Maternal dietary cholesterol and egg intake during pregnancy and large-for-gestational-age infants: a prospective cohort study.

BACKGROUND: Cholesterol plays a vital role in fetal growth and development during pregnancy. There remains controversial over whether pregnant women should limit their cholesterol intake. OBJECTIVES: To investigate the association between maternal dietary cholesterol intake during pregnancy and infant birth weight in a Chinese prospective cohort study. METHODS: A total of 4,146 mother-child pairs were included based on the Jiangsu Birth Cohort (JBC) study. Maternal dietary information was assessed with a semi-quantitative food-frequency questionnaire (FFQ). Birth weight z-scores and large-for-gestational-age (LGA) infants were converted by the INTERGROWTH-21st neonatal weight-for-gestational-age standard. Poisson regression and generalized estimating equations (GEE) were employed to examine the relationships between LGA and maternal dietary cholesterol across the entire pregnancy and trimester-specific cholesterol intake, respectively. RESULTS: The median intake of maternal total dietary cholesterol during the entire pregnancy was 671.06 mg/d, with eggs being the main source. Maternal total dietary cholesterol and egg-sourced cholesterol were associated with an increase of birth weight z-score, with per SD increase in maternal total and egg-sourced dietary cholesterol being associated with an increase of 0.16 (95% CI: 0.07, 0.25) and 0.06 (95% CI: 0.03, 0.09) in birth weight z-score, respectively. Egg-derived cholesterol intake in the first and third trimesters were positively linked to LGA, with adjusted relative risk (aRR) of 1.11 (95% CI: 1.04, 1.18) and 1.09 (95% CI: 1.00, 1.18). Compared to mothers consuming ≤7 eggs/week in the third trimester, aRR for having LGA newborn was 1.37 (95% CI: 1.09, 1.72) for consuming 8-10 eggs/week and 1.45 (95% CI: 1.12, 1.86) for consuming >10 eggs/week (p for trend=0.015). CONCLUSIONS: Maternal total dietary cholesterol intake, as well as consuming over 7 eggs/week during pregnancy displayed significant positive relationships with the incidence of LGA, suggesting that mothers should avoid excessive cholesterol intake during pregnancy to prevent adverse birth outcomes.

Phthalate and DINCH exposure and ovarian reserve markers among women seeking infertility care.

Phthalate exposure can adversely impact ovarian reserve, yet investigation on the influence of its alternative substance, the non-phthalate plasticizer diisononyl-cyclohexane-1,2-dicarboxylate (DINCH), on ovarian reserve is very sparce. We aimed to investigate the associations of phthalate and DINCH exposure as well as their combined mixture with ovarian reserve. This present study included 657 women seeking infertility care in Jiangsu, China (2015-2018). Urine samples during enrollment prior to infertility treatment were analyzed using high-performance liquid chromatography-isotope dilution tandem mass spectrometry (UPLC-MS/MS) to quantify 17 phthalate metabolites and 3 DINCH metabolites. Multivariate linear regression models, Poisson regression models and weighted quantile sum (WQS) regression were performed to access the associations of 17 urinary phthalate metabolites and 3 DINCH metabolites with ovarian reserve markers, including antral follicle count (AFC), anti-Mullerian hormone (AMH), and follicle-stimulating hormone (FSH). We found that the most conventional phthalates metabolites (DMP, DnBP, DiBP, DBP and DEHP) were inversely associated with AFC, and the DINCH metabolites were positively associated with serum FSH levels. The WQS index of phthalate and DINCH mixtures was inversely associated with AFC (% change = -8.56, 95 % CI: -12.63, -4.31) and positively associated with FSH levels (% change =7.71, 95 % CI: 0.21, 15.78). Our findings suggest that exposure to environmental levels of phthalate and DINCH mixtures is inversely associated with ovarian reserve.

Gsw-fi: a GLM model incorporating shrinkage and double-weighted strategies for identifying cancer driver genes with functional impact.

