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A severe decline in child births has occurred over the past half century, which will lead to considerable population declines, particularly in industrialized regions. A crucial question is whether this decline can be explained by economic and behavioural factors alone, as suggested by demographic reports, or to what degree biological factors are also involved. Here, we discuss data suggesting that human reproductive health is deteriorating in industrialized regions. Widespread infertility and the need for assisted reproduction due to poor semen quality and/or oocyte failure are now major health issues. Other indicators of declining reproductive health include a worldwide increasing incidence in testicular cancer among young men and alterations in twinning frequency. There is also evidence of a parallel decline in rates of legal abortions, revealing a deterioration in total conception rates. Subtle alterations in fertility rates were already visible around 1900, and most industrialized regions now have rates below levels required to sustain their populations. We hypothesize that these reproductive health problems are partially linked to increasing human exposures to chemicals originating directly or indirectly from fossil fuels. If the current infertility epidemic is indeed linked to such exposures, decisive regulatory action underpinned by unconventional, interdisciplinary research collaborations will be needed to reverse the trends.This article discusses trends in human reproductive behaviour and health that are associated with infertility. These changes have occurred over a period of only a couple of generations, so environmental factors are suggested to have a role.

Azoospermia is a condition defined as the absence of spermatozoa in the ejaculate, but the testicular phenotype of men with azoospermia may be very variable, ranging from full spermatogenesis, through arrested maturation of germ cells at different stages, to completely degenerated tissue with ghost tubules. Hence, information regarding the cell-type-specific expression patterns is needed to prioritise potential pathogenic variants that contribute to the pathogenesis of azoospermia. Thanks to technological advances within next-generation sequencing, it is now possible to obtain detailed cell-type-specific expression patterns in the testis by single-cell RNA sequencing. However, to interpret single-cell RNA sequencing data properly, substantial knowledge of the highly sophisticated data processing and visualisation methods is needed. Here we review the complex cellular structure of the human testis in different types of azoospermia and outline how known genetic alterations affect the pathology of the testis. We combined the currently available single-cell RNA sequencing datasets originating from the human testis into one dataset covering 62,751 testicular cells, each with a median of 2637 transcripts quantified. We show what effects the most common data-processing steps have, and how different visualisation methods can be used. Furthermore, we calculated expression patterns in pseudotime, and show how splicing rates can be used to determine the velocity of differentiation during spermatogenesis. With the combined dataset we show expression patterns and network analysis of genes known to be involved in the pathogenesis of azoospermia. Finally, we provide the combined dataset as an interactive online resource where expression of genes and different visualisation methods can be explored (https://testis.cells.ucsc.edu/).

Testicular germ cell tumours (TGCTs) are the most frequent cancer type in young men and originate from the common precursor germ cell neoplasia in situ (GCNIS). For decades, clinical management of patients with TGCT has relied on classic serum tumour markers: α-fetoprotein, human chorionic gonadotropin subunit-β and lactate dehydrogenase. In the past 10 years, microRNAs have been shown to outperform classic serum tumour markers in the diagnosis of primary tumours and in follow-up monitoring and prediction of relapse. miR-371a-3p is the most consistent marker and exhibits >90% diagnostic sensitivity and specificity in TGCT. However, miR-371a-3p cannot be used to diagnose GCNIS or mature teratoma. Future efforts must technically standardize the microRNA-based methods internationally and introduce miR-371a-3p as a molecular liquid biopsy-based marker for TGCTs in the clinic.Here, the authors discuss embryonic microRNAs that are highly expressed in testicular germ cell tumours, critically assess the clinical utility of monitoring these microRNAs in the circulation and compare their diagnostic performance with the classic serum tumour markers.

Background Pubertal timing is closely linked to growth regulated by the growth hormone/insulin-like factor (GH/IGF) axis that includes IGF-regulating factors such as pregnancy-associated plasma protein-A/A2 (PAPP-A/PAPP-A2) and stanniocalcin 2 (STC2). We investigated the association between height, IGF-I concentration, and PAPPA , PAPPA2 , and STC2 genotypes on the timing of female pubertal milestones. Methods Height, IGF-I, and genotypes were analyzed in 1382 Danish girls from the general population, 67 patients with tall stature (height ≥2 SD), and 124 patients with short stature (height ≤−2 SD). The main outcomes were breast stage and menarche. Results Thelarche occurred significantly earlier in patients with tall stature (mean age 9.37 years [95% confidence interval (CI) 8.87–9.87]) and later in patients with short stature (11.07 years [95% CI 10.7–11.43]) compared with girls within the normal range (9.96 years [95% CI 9.85–10.07]) ( p  = 0.02 and p  < 0.01, respectively). Girls with higher IGF-I levels experienced thelarche and menarche earlier compared with the rest of the cohort ( p  < 0.01). Genotypes were not associated with age at thelarche nor menarche, but the PAPPA2 minor allele carriers were shorter compared with major allele carriers, p  = 0.03. Conclusions Height and IGF-I, but not PAPP-A , PAPP-A2 , and STC2 genotypes, were negatively associated with age at thelarche and menarche. Impact Girls with tall and short stature enter puberty earlier and later compared with girls with normal height. Girls with higher insulin-growth factor-I in childhood enter puberty earlier. Pubertal timing is influenced by longitudinal growth and IGF-I levels earlier in childhood. Childhood growth and the levels of IGF-I in childhood may be biomarkers of pubertal timing.

