Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency.

Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated1. Gestational diabetes has profound and enduring effects on the long-term health of the offspring2,3. However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote4, is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene (Gck), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring.

Intracytoplasmic sperm injection versus conventional in-vitro fertilisation for couples with infertility with non-severe male factor: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Introduced in 1992, intracytoplasmic sperm injection (ICSI) was initially indicated for severe male infertility; however, its use has since been expanded to non-severe male infertility. We aimed to compare the efficacy and safety of ICSI versus conventional in-vitro fertilisation (IVF) in couples with infertility with non-severe male factor. METHODS: We conducted an investigator-initiated, multicentre, open-label, randomised controlled trial in ten reproductive medicine centres across China. Couples with infertility with non-severe male factor without a history of poor fertilisation were randomly assigned (1:1) to undergo either ICSI or conventional IVF. The primary outcome was live birth after first embryo transfer. We performed the primary analysis in the intention-to-treat population using log-binomial regression models for categorical outcomes or linear regression models for continuous outcomes, adjusting for centre. This trial is registered with Clinicaltrials.gov, NCT03298633, and is completed. FINDINGS: Between April 4, 2018, and Nov 15, 2021, 3879 couples were screened, of whom 2387 (61·5%) couples were randomly assigned (1184 [49·6%] to the ICSI group and 1203 [50·4%] to the conventional IVF group). After excluding couples who were ineligible, randomised twice, or withdrew consent, 1154 (97·5%) in the ICSI group and 1175 (97·7%) in the conventional IVF group were included in the primary analysis. Live birth after first embryo transfer occurred in 390 (33·8%) couples in the ICSI group and in 430 (36·6%) couples in the conventional IVF group (adjusted risk ratio [RR] 0·92 [95% CI 0·83-1·03]; p=0·16). Two (0·2%) neonatal deaths were reported in the ICSI group and one (0·1%) in the conventional IVF group. INTERPRETATION: In couples with infertility with non-severe male factor, ICSI did not improve live birth rate compared with conventional IVF. Given that ICSI is an invasive procedure associated with additional costs and potential increased risks to offspring health, routine use is not recommended in this population. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Beijing Municipal Science & Technology Commission, and Peking University Third Hospital.

Sex-Specific Alterations in Placental Proteomics Induced by Intrauterine Hyperglycemia.

Gestational diabetes mellitus (GDM) with intrauterine hyperglycemia induces a series of changes in the placenta, which have adverse effects on both the mother and the fetus. The aim of this study was to investigate the changes in the placenta in GDM and its gender differences. In this study, we established an intrauterine hyperglycemia model using ICR mice. We collected placental specimens from mice before birth for histological observation, along with tandem mass tag (TMT)-labeled proteomic analysis, which was stratified by sex. When the analysis was not segregated by sex, the GDM group showed 208 upregulated and 225 downregulated proteins in the placenta, primarily within the extracellular matrix and mitochondria. Altered biological processes included cholesterol metabolism and oxidative stress responses. After stratification by sex, the male subgroup showed a heightened tendency for immune-related pathway alterations, whereas the female subgroup manifested changes in branched-chain amino acid metabolism. Our study suggests that the observed sex differences in placental protein expression may explain the differential impact of GDM on offspring.

Polycystic Ovary Syndrome Fuels Cardiovascular Inflammation and Aggravates Ischemic Cardiac Injury.

BACKGROUND: Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear. METHODS: Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Women with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models. RESULTS: Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C+ monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C+ monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in women with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14++CD16- monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional Vcam1 silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI. CONCLUSIONS: Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.

Characterization of a novel adipose tissue located between abdominal lymph nodes and cervix/prostate in mice.

Perigonadal adipose tissue is a homogeneous white adipose tissue (WAT) in adult male mice, without any brown adipose tissue (BAT) present. However, there are congenital differences in the gonads between male and female mice. Whether heterogeneity existed in perigonadal ATs in female mice remains unknown. This study reported a perigonadal BAT located between abdominal lymph nodes and uterine cervix in female mice, termed lymph node-cervical adipose tissue (LNCAT). Its counterpart, lymph node-prostatic adipose tissue (LNPAT), exhibited white phenotype in adult virgin male mice. When exposed to cold, LNCAT/LNPAT increased UCP1 expression via activation of TH, in which abdominal lymph nodes were involved. Interestingly, the UCP1 expression in LNCAT/LNPAT varied under different reproductive stages. The UCP1 expression in LNCAT was upregulated at early pregnancy, declined at mid-late pregnancy, and reverted in weaning dams. Mating behavior stimulated LNPAT browning in male mice. We found that androgen but not estrogen or progesterone inhibited UCP1 expression in LNCAT. Androgen administration reversed the castration-induced LNPAT browning. Our results identified a perigonadal BAT in female mice and characterized its UCP1 expression patterns under various conditions.

