Placental DNA Methylation Related to Both Infant Toenail Mercury and Adverse Neurobehavioral Outcomes

Background: Prenatal mercury (Hg) exposure is associated with adverse child neurobehavioral outcomes. Because Hg can interfere with placental functioning and cross the placenta to target the fetal brain, prenatal Hg exposure can inhibit fetal growth and development directly and indirectly. Objectives: We examined potential associations between prenatal Hg exposure assessed through infant toenail Hg, placental DNA methylation changes, and newborn neurobehavioral outcomes. Methods: The methylation status of \u3e 485,000 CpG loci was interrogated in 192 placental samples using Illumina’s Infinium HumanMethylation450 BeadArray. Hg concentrations were analyzed in toenail clippings from a subset of 41 infants; neurobehavior was assessed using the NICU Network Neurobehavioral Scales (NNNS) in an independent subset of 151 infants. Results: We identified 339 loci with an average methylation difference \u3e 0.125 between any two toenail Hg tertiles. Variation among these loci was subsequently found to be associated with a high-risk neurodevelopmental profile (omnibus p-value = 0.007) characterized by the NNNS. Ten loci had p \u3c 0.01 for the association between methylation and the high-risk NNNS profile. Six of 10 loci reside in the EMID2 gene and were hypomethylated in the 16 high-risk profile infants’ placentas. Methylation at these loci was moderately correlated (correlation coefficients range, –0.33 to –0.45) with EMID2 expression. Conclusions: EMID2 hypomethylation may represent a novel mechanism linking in utero Hg exposure and adverse infant neurobehavioral outcomes

A Review on Automatic Analysis of Human Embryo Microscope Images

Over the last 30 years the process of in vitro fertilisation (IVF) has evolved considerably, yet the efficiency of this treatment remains relatively poor. The principal challenge faced by doctors and embryologists is the identification of the embryo with the greatest potential for producing a child. Current methods of embryo viability assessment provide only a rough guide to potential. In order to improve the odds of a successful pregnancy it is typical to transfer more than one embryo to the uterus. However, this often results in multiple pregnancies (twins, triplets, etc), which are associated with significantly elevated risks of serious complications. If embryo viability could be assessed more accurately, it would be possible to transfer fewer embryos without negatively impacting IVF pregnancy rates. In order to assist with the identification of viable embryos, several scoring systems based on morphological criteria have been developed. However, these mostly rely on a subjective visual analysis. Automated assessment of morphological features offers the possibility of more accurate quantification of key embryo characteristics and elimination of inter- and intra-observer variation. In this paper, we describe the main embryo scoring systems currently in use and review related works on embryo image analysis that could lead to an automatic and precise grading of embryo quality. We summarise achievements, discuss challenges ahead, and point to some possible future directions in this research field

Developmental Programming Mediated by Complementary Roles of Imprinted Grb10 in Mother and Pup

Developmental programming links growth in early life with health status in adulthood. Although environmental factors such as maternal diet can influence the growth and adult health status of offspring, the genetic influences on this process are poorly understood. Using the mouse as a model, we identify the imprinted gene Grb10 as a mediator of nutrient supply and demand in the postnatal period. The combined actions of Grb10 expressed in the mother, controlling supply, and Grb10 expressed in the offspring, controlling demand, jointly regulate offspring growth. Furthermore, Grb10 determines the proportions of lean and fat tissue during development, thereby influencing energy homeostasis in the adult. Most strikingly, we show that the development of normal lean/fat proportions depends on the combined effects of Grb10 expressed in the mother, which has the greater effect on offspring adiposity, and Grb10 expressed in the offspring, which influences lean mass. These distinct functions of Grb10 in mother and pup act complementarily, which is consistent with a coadaptation model of imprinting evolution, a model predicted but for which there is limited experimental evidence. In addition, our findings identify Grb10 as a key genetic component of developmental programming, and highlight the need for a better understanding of mother-offspring interactions at the genetic level in predicting adult disease risk

The Evolution of in Vitro Fertilization: Integration of Pharmacology, Technology, and Clinical Care