Homologous recombination rearranges genetic information during meiosis, creating new combinations of the genome while also introducing mutations, and influencing GC content. Here we report direct detection of recombination events using highly accurate long-read sequencing from testis tissue of 16 individuals across six primate species and three human sperm samples. Based on methylation patterns, we classify sequencing reads as originating from either somatic or germline cells. We identify 2881 crossovers, 2314 simple gene conversions, and 555 complex events, and analyze their chromosomal distribution. Crossovers are more telomeric, showing stronger concordance with recombination maps than gene conversions. Human samples align with a double-strand break map, whereas other species differ, consistent with variation in PRDM9-directed breaks, although the recombination process is otherwise conserved. Gene conversion tracts are short and of similar length across species (mean 22–95 bp), implying that most non-crossover events are undetectable. We observe GC-biased gene conversion for both single and multiple-SNV events, including sites flanking crossovers. We infer longer gene conversion tracts associated with crossovers (318–688 bp) than with non-crossovers. Highly accurate long-read sequencing combined with methylation-based classification of reads to specific cell types provides a powerful way of studying recombination events in single individuals of any mammalian species. Homologous recombination rearranges genetic information during meiosis to generate new combinations in the genome. Here, the authors report direct, single-individual detection of recombination in primates and humans using long-read sequencing.

Puberty marks numerous physiological processes which are initiated by central activation of the hypothalamic–pituitary–gonadal axis, followed by development of secondary sexual characteristics. To a large extent, pubertal timing is heritable, but current knowledge of genetic polymorphisms only explains few months in the large inter-individual variation in the timing of puberty. We have analysed longitudinal genome-wide changes in DNA methylation in peripheral blood samples (n = 102) obtained from 51 healthy children before and after pubertal onset. We show that changes in single methylation sites are tightly associated with physiological pubertal transition and altered reproductive hormone levels. These methylation sites cluster in and around genes enriched for biological functions related to pubertal development. Importantly, we identified that methylation of the genomic region containing the promoter of TRIP6 was co-ordinately regulated as a function of pubertal development. In accordance, immunohistochemistry identified TRIP6 in adult, but not pre-pubertal, testicular Leydig cells and circulating TRIP6 levels doubled during puberty. Using elastic net prediction models, methylation patterns predicted pubertal development more accurately than chronological age. We demonstrate for the first time that pubertal attainment of secondary sexual characteristics is mirrored by changes in DNA methylation patterns in peripheral blood. Thus, modulations of the epigenome seem involved in regulation of the individual pubertal timing.

A major part of the human Y chromosome consists of palindromes with multiple copies of genes primarily expressed in testis, many of which have been claimed to affect male fertility. Here we examine copy number variation in these palindromes based on whole genome sequence data from 11,527 Icelandic men. Using a subset of 7947 men grouped into 1449 patrilineal genealogies, we infer 57 large scale de novo copy number mutations affecting palindrome 1. This corresponds to a mutation rate of 2.34 × 10 −3 mutations per meiosis, which is 4.1 times larger than our phylogenetic estimate of the mutation rate (5.72 × 10 −4 ), suggesting that de novo mutations on the Y are lost faster than expected under neutral evolution. Although simulations indicate a selection coefficient of 1.8% against non-reference copy number carriers, we do not observe differences in fertility among sequenced men associated with their copy number genotype, but we lack statistical power to detect differences resulting from weak negative selection. We also perform association testing of a diverse set of 341 traits to palindromic copy number without any significant associations. We conclude that large-scale palindrome copy number variation on the Y chromosome has little impact on human phenotype diversity. A major part of the human Y chromosome consists of palindromes with multiple copies of genes primarily expressed in testis. Here, the authors investigate copy number variation in these palindromes based on whole genome sequence data from 11,527 Icelandic men.

