the quality of the oocytes from adult rats exposed to nicotine during intrauterine phase and breastfeeding. Pregnant Wistar rats received nicotine by osmotic mini-pumps and the female progenies were evaluated in adulthood for oocyte quality (viability, lipid peroxidation, generation of reactive oxygen species and mitochondrial integrity) and reproductive capacity. Embryos (3dpc) and fetuses (20dpc) generated by these rats were also evaluated. The results showed that the dose of 2 mg/kg/day of nicotine through placenta and breast milk does not affect the number of oocytes and the fertility capacity of adult rats. However, it causes some morphological alterations in oocytes, mitochondrial changes, embryonic fragmentation and disruption of fetal development. The malformations in fetuses generated from these gametes can also indicate the occurrence of epigenetic modifications.

Association of Chemotherapy Timing in Pregnancy With Congenital Malformation.

Importance: Chemotherapy during the first trimester of pregnancy should be avoided owing to the risk of congenital malformations. However, the precise gestational age at which chemotherapy can be initiated safely remains unclear. Objective: To assess congenital malformation rates associated with gestational age at initiation of chemotherapy among pregnant women with cancer. Design, Setting, and Participants: This multicenter cohort study evaluated all pregnant women who received chemotherapy between 1977 and 2019 registered in the International Network on Cancer, Infertility and Pregnancy (INCIP) database. Data were analyzed from February 15 to June 2, 2020. Exposures: Cancer treatment with chemotherapy during pregnancy. Main Outcomes and Measures: Analysis was focused on major and minor structural malformations in offspring, defined by EUROCAT, detected during pregnancy or at birth. Results: A total of 755 women in the INCIP database who underwent cancer treatment with chemotherapy during pregnancy were included in analysis. The median (range) age at cancer diagnosis was 33 (14-48) years. Among offspring, the major congenital malformation rate was 3.6% (95% CI, 2.4%-5.2%), and the minor congenital malformation rate was 1.9% (95% CI, 1.0%-3.1%). Chemotherapy exposure prior to 12 weeks gestational age was associated with a high rate of major congenital malformations, at 21.7% (95% CI, 7.5%-43.7%; odds ratio, 9.24 [95% CI, 3.13-27.30]). When chemotherapy was initiated after gestational age 12 weeks, the frequency of major congenital malformations was 3.0% (95% CI, 1.9%-4.6%), which was similar to the expected rates in the general population. Minor malformations were comparable when exposure occurred before or after gestational age 12 weeks (4.3% [95% CI, 0.1%-21.9%] vs 1.8% [95% CI, 1.0-3.0]; odds ratio, 3.13 [95% CI, 0.39-25.28]). Of 29 women who received chemotherapy prior to 12 weeks gestation, 17 (58.6%) were not aware of pregnancy, and 6 (20.7%) experienced a miscarriage (3 women [10.3%]) or decided to terminate their pregnancy (3 women [10.3%]). Conclusions and Relevance: This cohort study found that chemotherapy was associated with an increased risk of major congenital malformations only in the first 12 weeks of pregnancy. The risk of congenital malformations when chemotherapy was administered during the first trimester and the high number of incidental pregnancies during cancer treatment in the INCIP registry underscore the importance of contraceptive advice and pregnancy testing at the start of chemotherapeutic treatment in young women with cancer.

Ironing out mechanisms of iron homeostasis and disorders of iron deficiency.

Iron plays an important role in mammalian physiological processes. It is a critical component for the function of many proteins, including enzymes that require heme and iron-sulfur clusters. However, excess iron is also detrimental because of its ability to catalyze the formation of reactive oxygen species. As a result, cellular and systemic iron levels are tightly regulated to prevent oxidative damage. Iron deficiency can lead to a number of pathological conditions, the most prominent being anemia. Iron deficiency should be corrected to improve adult patients' symptoms and to facilitate normal growth during fetal development and childhood. However, inappropriate use of intravenous iron in chronic conditions, such as cancer and heart failure, in the absence of clear iron deficiency can lead to unwanted side effects. Thus, this form of therapy should be reserved for certain patients who cannot tolerate oral iron and need rapid iron replenishment. Here, we will review cellular and systemic iron homeostasis and will discuss complications of iron deficiency.

