2018年 · 第01卷第03期

While the influence of maternal environmental exposures on offspring long-term health is well recognized, paternal contributions are often overlooked. Recently, a growing body of evidence has revealed the relationship between paternal obesity and the phenotype of offspring. This review is focused on findings of the effects of paternal obesity upon sperm function and offspring health, and whether these effects can be reversed in human and animal studies. Furthermore, we also provide evidence that epigenetic modifications in sperm, including DNA methylation, chromatin histone modifications, and non-coding RNAs, are potential mechanistic candidates for intergenerational inheritance from father to offspring.

Initially discovered in the pituitary as stimulators of follicle stimulating hormone, activins are homo- or heterodimers of inhibin subunits, which belong to the transforming growth factor-β superfamily. Subsequent studies have demonstrated that these growth factors play multifaceted roles in regulating various functions in multiple organs, including the ovary. The spatial and temporal expression of inhibin subunits (α, βA, βB, and βC), their cognate receptors, and activin-binding proteins (inhibins and follistatins) in the principal cells of growing follicles in human ovaries indicates that these activin isoforms are involved in ovarian biology. Information collected from animal studies and clinical samples suggests that these locally produced growth factors are crucial modulators of various ovarian functions, including primordial germ cell development, follicular growth and development, ovarian steroidogenesis, extracellular matrix remodeling, oocyte maturation, ovulation, and luteal function. Along with gonadotropins, intrafollicular activins exert synergistic and complementary effects on growing follicles to help them develop a mature, competent oocyte that is prepared for fertilization. Abnormal activin expression, an imbalanced activin/follistatin ratio, and the dysregulation of the activin signaling pathway have been observed in several ovarian pathologies, such as reproductive aging, polycystic ovary syndrome, and ovarian cancers. Recent advancements in our understanding of the molecular interactions and mechanisms that underlie activins and the development of related ovarian abnormalities have provided insights into disease pathogenesis and increased opportunities to achieve efficient and safe therapies.

Frozen-thawed embryo transfer (FET) has been increasingly adopted as an adjunct to in vitro fertilization or intracytoplasmic sperm injection in recent years. It can reduce the risks of ovarian hyperstimulation syndrome and multiple pregnancies, and may even improve pregnancy outcomes in some subgroups such as patients with polycystic ovary syndrome. However, embryo cryopreservation may cause DNA damage, epigenetic changes, and alterations to gene expression profiles, and the potential impacts of cryopreservation on the embryos and on the long-term health of the resulting offspring are receiving increasing attention. Here, we aim to summarize the impact of cryopreservation on the embryos, perinatal outcomes, and long-term health of the offspring, hoping to explore the potential mechanisms and help guide the next steps in designing clinical studies. In this review, we found that there was no apparent difference in most perinatal outcomes between neonates born following FET and fresh embryo transfer, except for higher risks of large-for-gestational age and macrosomia in FET neonates. Studies on the long-term health and development of FET children are currently lacking; however, the limited evidence so far has found no risk of growth retardation, or chronic or malignant diseases. Large, well-designed, prospective studies taking full consideration of the confounding factors, including parental information, lifestyle, and environmental factors, are needed to confirm these conclusions.

With the development of medical genetics, reproductive medicine has made considerable contributions to treatment of birth defects, a reduction in the incidence of birth defects, implementation of eugenics and fertility, and improvement of population quality. Congenital heart disease is a common birth defect and is the most serious among all birth defect diseases and seriously endangers the physical and mental health of children in China. In this article, we review the latest research progress of congenital heart disease in the field of reproduction.

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine syndrome characterized by metabolic abnormality and reproductive dysfunction, including ovulation abnormality, hyperandrogenism and polycystic ovarian manifestations. Most PCOS patients are overweight or obese, particularly the central type. This aggravates the clinical manifestations of PCOS and ultimately increases the risk of infertility. Orlistat is the only weight loss drug approved by the US Food and Drug Administration. As a long-lasting gastrointestinal lipase inhibitor, orlistat can effectively reduce the absorption of lipid and increase lipid excretion, thereby achieving weight loss. In obese PCOS patients, orlistat can reduce weight, improve lipid metabolism and insulin resistance, improve sex hormone disorder, and have a positive effect on pregnancy outcome. This review summarizes the impact of orlistat treatment on metabolism and fertility in obese women with PCOS.