BACKGROUND: Cancer, a disease with high morbidity and mortality rates, poses a significant threat to human health. Driver genes, which harbor mutations accountable for the initiation and progression of tumors, play a crucial role in cancer development. Identifying driver genes stands as a paramount objective in cancer research and precision medicine. RESULTS: In the present work, we propose a method for identifying driver genes using a Generalized Linear Regression Model (GLM) with Shrinkage and double-Weighted strategies based on Functional Impact, which is named GSW-FI. Firstly, an estimating model is proposed for assessing the background functional impacts of genes based on GLM, utilizing gene features as predictors. Secondly, the shrinkage and double-weighted strategies as two revising approaches are integrated to ensure the rationality of the identified driver genes. Lastly, a statistical method of hypothesis testing is designed to identify driver genes by leveraging the estimated background function impacts. Experimental results conducted on 31 The Cancer Genome Altas datasets demonstrate that GSW-FI outperforms ten other prediction methods in terms of the overlap fraction with well-known databases and consensus predictions among different methods. CONCLUSIONS: GSW-FI presents a novel approach that efficiently identifies driver genes with functional impact mutations using computational methods, thereby advancing the development of precision medicine for cancer.

Exposure to particulate matter may affect semen quality via trace metals: Evidence from a retrospective cohort study on fertile males.

Particulate matter (PM) exposure may be associated with male semen quality. Besides, PM exposure induces up and down levels of trace metals in tissues or organs. The levels of trace metals in semen are critical for adverse male semen quality. This study aims to evaluate the concentrations of seminal-level trace metals in fertile men and assess its associations with PM exposure and to explore the mediation role of trace metals in seminal plasma plays in the relationship between PM exposure and semen quality. Total 1225 fertile men who participated in a cohort study from 2014 to 2016 were finally recruited. Multivariate linear regression was applied to explore associations between each two of PM exposure, trace metals and semen parameters. 1-year PM2.5 and PM10 exposure levels were positively associated with arsenic (As), mercury (Hg), lanthanum (La), praseodymium (Pr), neodymium (Nd) but negatively associated with vanadium (V), magnesium (Mg), strontium (Sr), barium (Ba) in semen. It was also found that most of the elements were associated with total sperm number, followed by sperm concentration. Redundancy analysis (RDA) also determined several strong positive correlations or negative correlations between 1-year PM exposure and trace metals. Mediation analysis found that trace metals had a potentially compensatory or synergetic indirect effect on the total effect of the association between 1-year PM exposure and semen quality. The retrospective cohort study provides long-term PM exposure that may cause abnormal semen quality by affecting seminal plasma element levels.

Combined-task deep network based on LassoNet feature selection for predicting the comorbidities of acute coronary syndrome.

Acute coronary syndrome (ACS) is a multifaceted cardiovascular condition frequently accompanied by multiple comorbidities, which can have significant implications for patient outcomes and treatment approaches. Precisely predicting these comorbidities is crucial for providing personalized care and making well-informed clinical decisions. However, there is a shortage of research investigating the identification of risk factors associated with ACS comorbidities and accurately predicting their likelihood of occurrence beyond heart failure. In this study, an approach called Combined-task Deep Network based on LassoNet feature selection (CDNL) is presented for predicting ACS comorbidities, including hypertension, diabetes, hyperlipidemia, and heart failure. In order to identify crucial biomarkers associated with ACS comorbidities, the proposed framework first incorporates LassoNet, which extends Lasso regression to the deep network by adding a skip (residual) layer. Additionally, a correlation score calculation method across tasks is introduced based on measuring the overlap of identified biomarkers and their assigned importance. This method enables the development of an optimal combined-task prediction model for each ACS comorbidity, addressing the challenge of limited representations in traditional multi-task learning. Our evaluation, conducted through a meticulous cross-sectional study at a tertiary hospital in China, involved a dataset of 2941 samples with 42 clinical features. The results demonstrate that CDNL facilitates the identification of significant biomarkers and achieves an average improvement in AUC of 4.93% and 8.58% compared to deep learning multi-layer neural network (DNN) and SVM, respectively. Additionally, it shows an average improvement of 2.64% and 1.92% compared to two state-of-the-art multi-task models.

Predicting anticancer drug sensitivity on distributed data sources using federated deep learning.