Maternal smoking during pregnancy and intelligence quotient in offspring: A systematic review and meta-analysis.

BACKGROUND: Exposure to tobacco during pregnancy may disrupt fetal brain development and impact offspring cognitive development. AIMS: To perform a systematic review and meta-analysis on maternal smoking during pregnancy and intelligence quotient (IQ) in childhood, adolescence, and adulthood. METHODS: We searched PubMed, Lilacs, PsycINFO, and Web of Science. Original articles evaluating tobacco use/exposure during pregnancy and the offspring's IQ as the outcome. The review protocol is registered in PROSPERO (number CRD 42,019,116,257). For the meta-analysis, we included studies with information on the regression coefficient and its confidence interval (CI) or standard error. Random effects model was used for pooling the estimates. RESULTS: 25 studies were included in the review, and of these 14 met the inclusion criteria for the meta-analysis. The overall pooled estimate showed that subjects who were exposed to maternal smoking during pregnancy presented lower IQ scores, compared to those not exposed to maternal smoking (ß -1.30; 95 % CI -1.74, -0.86; I2 = 87.8 %); IQ scores were also lower in crude (ß -5.46; 95 % CI -7.31, -3.60; I²: 79.0 %) and adjusted pooled estimates (ß =-0.45; 95 % CI -0.76, -0.13; I2 = 80.4 %), for the group exposed to maternal smoking. In the stratified analysis, an inverse association was also observed in studies with large sample size (n≥1000 participants) (ß=-0.49; 95 % CI -0.96, -0.02), among those performed with adolescents (ß=-1.16; 95 % CI -2.18, -0.14), and among those adjusted for maternal education (ß=-0.57; 95 % CI -1.05, -0.08). CONCLUSIONS: Our findings suggest that exposure to tobacco during pregnancy may have negative effects on IQ. However, the findings of this meta-analysis should be interpreted with caution.

Lycopene Modulates Placental Health and Fetal Development Under High-Fat Diet During Pregnancy of Rats.

Lycopene plays an important role in improving immunity, promoting antioxidant capacity, and regulating fat metabolism. The placenta, an important organ for nutrients exchange between mother and child during pregnancy, directly affects fetal development. This study aims to characterize effects of lycopene on placental health and fetal development under a high-fat diet, and utilize RNA sequencing (RNA-seq) to investigate and integrate the differences of molecular pathways and biological processes in placenta. For placental health, high-fat diet during pregnancy increases placental oxidative stress, inflammation, and fat deposition. However, lycopene reduces the negative effects of high-fat diet on placenta to some extent, and further promotes fetal development. Under high-fat diet, lycopene reduces the levels of Interleukin 17 (IL-17), Interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) in placenta (p < 0.05) through the IL-17 pathway. Furthermore, lycopene supplementation in high-fat diet increases Glutaredoxin (Glrx) gene and protein expression in the placenta (p < 0.05), increases Glutathione peroxidase (GSH-Px) and Total antioxidant capacity (T-AOC) levels (p < 0.05), decreases reactive oxygen species (ROS) (p < 0.01) and Hydrogen peroxide (H2 O2 ) levels (p < 0.05) in placenta. In addition, lycopene supplementation in high fat diet increases the expression of Lep gene and protein in placenta and increases the level of leptin (p < 0.05). In terms of fetal development, the average fetal weight and fetal litter weight are increased by lycopene compared to high-diet treatment.

Effects of general anaesthesia during pregnancy on neurocognitive development of the fetus: a systematic review and meta-analysis.