Retinitis pigmentosa (RP), a major cause of inherited blindness worldwide, is highly heterogeneous. This study aimed to identify mutations in a Chinese cohort of sporadic probands with presumptive RP. Whole exome sequencing represents a considerable advancement in the identification of mutations associated with Mendelian diseases, such as RP. In this study, whole exome sequencing analysis was performed in a Chinese cohort of 95 sporadic probands who were initially diagnosed with RP, in order to identify disease mutations. All detected variations were confirmed by direct Sanger sequencing, and potential pathogenicity was assessed by predictions of the mutations’ functions. The overall mutation rate of presumptive RP genes for this cohort was 30.5% (n= 29 of 95 probands). Forty-four mutations were identified in 19 RP genes, among which 40 mutations were novel. Eleven probands carried mutations in autosomal dominant genes (38.0%), 16 probands carried mutations in autosomal recessive genes (55.2%), and 2 probands carried mutations in X-linked genes (6.9%). Twenty-eight mutations in 18 genes linked to other retinal diseases in 23 probands were also identified. Overall, mutations were detected in 52 probands (54.7%). The recurrent and novel mutations reported here will expand potential understanding of the pathogenesis of RP and other retinal diseases.

Kabuki syndrome (KS) is a rare congenital mental retardation condition characterized by facial dysmorphia, visceral and skeletal malformations, and developmental delay. The integrated phenotype and genotype-based prioritization is critical for diagnoses of genetic diseases. In this study, a Chinese woman, presenting with characteristic facial features of KS, came for pre-pregnancy consultation. We aimed to clarify the diagnosis and provide pre-pregnancy genetic counseling. Facial dysmorphology analysis and next-generation sequencing-based multigene panel approach were used to identify candidate syndromes and causative variants, respectively. The candidate variant was verified by Sanger sequencing. We identified a novel de novo KDM6A pathogenic variant (c.3521G>A) in the woman, which was in line with the Face2Gene analysis result. Peripheral blood RNA assay showed that the variant transcript underwent the nonsense-mediated mRNA decay and led to subsequent haploinsufficiency of KDM6A. Our study provides the genetic diagnosis method for KS type 2 and identifies the first KDM6A point variant in Chinese patient.

The outcome of controlled ovarian hyperstimulation (COH) is various and unpredictable. According to previous studies, 2 single nucleotide polymorphisms, Asn680Ser and -29A/G, have a pharmacogenetic association with ovarian response to COH. However, studies on the Asn680Ser polymorphism have yielded inconsistent conclusions and only a few studies with small sample sizes have been performed on -29A/G. The association of these 2 polymorphisms with ovarian response remains unclear. The present study evaluated the association of Asn680Ser and -29A/G genotypes with COH. A total of 414 Chinese women undergoing in vitro fertilization-embryo transfer were included. Genotypes for these single nucleotide polymorphisms were identified by high-resolution melting-curve analysis. The value of exogenous follicle-stimulating hormone dosage per oocyte divided by the body surface area (Dosage/Oocyte × Surface) was calculated for each patient as an indicator of ovarian response. The results of statistical analyses showed no association between Asn680Ser genotype and ovarian response. As for -29A/G, heterozygote individuals had more oocytes retrieved (P= 0.034). Combinatorial analysis of these 2 single nucleotide polymorphisms showed that genotype A/G-Asn/Asn had lower basal-follicle-stimulating hormone and more oocytes retrieved. Analysis of genotype association with ovarian response also revealed this genotype had a significantly higher risk of developing hyper response (OR = 7.86; 95% CI: 1.31–9.43). To some extent, there were associations between the studied polymorphisms and ovarian response; however, the power of this link is weak and has limited value for clinical prediction.