Drug sensitivity prediction plays a crucial role in precision cancer therapy. Collaboration among medical institutions can lead to better performance in drug sensitivity prediction. However, patient privacy and data protection regulation remain a severe impediment to centralized prediction studies. For the first time, we proposed a federated drug sensitivity prediction model with high generalization, combining distributed data sources while protecting private data. Cell lines are first classified into three categories using the waterfall method. Focal loss for solving class imbalance is then embedded into the horizontal federated deep learning framework, i.e., HFDL-fl is presented. Applying HFDL-fl to homogeneous and heterogeneous data, we obtained HFDL-Cross and HFDL-Within. Our comprehensive experiments demonstrated that (i) collaboration by HFDL-fl outperforms private model on local data, (ii) focal loss function can effectively improve model performance to classify cell lines in sensitive and resistant categories, and (iii) HFDL-fl is not significantly affected by data heterogeneity. To summarize, HFDL-fl provides a valuable solution to break down the barriers between medical institutions for privacy-preserving drug sensitivity prediction and therefore facilitates the development of cancer precision medicine and other privacy-related biomedical research.

Effect of prenatal perfluoroheptanoic acid exposure on spermatogenesis in offspring mice.

BACKGROUND: Perfluoroheptanoic acid (PFHpA), a persistent organic pollutant widespread in the environment, is suspected as an environmental endocrine disruptor for its disturbance effect on hormone homeostasis and reproductive development. Whereas the effect of intrauterine PFHpA exposure during gestation on spermatogenesis of male offspring mice is still unknown. OBJECTIVE: This study aimed to explore the effect of prenatal PFHpA exposure on the reproductive development of male offspring mice and the role of N6-methyladenosine (m6A) during the process. METHODS: Fifty-six C57BL/6 pregnant mice were randomly divided into 4 groups. During the gestation period, the pregnant mice were exposed to 0, 0.0015, 0.015, and 0.15 mg/kg bw/d PFHpA from gestational day 1 (GD1) to GD16 by oral gavage. The male offspring mice were sacrificed by spinal dislocation at 7 weeks old. The body weight, testicular weight, and brain weight were weighed, and the intra-testicular testosterone was detected. The sperm qualities were analyzed with computer-aided sperm analysis (CASA). The testicular tissues were taken to analyze the pathological changes and examine the global m6A RNA methylation levels. Quantitative real-time PCR (qRT-PCR) was adopted to figure out the mRNA expression levels of m6A-related enzymes in testicular tissues of different PFHpA treated groups. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was applied to further explore the m6A RNA methylation at a whole-genome scale. RESULTS: Compared with the control group, no significant differences were observed in body weight, testicular weight, testicular coefficient, and the visceral-brain ratio of testicular tissue in the PFHpA treated groups. And no significant change was observed in intra-testicular testosterone among the four groups. CASA results showed a decrease of sperm count, sperm concentration, and total cell count, as well as an increase of sperm progressive cells' head area after prenatal PFHpA exposure (P < 0.05). Hematoxylin and eosin staining of pathological sections showed seminiferous tubules morphological change, disorder arrangement of seminiferous epithelium, and reduction of spermatogenic cells in the PFHpA treated groups. PFHpA significantly decreased global levels of m6A RNA methylation in testicular tissue (P < 0.05). Besides, qRT-PCR results showed significant alteration of the mRNA expression levels of seven m6A-related enzymes (Mettl3, Mettl5, Mettl14, Pcif1, Wtap, Hnrnpa2b1, and Hnrnpc) in the PFHpA treated groups (P < 0.05). MeRIP-seq results showed a correlation between prenatal PFHpA exposure and activation and binding of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Cnga3 and Mpzl3 showed differential expression in the enrichment subcategories or pathways. CONCLUSIONS: Exposure to PFHpA during the gestation period would adversely affect the development of seminiferous tubules and testicular m6A RNA methylation in offspring mice, which subsequently interferes with spermatogenesis and leads to reproductive toxicity.

Spatiotemporal transcriptomics and metabolic profiling provide insights into gene regulatory networks during lentil seed development.

Lentil (Lens culinaris Medik.) is a nutritious legume with seeds rich in protein, minerals and an array of diverse specialized metabolites. The formation of a seed requires regulation and tight coordination of developmental programs to form the embryo, endosperm and seed coat compartments, which determines the structure and composition of mature seed and thus its end-use quality. Understanding the molecular and cellular events and metabolic processes of seed development is essential for improving lentil yield and seed nutritional value. However, such information remains largely unknown, especially at the seed compartment level. In this study, we generated high-resolution spatiotemporal gene expression profiles in lentil embryo, seed coat and whole seeds from fertilization through maturation. Apart from anatomic differences between the embryo and seed coat, comparative transcriptomics and weighted gene co-expression network analysis revealed embryo- and seed coat-specific genes and gene modules predominant in specific tissues and stages, which highlights distinct genetic programming. Furthermore, we investigated the dynamic profiles of flavonoid, isoflavone, phytic acid and saponin in seed compartments across seed development. Coupled with transcriptome data, we identified sets of candidate genes involved in the biosynthesis of these metabolites. The global view of the transcriptional and metabolic changes of lentil seed tissues throughout development provides a valuable resource for dissecting the genetic control of secondary metabolism and development of molecular tools for improving seed nutritional quality.

