Paternal contribution: new insights and future challenges
TL;DR: To tackle some of the misconceptions surrounding the paternal contribution, the factors that are actually delivered by the sperm at fertilization and their potential developmental functions will be discussed using data from humans and animal models.
Abstract: It has been widely held that all that fathers essentially contribute to the next generation is half their genome. However, recent progress towards understanding biological processes such as sperm maturation and fertilization now indicates that the paternal contribution has been underestimated. To tackle some of the misconceptions surrounding the paternal contribution, the factors that are actually delivered by the sperm at fertilization and their potential developmental functions will be discussed using data from humans and animal models. Although still in their infancy, the practical applications of using sperm RNAs have already emerged in reproductive medicine as markers that are indicative of successful vasectomy. They are also beginning to appear in the forensic sciences and, within the next decade, might appear in the environmental sciences.
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TL;DR: This work reports a similar modification of the mouse Kit gene in the progeny of heterozygotes with the null mutant Kittm1Alf (a lacZ insertion), identifying an unexpected mode of epigenetic inheritance associated with the zygotic transfer of RNA molecules.
Abstract: Paramutation is a heritable epigenetic modification induced in plants by cross-talk between allelic loci Here we report a similar modification of the mouse Kit gene in the progeny of heterozygotes with the null mutant Kit(tm1Alf) (a lacZ insertion) In spite of a homozygous wild-type genotype, their offspring maintain, to a variable extent, the white spots characteristic of Kit mutant animals Efficiently inherited from either male or female parents, the modified phenotype results from a decrease in Kit messenger RNA levels with the accumulation of non-polyadenylated RNA molecules of abnormal sizes Sustained transcriptional activity at the postmeiotic stages--at which time the gene is normally silent--leads to the accumulation of RNA in spermatozoa Microinjection into fertilized eggs either of total RNA from Kit(tm1Alf/+) heterozygotes or of Kit-specific microRNAs induced a heritable white tail phenotype Our results identify an unexpected mode of epigenetic inheritance associated with the zygotic transfer of RNA molecules
846 citations
TL;DR: The present work reviews the articles published to date on the relationship between protamines and infertility and finds evidence that altered levels of protamines may result in an increased susceptibility to injury in the spermatozoan DNA causing infertility or poor outcomes in assisted reproduction.
Abstract: Protamines are the major nuclear sperm proteins. The human sperm nucleus contains two types of protamine: protamine 1 (P1) encoded by a single-copy gene and the family of protamine 2 (P2) proteins (P2, P3 and P4), all also encoded by a single gene that is transcribed and translated into a precursor protein. The protamines were discovered more than a century ago, but their function is not yet fully understood. In fact, different hypotheses have been proposed: condensation of the sperm nucleus into a compact hydrodynamic shape, protection of the genetic message delivered by the spermatozoa, involvement in the processes maintaining the integrity and repair of DNA during or after the nucleohistone-nucleoprotamine transition and involvement in the epigenetic imprinting of the spermatozoa. Protamines are also one of the most variable proteins found in nature, with data supporting a positive Darwinian selection. Changes in the expression of P1 and P2 protamines have been found to be associated with infertility in man. Mutations in the protamine genes have also been found in some infertile patients. Transgenic mice defective in the expression of protamines also present several structural defects in the sperm nucleus and have variable degrees of infertility. There is also evidence that altered levels of protamines may result in an increased susceptibility to injury in the spermatozoan DNA causing infertility or poor outcomes in assisted reproduction. The present work reviews the articles published to date on the relationship between protamines and infertility.
702 citations
Cites background from "Paternal contribution: new insights..."
...For further information on this subject, the reader is referred to excellent reviews and articles on the transcriptional, molecular and cellular mechanisms in spermatogenesis (Iatrou and Dixon, 1978; Mezquita, 1985; Hecht, 1988, 1993; Perreault, 1992; Braun et al., 1995; Dadoune, 1995, 2003; Kramer and Krawetz, 1997; Siffroi et al., 1999; Steger, 1999, 2001; Steger et al., 2000, 2002; Grootegoed et al., 2000; Aoki and Carrell, 2003; Hebbar and Archer, 2003; Kleene, 2003; Dadoune et al., 2004; Kierszenbaum and Tres, 2004; Kimmins et al., 2004; Rockett et al., 2004; Krawetz, 2005; Miller et al., 2005; Tanaka and Baba, 2005)....