Intrauterine hyperglycemia induces SIRT3-mediated mitochondrial dysfunction: the fetal origin pathogenesis of precocious osteoarthritis.

OBJECTIVE: Diabetes and other metabolic and inflammatory comorbidities are highly associated with osteoarthritis (OA). However, whether early-life hyperglycemia exposure affects susceptibility to long-term OA is still unknown. The purpose of this study was to explore the fetal origins of OA and provide insights into early-life safeguarding for individual health. METHOD: This study utilized streptozotocin to induce intrauterine hyperglycemia and performed destabilization of the medial meniscus surgery on the knee joints of the offspring mice to induce accelerated OA. Cartilage degeneration-related markers, as well as the expression levels of mitochondrial respiratory chain complexes and mitophagy genes in the adult offspring mice, were investigated. In vitro, mitochondrial function and mitophagy of chondrocyte C28/I2 cells stimulated under high glucose conditions were also evaluated. The methylation levels of the sirt3 gene promoter region in the articular cartilage of intrauterine hyperglycemia-exposed offspring mice were further analyzed. RESULTS: In this study, we found that the intrauterine hyperglycemic environment could lead to an increase in individual susceptibility to OA in late adulthood, mainly due to persistently low levels of Sirt3 expression. Downregulation of Sirt3 causes impaired mitophagy in chondrocytes and abnormal mitochondrial respiratory function due to a failure to clear aged and damaged mitochondria in a timely manner. Overexpressing Sirt3 at the cellular level or using Sirt3 agonists like Honokiol in mouse models can partially rescue mitophagy disorders caused by the hyperglycemic environment and thus alleviate the progression of OA. CONCLUSION: Our study revealed a significantly increased susceptibility to OA in the gestational diabetes mellitus offspring, which is partly attributed to exposure to adverse factors in utero and ultimately to the onset of disease via epigenetic modulation.

A morphological study of symptomatic uterine niche using three-dimensional models from thin-slice magnetic resonance imaging.

RESEARCH QUESTION: Is there a correlation between various morphological parameters of the uterine niche and post-menstrual spotting using three-dimensional models from thin-slice (1 mm) magnetic resonance imaging (MRI)? DESIGN: This study retrospectively identified women diagnosed with a symptomatic niche by thin-slice MRI between December 2019 and December 2021. Univariable and multivariable linear regression models assessed the correlations between morphological parameters and the duration post-menstrual spotting. Morphological differences of the niche formed by one versus two Caesarean sections were analysed by univariable and multivariable logistic analysis. RESULTS: A total of 205 women diagnosed with symptomatic niche were included in the study. The niche among most women with post-menstrual spotting was ellipsoidal, with width greater than length greater than depth, from which niche volume was estimated based on manual measurements (volume = 0.520 × length × width × depth). Manually calculated niche length (ß = 0.257, 95% confidence interval [CI] 0.040-0.473, P = 0.020) and radiomically assessed minor axis length (ß = 0.329, 95% CI 0.009-0.795, P = 0.045) both positively correlated with the duration of post-menstrual spotting, whereas the distance between the niche and external os (ß = -0.120, 95% CI -0.202 to -0.038, P = 0.004) was inversely correlated. Women with two Cesarean sections reported more days of post-menstrual spotting (8.76 ± 3.54 versus 6.68 ± 3.90 days, P < 0.001) and had increased niche length diameter (adjusted odds ratio [aOR] 1.304, 95% CI 1.190-1.429) and a smaller surface-area-to-volume ratio (aOR 0.296, 95% CI 0.129-0.680). CONCLUSIONS: Niche-associated post-menstrual spotting correlates with the length diameter of the niche and the distance between the niche and external os. Niches in women after two Caesarean sections tend to be longer in length diameter and more spherical.

Parental mosaicism detection and preimplantation genetic testing in families with multiple transmissions of de novo mutations.