Klinefelter syndrome (47,XXY) causes infertility with a testicular histology comprising two types of Sertoli cell-only tubules, representing mature and immature-like Sertoli cells, and occasionally focal spermatogenesis. Here, we show that the immature-like Sertoli cells highly expressed XIST and had two X-chromosomes, while the mature Sertoli cells lacked XIST expression and had only one X-chromosome. Sertoli cells supporting focal spermatogenesis also lacked XIST expression and the additional X-chromosome, while the spermatogonia expressed XIST despite having only one X-chromosome. XIST was expressed in Sertoli cells until puberty, where a gradual loss was observed. Our results suggest that a micro-mosaic loss of the additional X-chromosome is needed for Sertoli cells to mature and to allow focal spermatogenesis.

ObjectivesConsiderable interest and controversy over a possible decline in semen quality during the 20th century raised concern that semen quality could have reached a critically low level where it might affect human reproduction. The authors therefore initiated a study to assess reproductive health in men from the general population and to monitor changes in semen quality over time.DesignCross-sectional study of men from the general Danish population. Inclusion criteria were place of residence in the Copenhagen area, and both the man and his mother being born and raised in Denmark. Men with severe or chronic diseases were not included.SettingDanish one-centre study.Participants4867 men, median age 19 years, included from 1996 to 2010.Outcome measuresSemen volume, sperm concentration, total sperm count, sperm motility and sperm morphology.ResultsOnly 23% of participants had optimal sperm concentration and sperm morphology. Comparing with historic data of men attending a Copenhagen infertility clinic in the 1940s and men who recently became fathers, these two groups had significantly better semen quality than our study group from the general population. Over the 15 years, median sperm concentration increased from 43 to 48 million/ml (p=0.02) and total sperm count from 132 to 151 million (p=0.001). The median percentage of motile spermatozoa and abnormal spermatozoa were 68% and 93%, and did not change during the study period.ConclusionsThis large prospective study of semen quality among young men of the general population showed an increasing trend in sperm concentration and total sperm count. However, only one in four men had optimal semen quality. In addition, one in four will most likely face a prolonged waiting time to pregnancy if they in the future want to father a child and another 15% are at risk of the need of fertility treatment. Thus, reduced semen quality seems so frequent that it may impair the fertility rates and further increase the demand for assisted reproduction.

Male infertility has been linked to M1AP. In mice, M1AP interacts with the ZZS proteins SHOC1/TEX11/SPO16, promoting DNA class I crossover formation during meiosis. To determine whether M1AP and ZZS proteins are involved in human male infertility by recombination failure, we screened for biallelic/hemizygous loss-of-function (LoF) variants in the human genes to select men with presumed protein deficiency ( N  = 24). After in-depth characterisation of testicular phenotypes, we identified gene-specific meiotic impairments: men with ZZS deficiency shared an early meiotic arrest. Men with LoF variants in M1AP exhibited a predominant metaphase I arrest with rare haploid round or even elongated spermatids. These differences were explained by different recombination failures: deficient ZZS function led to incorrect synapsis of homologous chromosomes, unrepaired DNA double-strand breaks, and incomplete recombination. Abolished M1AP led to a reduced number of recombination intermediates and class I crossover. Medically assisted reproduction resulted in the birth of a healthy child, offering the possibility of fatherhood to men with LoF variants in M1AP . Our study establishes M1AP as an important, but non-essential, functional enhancer in meiotic recombination. Synopsis One cause of male infertility is meiotic arrest and azoospermia. This condition can be caused by variants in M1AP or the ZZS complex components SHOC1, TEX11, and SPO16, which play a role in meiotic recombination. This study provides implications for evidence-based treatment options. The first biallelic loss-of-function variant in SPO16 is reported associated with male infertility, specifically complete meiotic arrest. Presumed deficiency of SHOC1, TEX11, or SPO16 results in an early meiotic arrest and the absence of haploid gametes. Presumed M1AP deficiency results in metaphase I arrest with few haploid germ cells, sufficient to allow affected men to conceive a child through medically assisted reproduction. Meiotic recombination is severely impaired in men with a presumed deficiency of SHOC1, TEX11, or SPO16 but less in men with a presumed deficiency of M1AP, suggesting different treatment options. One cause of male infertility is meiotic arrest and azoospermia. This condition can be caused by variants in M1AP or the genes encoding the ZZS complex components SHOC1, TEX11, and SPO16, which play a role in meiotic recombination. This study provides implications for evidence-based treatment options.