Comprehensive compositional assessment of bioactive compounds in diverse pea accessions.

Pea (Pisum sativum L.) is an important legume crop providing a good source of protein, vitamins, minerals and bioactive compounds with health benefits for humans. In this study, an improved method for simultaneous analysis of multiple phytoestrogens among 100 pea accessions was developed. Ipriflavone, (a synthetic isoflavone), was used as an internal standard for the semiquantitative analysis of 17 phytoestrogens including isoflavone aglycones and conjugates, allowing direct analysis of isoflavones in their naturally occurring forms. This comprehensive dataset demonstrated that the isoflavones varied greatly and some accessions tended to have high levels of multiple phytoestrogens among the 100 accessions analyzed. Isoliquiritigenin followed by glycitein were the predominant compounds detected in the accessions and showed the highest correlation with the total phytoestrogens content. Secoisolariciresinol content was consistently higher in yellow cotyledon peas than in green cotyledon peas, whereas the contents of coumestrol, genestein and secoisolariciresinol were significantly correlated with seed coat color. The total phenolics and saponins showed a wide range of variability among the accessions with higher concentrations of total phenolics observed in seeds with pigmented seed coat or yellow cotyledon seeds, suggesting the synthesis of saponins and phenolics are significantly affected by metabolic pathway genes controlling cotyledon color or seed coat color. This study profiled the variability of bioactive compounds of pea seed quality traits in diverse pea accessions and provides an immense resource for continued research, breeding and selection of genotypes for a wide range of applications.

Prenatal titanium exposure and child neurodevelopment at 1 year of age: A longitudinal prospective birth cohort study.

Previous animal studies provided the evidence that prenatal titanium exposure can cause neurotoxicity in their offspring, while human data is vacant. Our aim was to identify the associations of prenatal titanium exposure with the child neurodevelopment. Participants in present study were recruited during early pregnancy between 2014 and 2017. Urinary concentrations of titanium at first trimester were determined. We assessed child neurodevelopment using the Chinese version of Gesell Developmental Schedules at first year follow-up. The multivariable linear regressions and the robust modified Poisson regressions were used to estimate the associations of specific gravity corrected urinary titanium concentrations with the child neurodevelopment. In adjusted models, children's developmental quotient scores in the language domain were 2.03 points (95% CI: -3.66, -0.40) lower in the highest tertile of prenatal urinary titanium than in the lowest tertile. Also, children with prenatal urinary titanium in the highest tertile had 1.42 times (95% CI: 1.17, 1.72) increased risk of language development delay compared to those in the lowest tertile. No statistically significant associations were observed between titanium exposure and child development delay in motor, adaptive and social areas. The findings indicated that prenatal higher titanium exposure was associated with impaired language development, suggesting that titanium might act as developmental neurotoxicants.

Leukocyte telomere length in children born following blastocyst-stage embryo transfer.

Perinatal and childhood adverse outcomes associated with assisted reproductive technology (ART) has been reported, but it remains unknown whether the initial leukocyte telomere length (LTL), which is an indicator of age-related phenotypes in later life, is affected. Here, we estimated the LTLs of 1,137 individuals from 365 families, including 202 children conceived by ART and 205 children conceived spontaneously from two centers of the China National Birth Cohort, using whole-genome sequencing (WGS) data. One-year-old children conceived by ART had shorter LTLs than those conceived spontaneously (beta, -0.36; P = 1.29 × 10-3) after adjusting for plurality, sex and other potential confounding factors. In particular, blastocyst-stage embryo transfer was associated with shorter LTL (beta, -0.54, P = 2.69 × 10-3) in children conceived by ART. The association was validated in 586 children conceived by ART from five centers using different LTL quantification methods (that is, WGS or qPCR). Blastocyst-stage embryo transfer resulted in shorter telomere lengths in mice at postnatal day 1 (P = 2.10 × 10-4) and mice at 6 months (P = 0.042). In vitro culturing of mice embryos did not result in shorter telomere lengths in the late cleavage stage, but it did suppress telomerase activity in the early blastocyst stage. Our findings demonstrate the need to evaluate the long-term consequences of ART, particularly for aging-related phenotypes, in children conceived by ART.