BACKGROUND: The US Food and Drug Administration warned that exposure of pregnant women to general anaesthetics may impair fetal brain development. This review systematically evaluates the evidence underlying this warning. METHODS: PubMed, EMBASE, and Web of Science were searched from inception until April 3, 2020. Preclinical and clinical studies were eligible. Exclusion criteria included case reports, in vitro models, chronic exposures, and exposure only during delivery. Meta-analyses were performed on standardised mean differences. The primary outcome was overall effect on learning/memory. Secondary outcomes included markers of neuronal injury (apoptosis, synapse formation, neurone density, and proliferation) and subgroup analyses. RESULTS: There were 65 preclinical studies included, whereas no clinical studies could be identified. Anaesthesia during pregnancy impaired learning and memory (standardised mean difference -1.16, 95% confidence interval -1.46 to -0.85) and resulted in neuronal injury in all experimental models, irrespective of the anaesthetic drugs and timing in pregnancy. Risk of bias was high in most studies. Rodents were the most frequently used animal species, although their brain development differs significantly from that in humans. In a minority of studies, anaesthesia was combined with surgery. Monitoring and strict control of physiological homeostasis were below preclinical and clinical standards in many studies. The duration and frequency of exposure and anaesthetic doses were often much higher than in clinical routine. CONCLUSION: Anaesthesia-induced neurotoxicity during pregnancy is a consistent finding in preclinical studies, but translation of these results to the clinical situation is limited by several factors. Clinical observational studies are needed. PROSPERO REGISTRATION NUMBER: CRD42018115194.

Fetal methylphenidate exposure induced ADHD-like phenotypes and decreased Drd2 and Slc6a3 expression levels in mouse offspring.

Methylphenidate (MPD) is used as a first-line treatment for attention-deficit/hyperactivity disorder (ADHD). The number of prescriptions for ADHD patients is increasing, suggesting that the number of fertile women using such medication might be also increasing. The purpose of this study was to clarify the effects of MPD exposure during the fetal period on infant development, behavior, learning, and memory in mice. Expression levels of candidate genes associated with ADHD were also determined in the brain of pups born to MDP-treated dams who were administered MPD orally at a dose of 2.5, 7.5, or 15 mg/kg daily from gestational day 1 to the day before delivery. Offspring aged 6-8 weeks were subjected to the spontaneous locomotor activity, elevated plus-maze, and passive avoidance tests and therapeutic treatments with MPD or atomoxetine. Fetal MPD exposure induced ADHD-like phenotypes, such as hyperactivity and impulsivity, in mouse offspring, which were suppressed by treatment with MPD and atomoxetine. These mice showed decreased Drd2 and Slc6a3 expression levels in the brain, which are often observed in ADHD model animals. Our results suggest that continuous use of MPD during pregnancy induces ADHD phenotypes in the offspring.

Exposure to 4-bromodiphenyl ether during pregnancy blocks testis development in male rat fetuses.

4-Bromodiphenyl ether (BDE3) is a photodegradation product of higher polybrominated diphenyl ether flame retardants and is known as an endocrine disruptor. However, it is unclear whether and how BDE3 affects the development of fetal testes. This study aimed to investigate the effect of in utero exposure to BDE3 on fetal testicular development in rats. From gestational day (GD) 12-21, BDE3 (0, 50, 100, and 200 mg/kg) was daily gavaged to female pregnant Sprague Dawley rats. BDE3 significantly reduced serum testosterone levels of male pups starting at 50 mg/kg. BDE3 reduced fetal Leydig cell number at a dose of 200 mg/kg without affecting fetal Leydig cell cluster frequency and Sertoli cell number. In addition, BDE3 down-regulated the expression of fetal Leydig cell genes (Cyp11a1, Hsd3b1, Cyp17a1, and Hsd17b3) and their proteins at 100 and/or 200 mg/kg. RNA-seq analysis showed that genes responsive to cAMP (Ass1, Gpd1, Rpl13a) were down-regulated and hypoxia-related genes (Egln3 and P4ha1) were up-regulated at 200 mg/kg. In utero exposure to BDE3 can promote autophagy and apoptosis of fetal Leydig cells via increasing the levels of Beclin1, LC3-II, BAX, and by decreasing the levels of p62 and BCL2. In conclusion, in utero exposure to BDE3 blocks the development of fetal rat testes.