‘Man Up’:the importance and strategy for placing male reproductive health centre stage in the political and research agenda.

Approximately 1 in 20 young men today have sperm counts low enough to impair fertility, whereas this may not have been the case historically. The cause(s) of such a decline in male reproductive health is unknown, despite it being a global health issue. Concomitantly, little progress has been made in answering fundamental questions in andrology or in developing new diagnostic tools or alternative management strategies to ICSI in infertile men. We advocate formulation of a detailed roadmap for male reproductive health to facilitate development of a research agenda that highlights the present unmet needs and key unanswered questions, and seeks to deliver effective funding and investment to address them. This vision we term a Male Reproductive Health Ecosystem

The diagnosis of male infertility:an analysis of the evidence to support the developments of global WHO guidance. Challenges and future research opportunities

Background: Herein, we describe the consensus guideline methodology, summarize the evidence-based recommendations we provided to the World Health Organization (WHO) for their consideration in the development of global guidance and present a narrative review of the diagnosis of male infertility as related to the eight prioritized (problem or population (P), intervention (I), comparison (C) and outcome(s) (O) (PICO)) questions. Additionally, we discuss the challenges and research gaps identified during the synthesis of this evidence.Objective and Rationale: The aim of this paper is to present an evidence-based approach for the diagnosis of male infertility as related to the eight prioritized PICO questions.Search Methods: Collating the evidence to support providing recommendations involved a collaborative process as developed by WHO, namely: identification of priority questions and critical outcomes; retrieval of up-to-date evidence and existing guidelines; assessment and synthesis of the evidence; and the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation the quality of the supporting evidence was then graded and assessed for consideration during a WHO consensus.Outcomes: Evidence was synthesized and recommendations were drafted to address the diagnosis of male infertility specifically encompassing the following: What is the prevalence of male infertility and what proportion of infertility is attributable to the male? Is it necessary for all infertile men to undergo a thorough evaluation? What is the clinical (ART/non ART) value of traditional semen parameters? What key male lifestyle factors impact on fertility (focusing on obesity, heat and tobacco smoking)? Do supplementary oral antioxidants or herbal therapies significantly influence fertility outcomes for infertile men? What are the evidence-based criteria for genetic screening of infertile men? How does a history of neoplasia and related treatments in the male impact on (his and his partner’s) reproductive health and fertility options? And lastly, what is the impact of varicocele on male fertility and does correction of varicocele improve semen parameters and/or fertility?Wider Implications: This evidence synthesis analysis has been conducted in a manner to be considered for global applicability for the diagnosis of male infertility

Epigenetics and developmental programming of welfare and production traits in farm animals

The concept that postnatal health and development can be influenced by events that occur in utero originated from epidemiological studies in humans supported by numerous mechanistic (including epigenetic) studies in a variety of model species. Referred to as the ‘developmental origins of health and disease’ or ‘DOHaD’ hypothesis, the primary focus of large-animal studies until quite recently had been biomedical. Attention has since turned towards traits of commercial importance in farm animals. Herein we review the evidence that prenatal risk factors, including suboptimal parental nutrition, gestational stress, exposure to environmental chemicals and advanced breeding technologies, can determine traits such as postnatal growth, feed efficiency, milk yield, carcass composition, animal welfare and reproductive potential. We consider the role of epigenetic and cytoplasmic mechanisms of inheritance, and discuss implications for livestock production and future research endeavours. We conclude that although the concept is proven for several traits, issues relating to effect size, and hence commercial importance, remain. Studies have also invariably been conducted under controlled experimental conditions, frequently assessing single risk factors, thereby limiting their translational value for livestock production. We propose concerted international research efforts that consider multiple, concurrent stressors to better represent effects of contemporary animal production systems