Persistent visible luminescence of SrF2:Pr3+ for ratiometric thermometry.

Luminescence-based thermometry, especially the ratiometric temperature sensing technology, has attracted considerable attention recently due to its characteristics such as non-contact operating mode and strong capacity of resisting disturbance. Differing from the conventional strategy that usually needs continuous excitation, here an optical thermometry, which we have named the persistent luminescence intensity ratio (PLIR) thermometry, is proposed. The PLIR thermometry relies on the optical material SrF2:Pr3+ that could emit luminescence for several hours and even longer after being charged by X-ray. It has been demonstrated that the PLIR is sensitive to the variation of temperature and complies with the Boltzmann distribution. More importantly, the reliability of the proposed PLIR thermometry is verified. Our work may inspire others to develop more persistent luminescence thermometry.

Boltzmann-distribution-dominated persistent luminescence ratiometric thermometry in NaYF4:Pr3.

A novel, to the best of our knowledge, optical temperature measurement method is proposed, i.e., persistent luminescence intensity ratio (PLIR) thermometry. The PLIR thermometry relies on the micro-sized NaYF4:Pr3+ material that can emit persistent luminescence (PersL) uninterruptedly after being charged by x ray irradiation. The 3P1→3H5 and 3P0→3H5 PersL transitions, locating separately at ∼ 522 and 538 nm, have been confirmed to follow the Boltzmann distribution. The emitting intensity ratio of this pair of PersL lines is thus found to be a good indicator of the variation of temperature. Our work is expected to enrich the optical temperature sensing family.

Semen quality and sperm DNA methylation in relation to long-term exposure to air pollution in fertile men: A cross-sectional study.

Some studies have examined the association between air pollution and semen quality. While it is less of evidence on the sperm quality after long-term air pollution exposure, especially the co-exposure of different air pollution components. Additionally, the role of DNA methylation in it hasn't been confirmed. This study aimed to investigate whether long-term exposure to air pollution was associated with semen quality, as well as to explore the effect of sperm DNA methylation in such association. From 2014 to 2016, 1607 fertile men were enrolled to evaluate 14 parameters of semen quality. Exposure window was defined as one-year before semen sampling. Multivariable linear regression and weighted quantile sum (WQS) regression model were used to investigate the association between six air pollutants co-exposure and semen quality. Sensitivity analysis regarding at the normal semen quality group was also conducted. Semen samples were randomly selected from 200 participants to detect the genomic 5-methylcytosine (5 mC) and 5-hydroxymethylcytosine (5-hmC) levels in sperm. In the total population, PM10, PM2.5, SO2, and NO2 were negatively associated with sperm total motility (PM10: ß = -2.67, P = 0.009; PM2.5: ß = -2.86, P = 0.004; SO2: ß = -2.32, P = 0.011; NO2: ß = -2.21, P = 0.012). Results of the normal semen quality group were consistent with those from the whole population. WQS regression results indicated significant decreasing sperm total motility after the co-exposure of the six air pollutants (ß = -1.64, P = 0.003) in whole participants. Wherein, PM10 accounted for largest proportion (43.4%). The 5-hmC level was positively associated with PM10 exposure (ß = 0.002, P < 0.001). Long-term exposure to PM10, PM2.5, SO2, and NO2, as well as co-exposure to six air pollutants, reduced semen quality in fertile men. As the most significant contributor of air pollutant, PM10 exposure decreased sperm DNA methylation.

A metabolomic study on the effect of prenatal exposure to Benzophenone-3 on spontaneous fetal loss in mice.