BACKGROUND: De novo mutations (DNMs) are linked with many severe early-onset disorders ranging from rare congenital malformation to intellectual disability. Conventionally, DNMs are considered to have an estimated recurrence rate of 1%. Recently, studies have revealed a higher prevalence of parental mosaicism, leading to a greater recurrence risk, resulting in a second child harbouring the same DNM as a previous child. METHODS: In this study, we included 10 families with DNMs leading to adverse pregnancy outcomes. DNA was extracted from tissue samples, including parental peripheral blood, parental saliva and paternal sperm. High-throughput sequencing was used to screen for parental mosaicism with a depth of more than 5000× on average and a variant allele fraction (VAF) detection limit of 0.5%. RESULTS: The presence of mosaicism was detected in sperms in two families, with VAFs of 2.8% and 2.5%, respectively. Both families have a history of multiple adverse pregnancies and DNMs shared by siblings. Preimplantation genetic testing (PGT) and prenatal diagnosis were performed in one family, thereby preventing the reoccurrence of DNMs. CONCLUSION: This study is the first to report the successful implementation of PGT for monogenic/single gene defects in the parental mosaicism family. Our study suggests that mosaic detection of paternal sperm is warranted in families with recurrent DNMs leading to adverse pregnancy outcomes, and PGT can effectively block the transmission of the pathogenic mutation.

Long-term health risk of offspring born from assisted reproductive technologies.

Since the world's first in vitro fertilization baby was born in 1978, there have been more than 8 million children conceived through assisted reproductive technologies (ART) worldwide, and a significant proportion of them have reached puberty or young adulthood. Many studies have found that ART increases the risk of adverse perinatal outcomes, including preterm birth, low birth weight, small size for gestational age, perinatal mortality, and congenital anomalies. However, data regarding the long-term outcomes of ART offspring are limited. According to the developmental origins of health and disease theory, adverse environments during early life stages may induce adaptive changes and subsequently result in an increased risk of diseases in later life. Increasing evidence also suggests that ART offspring are predisposed to an increased risk of non-communicable diseases, such as malignancies, asthma, obesity, metabolic syndrome, diabetes, cardiovascular diseases, and neurodevelopmental and psychiatric disorders. In this review, we summarize the risks for long-term health in ART offspring, discuss the underlying mechanisms, including underlying parental infertility, epigenetic alterations, non-physiological hormone levels, and placental dysfunction, and propose potential strategies to optimize the management of ART and health care of parents and children to eliminate the associated risks. Further ongoing follow-up and research are warranted to determine the effects of ART on the long-term health of ART offspring in later life.

Effects of exposure to multiple metallic elements in the first trimester of pregnancy on the risk of preterm birth.

Exposure to certain heavy metals has been demonstrated to be associated with a higher risk of preterm birth (PTB). However, studies focused on the effects of other metal mixtures were limited. A nested case‒control study enrolling 94 PTB cases and 282 controls was conducted. Metallic elements were detected in maternal plasma collected in the first trimester using inductively coupled plasma‒mass spectrometry. The effect of maternal exposure on the risk of PTB was investigated using logistic regression, least absolute shrinkage and selection operator, restricted cubic spline (RCS), quantile g computation (QGC) and Bayesian kernel machine regression (BKMR). Vanadium (V) and arsenic (As) were positively associated with PTB risk in the logistic model, and V remains positively associated in the multi-exposure logistic model. QGC analysis determined V (69.42%) and nickel (Ni) (70.30%) as the maximum positive and negative contributors to the PTB risk, respectively. BKMR models further demonstrated a positive relationship between the exposure levels of the mixtures and PTB risk, and V was identified as the most important independent variable among the elements. RCS analysis showed an inverted U-shape effect of V and gestational age, and plasma V more than 2.18 µg/L was considered a risk factor for shortened gestation length. Exposure to metallic elements mixtures consisting of V, As, cobalt, Ni, chromium and manganese in the first trimester was associated with an increased risk of PTB, and V was considered the most important factor in the mixtures in promoting the incidence of PTB.

[Reproductive Health-Oriented Development in Assisted Reproductive Technologies]. / ä»¥ç”Ÿæ®–å¥åº·ä¸ºå¯¼å‘çš„è¾ åŠ©ç”Ÿæ®–æŠ€æœ¯å‘å±•.