ABSTRACT For the couple having trouble achieving pregnancy, the options and opportunities for assistance have never been brighter. Options such as controlled ovarian hyperstimulation, in vitro fertilization, and intracytoplasmic sperm injection have been developed over the past five decades and provide hope for couples that previously would have been considered infertile. In vitro fertilization and intracytoplasmic sperm injection represent a coalescence of advances in physiology, endocrinology, pharmacology, technology, and clinical care. In vitro fertilization has assisted well over one million couples in their efforts to start or build a family, and the demand for such services continues to increase. The purpose of this manuscript is to review the pharmacological advances that made controlled ovarian hyperstimulation, and therefore in vitro fertilization and intracytoplasmic sperm injection, possible. We will discuss the early stages of gonadotropin use to stimulate ovarian production of multiple mature eggs, the advances in recombinant technology that allowed purified hormone for therapy, and the use of other hormones to regulate the menstrual cycle such that the likelihood of successful oocyte retrieval and embryo implantation is optimized. Finally, we will review current areas that require particular attention if we are to provide more opportunity for infertile couples. Controlled ovarian hyperstimulation (COH), in vitro fertilization (IVF), and intracytoplasmic sperm injection have become the standard of care for many couples with infertility. The combination of pharmacologic and surgical manipulation of the menstrual cycle is the key to improving pregnancy rates. The history and evolution of COH, IVF, and intracytoplasmic sperm injection has been rapidly developing and continues to change at an ever increasing pace In a typical menstrual cycle, there is the formation of a single dominant follicle, from which ovulation of a single oocyte occurs each month. For the fertile couple, this menstrual cycle has a 20% chance of resulting in a pregnancy; however, for infertile couples, the chance of pregnancy with one oocyte can be well under 5% per cycle. Over the past 50 years, pharmacologic agents have been developed to increase the likelihood of pregnancy by increasing the number of eggs released and available for fertilization. To clarify the obstacles to fertility that have been overcome as well as the challenges that remain, we will review the physiology of the menstrual cycle, major historical developments, and the therapeutic evolution and current use of medications used during controlled ovarian hyperstimulation and in vitro fertilization. This review, by design, will be a brief overview. Those Article, publication date, and citation information can be found a

Transcriptome analysis of human cumulus cells reveals hypoxia as the main determinant of follicular senescence

STUDY QUESTION: Can RNA sequencing of human cumulus cells (CC) reveal molecular pathways involved in the physiology of reproductive aging? STUDY FINDING: Senescent but not young CC activate gene pathways associated with hypoxia and oxidative stress. WHAT IS KNOWN ALREADY: Shifts in socioeconomic norms are resulting in larger numbers of women postponing childbearing. The reproductive potential is sharply decreased with aging, and the reasons are poorly understood. Since CCs play an integral role in oocyte maturation and direct access to human oocytes is limited, we used whole transcriptome analysis of these somatic cells to gain insights into the molecular mechanisms playing a role in follicular senescence. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Twenty CC samples (from a total of 15 patients) were obtained from oocytes of either male factor or egg donor patients. RNA sequencing and bioinformatic tools were used to identify differentially expressed genes between CCs from seven aged and eight young patients (<35 (years old) y.o. vs >40 y.o.). Quantitative-PCR and immunoflourescent staining were used for validation. MAIN RESULTS AND THE ROLE OF CHANCE: RNA sequencing identified 11 572 genes expressed in CC of both age cohorts, 45 of which were differentially expressed. In CC collected from patients >40 y.o., genes involved in the hypoxia stress response (NOS2, RORA and NR4A3), vasculature development (NR2F2, PTHLH), glycolysis (RALGAPA2 and TBC1D4) and cAMP turnover (PDE4D) were significantly overexpressed when compared with CC of patients younger than 35 y.o. LIMITATIONS, REASONS FOR CAUTION: This study focused almost exclusively on assessing the genetic differences in CC transcriptome between young and older women. These genetic findings were not fully correlated with embryonic development and clinical outcome. WIDER IMPLICATIONS OF THE FINDINGS: Our data provide a new hypothesis—follicular hypoxia—as the main mechanism leading to ovarian follicular senescence and suggest a link between cumulus cell aging and oocyte quality decay. If specific molecular findings of hypoxia would be confirmed also in oocytes, genetic platforms could screen CC for hypoxic damage and identify healthier oocytes. Protocols of ovarian stimulation in older patients could also be adjusted to diminish oocyte exposure time to hypoxic follicles. LARGE SCALE DATA: GEO accession number: GSE81579 STUDY FUNDING AND COMPETING INTEREST(S): Funded in part by EMD Serono Grant for Fertility Innovation (GFI)