Benzophenone-3 (BP-3) is widely used in a variety of cosmetics and is prevalent in drinking water or food, and women were under notable high exposure burden of BP-3. Reports show the associations between prenatal exposure to BP-3 and the risk of fetal loss, but its underlying mechanism remains largely unknown. Pregnant ICR mice were gavaged with BP-3 from gestational day (GD) 0 to GD 6 at doses of 0.1, 10 and 1000 mg/kg/day. The samples were collected on GD 12. Ultra-performance liquid chromatography coupled with mass spectrometry-based metabolomics was used to detect metabolome changes in fetal mice, the uterus and the placenta to identify the underlying mechanism. The results showed that the body weight and relative organ weights of the liver, brain and uterus of pregnant mice were not significantly changed between the control group and the treatment group. BP-3 increased fetal loss, and induced placental thrombosis and tissue necrosis with enhancement of platelet aggregation. Metabolomic analysis revealed that fructose and mannose metabolism, the TCA cycle, arginine and proline metabolism in the fetus, arginine and proline metabolism and biotin metabolism in the uterus, and arginine biosynthesis and pyrimidine metabolism in the placenta were the key changed pathways involved in the above changes. Our study indicates that exposure to BP-3 can induce placental thrombosis and fetal loss via the disruption of maternal and fetal metabolism in mice, providing novel insights into the influence of BP-3 toxicity on the female reproductive system.

Adaptive Optimal Control for Unknown Constrained Nonlinear Systems With a Novel Quasi-Model Network.

A policy-iteration-based algorithm is presented in this article for optimal control of unknown continuous-time nonlinear systems subject to bounded inputs by utilizing the adaptive dynamic programming (ADP). Three neural networks (NNs), called critic network, actor network, and quasi-model network, are utilized in the proposed algorithm to give approximations of the control law, the cost function, and the function constituted by partial derivatives of value functions with respect to states and unknown input gain dynamics, respectively. At each iteration, based on the least sum of squares method, the parameters of critic and quasi-model networks will be tuned simultaneously, which eliminates the necessity of separately learning the system model in advance. Then, the control law is improved by satisfying the necessary optimality condition. Then, the proposed algorithm's optimality and convergence properties are exhibited. Finally, the simulation results demonstrate the availability of the proposed algorithm.

Stress, anxiety, and depression in infertile couples are not associated with a first IVF or ICSI treatment outcome.

BACKGROUND: Psychological distress may exert a negative influence on reproductive function of couples at reproductive age. Couples seeking assisted reproductive technology (ART) treatment may have a higher prevalence of psychological distress than fertile couples. However, whether psychological distress is associated with the outcome of ART treatment remains unknown. We aimed to investigate the association of pre-treatment psychological distress and clinical pregnancy rate among infertility couples undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. METHODS: This nested case-control study was conducted based on women who underwent their first fresh IVF or ICSI cycle in the Jiangsu Birth Cohort Study (JBC) between November 2015 and January 2019. A total of 150 women who did not obtain clinical pregnancy after first IVF or ICSI fresh embryo transfer were identified as cases, and a total of 300 age matched women who obtained clinical pregnancy were identified as controls. Conditional logistic regression analyses were used to investigate the association between psychological distress and the outcome of first IVF or ICSI treatment, adjusting for multiple potential confounders. RESULTS: No statistically significant association was observed between score of maternal symptoms of psychological distress and clinical pregnancy. Adjusted ORs of logistic regression were 1.00 (95% CI 0.97-1.03) for anxiety, 0.98 (95% CI 0.95-1.02) for depression, and 0.98 (95% CI 0.95-1.01) for perceived stress, respectively. When treat depression and anxiety as categorical variables, 62 (13.8%) were classified as clinical depression, 11 (2.4%) were classified as clinical anxiety, among 450 women in the present study. Psychological distress symptoms were also not associated with clinical pregnancy rate. Adjusted ORs of logistic regression were 0.27 (95% CI 0.03-2.33) for anxiety, 0.88 (95% CI 0.46-1.68) for depression, respectively. CONCLUSIONS: Our findings firstly indicated that psychological distress experienced prior to IVF/ICSI treatment was not associated with clinical pregnancy.

Effects of 2,2',4,4'-tetrabromodiphenyl ether on the development of mouse embryonic stem cells.