Assisted reproductive technologies (ARTs) are core components of the field of reproductive medicine, encompassing multiple pivotal stages of early development from gamete maturation and fertilization to embryo development. Against the backdrop of a deteriorating trend of global decline in fertility rates, patients with infertility problems increasingly turn to ARTs to realize their dreams of parenthood. However, concomitant with this trend is a growing apprehension regarding the potential adverse effects of ARTs. Herein, we endeavor to discuss several common ARTs procedures utilized in clinical settings and the relevant cutting-edge advancements. The ARTs discussed in the article include in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), biphasic in vitro maturation (biphasic IVM), frozen embryo transfer (FET), preimplantation genetic testing (PGT), non-invasive PGT (niPGT), etc. In addition, we reevaluated their roles within the broader context of assisted reproduction aimed at promoting reproductive health. Additionally, we will delve into the impact of ARTs on the reproductive health of the offspring. By prioritizing the reproductive well-being of both patients and their offspring, the ongoing development and improvement of ARTs to enhance their efficacy and safety will contribute significantly to the advancement of human reproductive health.

Chinese experts' consensus guideline on preimplantation genetic testing of monogenic disorders.

Recent developments in molecular biological technologies and genetic diagnostic methods, accompanying with updates of relevant terminologies, have enabled the improvements of new strategies of preimplantation genetic testing for monogenic (single gene) disorders (PGT-M) to prevent the transmission of inherited diseases. However, there has been much in the way of published consensus on PGT-M. To properly regulate the application of PGT-M, Chinese experts in reproductive medicine and genetics have jointly developed this consensus statement. The consensus includes indications for patient selection, genetic and reproductive counseling, informed consent, diagnostic strategies, report generation, interpretation of results and patient follow-ups. This consensus statement serves to assist in establishment of evidence-based clinical and laboratory practices for PGT-M.

Effects of Particulate Matter on the Risk of Gestational Hypertensive Disorders and Their Progression.

Associations between particulate matter (PM) and gestational hypertensive disorders (GHDs) are well documented, but there is no evidence on the associations between PM and GHD progression, especially among those with assisted reproductive technology (ART) conceptions. To explore the effects of PM on the risk of GHDs and their progression among pregnant women with natural or ART conception, we enrolled 185,140 pregnant women during 2014-2020 in Shanghai and estimated the associations during different periods using multivariate logistic regression. During the 3 months of preconception, 10 µg/m3 increases in PM concentrations were associated with increased risks of gestational hypertension (GH) (PM2.5: aOR = 1.076, 95% CI: 1.034-1.120; PM10: aOR = 1.042, 95% CI: 1.006-1.079) and preeclampsia (PM2.5: aOR = 1.064, 95% CI: 1.008-1.122; PM10: aOR = 1.048, 95% CI: 1.006-1.092 ) among women with natural conception. Furthermore, for women with ART conceptions who suffered current GHD, 10 µg/m3 increases in PM concentrations in the third trimester elevated the risk of progression (PM2.5: aOR = 1.156, 95% CI: 1.022-1.306 ; PM10: aOR = 1.134, 95% CI: 1.013-1.270). In summary, women with natural conception should avoid preconceptional PM exposure to protect themselves from GH and preeclampsia. For women with ART conceptions suffering from GHD, it is necessary to avoid PM exposure in late pregnancy to prevent the disease from progressing.

Mixed exposure effect of seminal metals on semen quality, mediation of total antioxidant capacity, and moderation of GSTM1/GSTT1 gene deletion in Chinese reproductive-aged men.

BACKGROUND: The effects of metal exposure on semen quality and the role of oxidative damage in this process remain unclear. METHODS: We recruited 825 Chinese male volunteers, and 12 seminal metals (Mn, Cu, Zn, Se, Ni, Cd, Pb, Co, Ag, Ba, Tl, and Fe), the total antioxidant capacity (TAC), and reduced glutathione were measured. Semen parameters and GSTM1/GSTT1-null genotypes were also detected. Bayesian kernel machine regression (BKMR) was applied to evaluate the effect of the mixed exposure to metals on semen parameters. The mediation of TAC and moderation of GSTM1/GSTT1 deletion were analyzed. RESULTS: Most seminal metal concentrations were correlated with each other. The BKMR models revealed a negative association between the semen volume and metal mixture, with Cd (cPIP = 0.60) and Mn (cPIP = 0.10) as the major contributors. Compared to fixing all scaled metals at their median value (50th percentiles), fixing the scaled metals at their 75th percentiles decreased the TAC by 2.17 units (95%CI: -2.60, -1.75). Mediation analysis indicated that Mn decreased the semen volume, with 27.82% of this association mediated by TAC. Both the BKMR and multi-linear models showed that seminal Ni was negatively correlated with sperm concentration, total sperm count, and progressive motility, which was modified by GSTM1/GSTT1. Furthermore, Ni and the total sperm count showed a negative association in GSTT1 and GSTM1 null males (ß[95%CI]: 0.328 [-0.521, -0.136]) but not in males with GSTT1 and/or GSTM1. Although Fe and the sperm concentration and total sperm count were positively correlated, they showed inverse "U" shapes in univariate analysis. CONCLUSION: Exposure to the 12 metals was negatively associated with semen volume, with Cd and Mn as the major contributors. TAC may mediate this process. GSTT1 and GSTM1 can modify the reduction in the total sperm count caused by seminal Ni exposure.