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...…1999; Steger, 1999, 2001; Steger et al., 2000, 2002; Grootegoed et al., 2000; Aoki and Carrell, 2003; Hebbar and Archer, 2003; Kleene, 2003; Dadoune et al., 2004; Kierszenbaum and Tres, 2004; Kimmins et al., 2004; Rockett et al., 2004; Krawetz, 2005; Miller et al., 2005; Tanaka and Baba, 2005)....
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TL;DR: The evidence for transgenerational epigenetic inheritance via the gametes is considered, including cases of environmentally induced epigenetic changes.
Abstract: It is known that information that is not contained in the DNA sequence — epigenetic information — can be inherited from the parent to the offspring. However, many questions remain unanswered regarding the extent and mechanisms of such inheritance. In this Review, we consider the evidence for transgenerational epigenetic inheritance via the gametes, including cases of environmentally induced epigenetic changes. The molecular basis of this inheritance remains unclear, but recent evidence points towards diffusible factors, in particular RNA, rather than DNA methylation or chromatin. Interestingly, many cases of epigenetic inheritance seem to involve repeat sequences.
626 citations
TL;DR: Diet‐induced paternal obesity modulates sperm microRNA content and germ cell methylation status, which are potential signals that program offspring health and initiate the transmission of obesity and impaired metabolic health to future generations.
Abstract: Obesity is highly prevalent, and its incidence is increasing. The previous study showing a major effect of paternal obesity on metabolic health of offspring is confounded by comorbidity with diabetes. Therefore, we investigated the effect of diet-induced paternal obesity, in the absence of diabetes, on the metabolic health of two resultant generations and the molecular profiles of the testes and sperm. Founder (F0) male C57BL6 mice were fed either a high-fat diet (HFD) or a control diet (CD); n = 10/diet for a period of 10 wk. Testis expression of mRNA/microRNAs was analyzed by microarray and qPCR and sperm microRNA abundance by qPCR. Two subsequent generations were generated by mating F0 and then F1 mice to CD mice, and their metabolic health was investigated. All mice, other than F0 males, were maintained on a CD. HFD feeding induced paternal obesity with a 21% increase in adiposity, but not overt diabetes, and initiated intergenerational transmission of obesity and insulin resistance in two generations of offspring. This distinct phenotypic constellation is either partially or fully transmitted to both female and male F1 offspring and further transmitted through both parental lineages to the F2 generation, with a heightened effect on female F1 offspring (+67% in adiposity) and their F2 sons (+24% in adiposity). Founder male obesity altered the testes expression of 414 mRNAs by microarray and 11 microRNAs by qPCR, concomitant with alterations in sperm microRNA content and a 25% reduction in global methylation of germ cell DNA. Diet-induced paternal obesity modulates sperm microRNA content and germ cell methylation status, which are potential signals that program offspring health and initiate the transmission of obesity and impaired metabolic health to future generations. This study implicates paternal obesity in the transgenerational amplification of obesity and type 2 diabetes in humans.
477 citations
TL;DR: Evidence is provided that sperm-borne miR-34c is important for the first cell division via modulation of Bcl-2 expression in the zygotes through modulation of UTR luciferase activity.
Abstract: In mammals, the sperm deliver mRNA of unknown function into the oocytes during fertilization. The role of sperm microRNAs (miRNAs) in preimplantation development is unknown. miRNA profiling identified six miRNAs expressed in the sperm and the zygotes but not in the oocytes or preimplantation embryos. Sperm contained both the precursor and the mature form of one of these miRNAs, miR-34c. The absence of an increased level of miR-34c in zygotes derived from α-amanitin–treated oocytes and in parthenogenetic oocytes supported a sperm origin of zygotic miR-34c. Injection of miR-34c inhibitor into zygotes inhibited DNA synthesis and significantly suppressed first cleavage division. A 3′ UTR luciferase assay and Western blotting demonstrated that miR-34c regulates B-cell leukemia/lymphoma 2 (Bcl-2) expression in the zygotes. Coinjection of anti–Bcl-2 antibody in zygotes partially reversed but injection of Bcl-2 protein mimicked the effect of miR-34c inhibition. Oocyte activation is essential for the miR-34c action in zygotes, as demonstrated by a decrease in 3′UTR luciferase reporter activity and Bcl-2 expression after injection of precursor miR-34c into parthenogenetic oocytes. Our findings provide evidence that sperm-borne miR-34c is important for the first cell division via modulation of Bcl-2 expression.