Sperm histone methylation is implicated in paternal epigenetic inheritance

Paternal epigenetic inheritance has been described in human cohorts and animal models ranging from worm to mouse. Chemical or nutritional challenge during key developmental time points have been correlated with physiological change in future offspring that oftentimes span multiple generations. Despite these observations, the underlying molecular mechanisms of non-genetic (epigenetic) inheritance remain unknown. Recent studies have shown that sperm histones are retained at genomic regions high in CpG. Specifically, activating histone marks, such as histone H3 lysine 4 di-methylation (H3K4me2) and H3 lysine 4 tri-methylation (H3K4me3), are retained at promoters of genes with functional roles in embryonic development. Therefore, we hypothesize that the methylation of sperm histones is important to the health and development of future offspring and is involved in paternal epigenetic inheritance. To test this hypothesis, we designed a transgenic inbred mouse model that overexpressed the histone demethylase KDM1A in mouse testes with the goal of disrupting the sperm epigenome. This thesis shows that specific alterations of the sperm histones H3K4me2 and H3K4me3 in transgenic (TG) sires were related to severe abnormal phenotypes and gene expression changes in TG offspring and 2-cell embryos. Strikingly, abnormal embryonic development was inherited transgenerationally for two subsequent generations. Furthermore, we quantified consistent intergenerational differences in sperm H3K4me3 and RNA content, which for the first time, implicate mammalian sperm histone methylation in the mechanisms of paternal epigenetic inheritance.Le phénomène d'héritage épigénétique venant du père a été identifié lors de plusieurs études épidémiologiques chez l'humain ainsi que dans de nombreux modèles animaux allant des nématodes aux rongeurs. De plus, l'apport de certaines molécules ou nutriments à des moments clés du développement chez le père a été corrélé à des changements physiologiques dans la progéniture pouvant perdurer pendant de multiples générations. Malgré ces observations, les mécanismes de cet héritage non-génétique (épigénétique) demeurent inconnus. Des études récentes ont montré que des histones sont conservés dans le sperme au niveau des régions du génome riches en CpG. Plus spécifiquement, les modifications des histones activatrices de la transcription, telles que la di-méthylation de l'histone H3 à la lysine 4 (H3K4me2), sont présentes au niveau des promoteurs des gènes impliqués dans le développement embryonnaire. De ce fait, nous postulons l'hypothèse que la méthylation des histones spermatiques joue un rôle dans la santé et le développement de la progéniture et est impliquée dans le phénomène d'héritage épigénétique paternel. Afin de tester cette hypothèse, nous avons créé un modèle de souris transgéniques qui sur expriment la déméthylase d'histone KDM1A dans les testicules de souris dans le but d'altérer l'épigénome spermatique. Nous avons observé des altérations spécifiques de la di et tri méthylation de l'histone H3 au niveau de la lysine 4 (H3K4me2 et H3K4me3, respectivement) chez les animaux transgéniques, ainsi que de leurs ARNs spermatiques, une modification de l'expression génique dans leur embryons au stade 2 cellules mais pas de changement au niveau de la méthylation de l'ADN. Les souriceaux nés de pères transgéniques présentaient de nombreuses anomalies développementales au stade E18.5 et une survie réduite après la naissance. Ces phénotypes sont hérités par les deux générations suivantes, ce qui démontre pour la première fois le rôle des histones présents dans le sperme dans l'héritage épigénétique venant du père

Sperm histone H3 lysine 4 trimethylation is altered in a genetic mouse model of transgenerational epigenetic inheritance

AbstractAdvancing the molecular knowledge surrounding fertility and inheritance has become critical given the halving of sperm counts in the last 40 years, and the rise in complex disease which cannot be explained by genetics alone. The connection between both these trends may lie in alterations to the sperm epigenome and occur through environmental exposures. Changes to the sperm epigenome are also associated with health risks across generations such as metabolic disorders and cancer. Thus, it is imperative to identify the epigenetic modifications that escape reprogramming during spermatogenesis and embryogenesis. Here, we aimed to identify the chromatin signature(s) involved in transgenerational phenotypes in our genetic mouse model of epigenetic inheritance that overexpresses the histone demethylase KDM1A in their germ cells. We used sperm-specific chromatin immunoprecipitation followed by in depth sequencing (ChIP-seq), and computational analysis to identify whether differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3), and histone H3 lysine 27 trimethylation (H3K27me3) serve as mechanisms for transgenerational epigenetic inheritance through the paternal germline. Our analysis on the sperm of KDM1A transgenic males revealed specific changes in H3K4me3 enrichment that predominantly occurred independently from bivalent H3K4me3/H3K27me3 regions. Many regions with altered H3K4me3 enrichment in sperm were identified on the paternal allele of the pre-implantation embryo. These findings suggest that sperm H3K4me3 functions in the transmission of non-genetic phenotypes transgenerationally.</jats:p

Disruption of histone methylation in developing sperm impairs offspring health transgenerationally

Generations affected by histone changes Parent and even grandparent environmental exposure can transmit adverse health effects to offspring. The mechanism of transmission is unclear, but some studies have implicated variations in DNA methylation. In a mouse model, Siklenka et al. found that alterations in histone methylation during sperm formation in one generation leads to reduced survival and developmental abnormalities in three subsequent generations (see the Perspective by McCarrey). Although changes in DNA methylation were not observed, altered sperm RNA content and abnormal gene expression in offspring were measured. Thus, chromatin may act as a mediator of molecular memory in transgenerational inheritance. Science , this issue p. 10.1126/science.aab2006 ; see also p. 634 </jats:p

Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens

Gene-level gRNA aggregation for bulk CRISPR screens