Fetal weight estimation based on deep neural network: a retrospective observational study.

BACKGROUND: Improving the accuracy of estimated fetal weight (EFW) calculation can contribute to decision-making for obstetricians and decrease perinatal complications. This study aimed to develop a deep neural network (DNN) model for EFW based on obstetric electronic health records. METHODS: This study retrospectively analyzed the electronic health records of pregnant women with live births delivery at the obstetrics department of International Peace Maternity & Child Health Hospital between January 2016 and December 2018. The DNN model was evaluated using Hadlock's formula and multiple linear regression. RESULTS: A total of 34824 live births (23922 primiparas) from 49896 pregnant women were analyzed. The root-mean-square error of DNN model was 189.64 g (95% CI 187.95 g-191.16 g), and the mean absolute percentage error was 5.79% (95%CI: 5.70%-5.81%), significantly lower compared to Hadlock's formula (240.36 g and 6.46%, respectively). By combining with previously unreported factors, such as birth weight of prior pregnancies, a concise and effective DNN model was built based on only 10 parameters. Accuracy rate of a new model increased from 76.08% to 83.87%, with root-mean-square error of only 243.80 g. CONCLUSIONS: Proposed DNN model for EFW calculation is more accurate than previous approaches in this area and be adopted for better decision making related to fetal monitoring.

Carrier burden of over 300 diseases in Han Chinese identified by expanded carrier testing of 300 couples using assisted reproductive technology.

BACKGROUND: Expanded carrier screening (ECS) has become a common practice for identifying carriers of monogenic diseases. However, existing large gene panels are not well-tailored to Chinese populations. In this study, ECS testing for pathogenic variants of both single-nucleotide variants (SNVs) and copy number variants (CNVs) in 330 genes implicated in 342 autosomal recessive (AR) or X-linked diseases was carried out. We assessed the differences in allele frequencies specific to the Chinese population who have used assisted reproductive technology (ART) and the important genes to screen for in this population. METHODOLOGY: A total of 300 heterosexual couples were screened by our ECS panel using next-generation sequencing. A customed bioinformatic algorithm was used to analyze SNVs and CNVs. Guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology were adapted for variant interpretation. Pathogenic or likely pathogenic (P/LP) SNVs located in high homology regions/deletions and duplications of one or more exons in length were independently verified with other methods. RESULTS: 64.83% of the patients were identified to be carriers of at least one of 342 hereditary conditions. We identified 622 P/LP variants, 4.18% of which were flagged as CNVs. The rate of at-risk couples was 3%. A total of 149 AR diseases accounted for 64.05% of the cumulative carrier rate, and 48 diseases had a carrier rate above 1/200 in the test. CONCLUSION: An expanded screening of inherited diseases by incorporating different variant types, especially CNVs, has the potential to reduce the occurrence of severe monogenic diseases in the offspring of patients using ART in China.

Research Progress on the effects of adverse exposure during pregnancy on skeletal muscle function in offspring. / å¦Šå¨ æœŸä¸è‰¯æš´éœ²å¯¹å­ä»£éª¨éª¼è‚ŒåŠŸèƒ½å½±å“çš„ç ”ç©¶è¿›å±•.