368 citations
Cites background from "Paternal contribution: new insights..."
...Phospholipase Cζ and postacrosomal sheath WW domain-binding protein of the sperm initiate calcium signaling crucial to oocyte activation (1) and promote meiotic resumption and pronuclear formation (2)....
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References
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TL;DR: Two founding members of the microRNA family were originally identified in Caenorhabditis elegans as genes that were required for the timed regulation of developmental events and indicate the existence of multiple RISCs that carry out related but specific biological functions.
Abstract: MicroRNAs are a family of small, non-coding RNAs that regulate gene expression in a sequence-specific manner. The two founding members of the microRNA family were originally identified in Caenorhabditis elegans as genes that were required for the timed regulation of developmental events. Since then, hundreds of microRNAs have been identified in almost all metazoan genomes, including worms, flies, plants and mammals. MicroRNAs have diverse expression patterns and might regulate various developmental and physiological processes. Their discovery adds a new dimension to our understanding of complex gene regulatory networks.
6,282 citations
TL;DR: A large number of microRNAs have been identified in almost all metazoan genomes, including worms, flies, plants and mammals, and their discovery adds a new dimension to the understanding of complex gene regulatory networks.
Abstract: Nature Reviews Genetics 5, 522–531 (2004) In figure 2, the orientation of some RNA structures was incorrect. The corrected version is shown below. This correction has been made to the online enhanced text and PDF version of this review.
2,555 citations
TL;DR: There has been a genuine decline in semen quality over the past 50 years, and as male fertility is to some extent correlated with sperm count the results may reflect an overall reduction in male fertility.
Abstract: OBJECTIVE--To investigate whether semen quality has changed during the past 50 years. DESIGN--Review of publications on semen quality in men without a history of infertility selected by means of Cumulated Index Medicus and Current List (1930-1965) and MEDLINE Silver Platter database (1966-August 1991). SUBJECTS--14,947 men included in a total of 61 papers published between 1938 and 1991. MAIN OUTCOME MEASURES--Mean sperm density and mean seminal volume. RESULTS--Linear regression of data weighted by number of men in each study showed a significant decrease in mean sperm count from 113 x 10(6)/ml in 1940 to 66 x 10(6)/ml in 1990 (p < 0.0001) and in seminal volume from 3.40 ml to 2.75 ml (p = 0.027), indicating an even more pronounced decrease in sperm production than expressed by the decline in sperm density. CONCLUSIONS--There has been a genuine decline in semen quality over the past 50 years. As male fertility is to some extent correlated with sperm count the results may reflect an overall reduction in male fertility. The biological significance of these changes is emphasised by a concomitant increase in the incidence of genitourinary abnormalities such as testicular cancer and possibly also cryptorchidism and hypospadias, suggesting a growing impact of factors with serious effects on male gonadal function.
2,481 citations
TL;DR: The study of imprinting provides new insights into epigenetic gene modification during development, and is thought to influence the transfer of nutrients to the fetus and the newborn from the mother.
Abstract: Genomic imprinting affects several dozen mammalian genes and results in the expression of those genes from only one of the two parental chromosomes. This is brought about by epigenetic instructions--imprints--that are laid down in the parental germ cells. Imprinting is a particularly important genetic mechanism in mammals, and is thought to influence the transfer of nutrients to the fetus and the newborn from the mother. Consistent with this view is the fact that imprinted genes tend to affect growth in the womb and behaviour after birth. Aberrant imprinting disturbs development and is the cause of various disease syndromes. The study of imprinting also provides new insights into epigenetic gene modification during development.
2,212 citations
TL;DR: The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active environmental chemicals during fetal and childhood development.
Abstract: Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.
1,458 citations