2,2',4,4'-Tetrabromodiphenyl ether (BDE47) poses potential risks to reproduction and development, but the mechanism of its toxicity has not yet been elucidated. To explore the developmental toxicity of BDE47, mouse embryonic stem cells (mESCs), which are ideal models for testing the developmental toxicity of environmental contaminants in vitro, were exposed to BDE47 (0.04 µM, 1 µM, 25 µM, or 100 µM) for 24 h or 48 h in this study. Our results indicated that BDE47 treatment changed the morphology of mESCs, inhibited cell viability and increased apoptosis. In addition, alkaline phosphatase (AP) staining in mESCs was significantly decreased after BDE47 treatment (25 µM and 100 µM), indicating that BDE47 treatment affected the pluripotency of mESCs. Through a cell immunofluorescence assay, we found that the fluorescence intensities of Oct4, Sox2 and Nanog were all significantly lower in the group treated with the highest BDE47 concentration (100 µM) than in the control group, consistent with the qRT-PCR and Western blot results. The levels of miR-145 and miR-34a, which regulate genes related to cell differentiation, were significantly increased in BDE47-treated mESCs, further clarifying the potential mechanism. Overall, our findings demonstrate that BDE47 exposure upregulates the expression of miR-145 and miR-34a and in turn downregulates the expression of Oct4, Sox2 and Nanog, thereby affecting apoptosis and pluripotency and causing toxicity during embryonic development.

Assisted reproductive technology and birth defects in a Chinese birth cohort study.

BACKGROUND: It has been consistently shown in several meta-analyses that infants born after ART have an excess of birth defects compared with those after spontaneous conception, however, the prevalence of birth defects among ART offspring in China is incompletely studied. Moreover, it is unclear to what extent the risk of birth defects is associated with parental infertility characteristics, specific ART procedures and twinning. METHODS: In the prospective cohort study, we included women who participated in the cohort, and had pregnancies of at least 20 gestational weeks between August 2016 and May 2019, and followed them until their children reached 1 year of age. Exposures of interest were ART, as well as infertility-related characteristics, certain ART procedures and specific medication usage. The primary outcome was birth defects including both major and minor defects, which we analysed with logistic generalized estimating equations to investigate the association with ART and certain ART characteristics. FINDINGS: A total of 1,825 women with ART-pregnancy and 3,483 women with spontaneous-pregnancy were included in the analysis. The prevalence of any defects was significantly higher among ART-births than their non-ART counterparts at each follow-up, specifically at prenatal screening (2•2% vs. 1•2%), at delivery (4•9% vs. 2•9%), at 6 months (10•4% vs. 5•3%) and 1 year of age (13•9% vs. 7•0%), and the associations between ART and increased risk of birth defects at each follow-up were similarly robust. Among ART-births, GnRH antagonist regimen for ovulation induction in women was associated with an increased risk of birth defects in their offspring after taking into account potential influencing factors (Multivariable model: adjusted risk ratio [aRR] 1•47, 1•04-2•07). Additionally, mediation through twinning accounted for 31•1% of the risk of ART-associated birth defects. INTERPRETATION: The results suggest that ART confers an increased risk for birth defects in offspring. The risk is partly attributable to infertility characteristics, certain ovulation induction regimen, and to some extent mediated by twinning. Our findings highlight the importance of long-term follow-up of children conceived via ART for health conditions. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China and Natural Science Foundation of Jiangsu Province.

Association of assisted reproductive technology, germline de novo mutations and congenital heart defects in a prospective birth cohort study.

Emerging evidence suggests that children conceived through assisted reproductive technology (ART) have a higher risk of congenital heart defects (CHDs) even when there is no family history. De novo mutation (DNM) is a well-known cause of sporadic congenital diseases; however, whether ART procedures increase the number of germline DNM (gDNM) has not yet been well studied. Here, we performed whole-genome sequencing of 1137 individuals from 160 families conceived through ART and 205 families conceived spontaneously. Children conceived via ART carried 4.59 more gDNMs than children conceived spontaneously, including 3.32 paternal and 1.26 maternal DNMs, after correcting for parental age at conception, cigarette smoking, alcohol drinking, and exercise behaviors. Paternal DNMs in offspring conceived via ART are characterized by C>T substitutions at CpG sites, which potentially affect protein-coding genes and are significantly associated with the increased risk of CHD. In addition, the accumulation of non-coding functional mutations was independently associated with CHD and 87.9% of the mutations were originated from the father. Among ART offspring, infertility of the father was associated with elevated paternal DNMs; usage of both recombinant and urinary follicle-stimulating hormone and high-dosage human chorionic gonadotropin trigger was associated with an increase of maternal DNMs. In sum, the increased gDNMs in offspring conceived by ART were primarily originated from fathers, indicating that ART itself may not be a major reason for the accumulation of gDNMs. Our findings emphasize the importance of evaluating the germline status of the fathers in families with the use of ART.