Skeletal muscle plays a crucial role in maintaining metabolic function, energy homeostasis, movement function, as well as endocrine function. The gestation period is a critical stage for the myogenesis and development of skeletal muscle. Adverse environmental exposures during pregnancy would impose various effects on the skeletal muscle health of offspring. Maternal obesity during pregnancy can mediate lipid deposition in skeletal muscle of offspring by affecting fetal skeletal muscle metabolism and inflammation-related pathways. Poor dietary habits during pregnancy, such as high sugar and high fat intake, can affect the autophagy function of skeletal muscle mitochondria and reduce the quality of offspring skeletal muscle. Nutritional deficiencies during pregnancy can affect the development of offspring skeletal muscle through epigenetic modifications. Gestational diabetes may affect the function of offspring skeletal muscle by upregulating the levels of miR-15a and miR-15b in offspring. Exposure to environmental endocrine disruptors during pregnancy may impair skeletal muscle function by interfering with insulin receptor-related signaling pathways in offspring. This article reviews the research progress on effects and possible mechanisms of adverse maternal exposures during pregnancy on offspring skeletal muscle function in clinical and animal studies, aiming to provide scientific evidence for the prevention and treatment strategy of birth defects in skeletal muscle.

Research progress and challenges of preimplantation genetic testing for polygenic diseases. / å¤šåŸºå› ç–¾ç— èƒšèƒŽæ¤å ¥å‰é—ä¼ å­¦æ£€æµ‹çš„ç ”ç©¶è¿›å±•åŠæŒ‘æˆ˜.

Preimplantation genetic testing is an important part in assisted reproductive technology, which can block the intergenerational inheritance of single gene or chromosomal diseases. Preimplantation genetic testing for polygenic disease risk (PGT-P) is the latest development in the field. It is known that polygenic diseases usually have the characteristics of high incidence, late onset, affecting the quality of life and mental health of patients. On the basis of the development of artificial intelligence and genetic detection technology, PGT-P can analyze genetic material, calculate polygenic risk score turning into incidence probability. Embryos with relatively low incidence probability can be screened for transfer, so as to reduce the possibility of offspring suffering from the disease in the future, which has significant clinical and social significance. At present, PGT-P has been applied clinically and made phased progress at home and abroad. At the same time, as a developing technology, PGT-P still has some technical defects, unstable results, environmental influences and racial differences cannot be ruled out. From the perspective of ethics, if the screening indications are not strictly regulated, it is likely to cause new social problems. In this paper, we review the technical composition and recent progress of PGT-P, and put forward the prospect of its future development, especially how to establish a complete and suitable screening model for Chinese population.

Environmental epigenetic interaction of gametes and early embryos†.

In recent years, the developmental origins of diseases have been increasingly recognized and accepted. As such, it has been suggested that most adulthood chronic diseases such as diabetes, obesity, cardiovascular disease, and even tumors may develop at a very early stage. In addition to intrauterine environmental exposure, germ cells carry an important inheritance role as the primary link between the two generations. Adverse external influences during differentiation and development can cause damage to germ cells, which may then increase the risk of chronic disease development later in life. Here, we further elucidate and clarify the concept of gamete and embryo origins of adult diseases by focusing on the environmental insults on germ cells, from differentiation to maturation and fertilization.

Activin A promotes hyaluronan production and upregulates versican expression in human granulosa cells†.

Hyaluronan is a structural component of the expanded cumulus matrix, and hyaluronan synthase 2 is the major enzyme for the synthesis of hyaluronan in humans. Versican cross-links the hyaluronan-rich matrix to cumulus cells and is critical for successful ovulation. Activin A is a critical intrafollicular regulator of ovarian function. Although activin A has been shown to promote cumulus matrix expansion in mice, the functional role of activin A in the regulation of cumulus expansion in the human ovary remains to be elucidated. Using primary and immortalized human granulosa-lutein cells as study models, we provide the first data showing that activin A increased the production of hyaluronan by upregulating the expression of hyaluronan synthase 2 in these cells. Additionally, activin A also promoted the expression of the hyaluronan-binding protein versican. Moreover, using inhibitor- and small interfering RNA-mediated inhibition approaches, we found that these stimulatory effects of activin A are most likely mediated through the type I receptor activin receptor-like kinase (ALK4)-mediated Sma- and Mad-related protein (SMAD2)/SMAD3-SMAD4 signaling pathway. Notably, the chromatin immunoprecipitation analyses demonstrated that SMAD4 could bind to human hyaluronan synthase 2 and VERSICAN promoters. The results obtained from this in vitro study suggest that locally produced activin A plays a functional role in the regulation of hyaluronan production and stabilization in human granulosa-lutein cells.