Paternal Factors as an Etiology of Recurrent Pregnancy Loss

Historically, it had always been assumed that the distressing issue of recurrent pregnancy loss (RPL) results from maternal rejection of normal fetuses. The evidences from clinical, epidemiological and basic sciences cited the ‘selection failure hypothesis’ which states that the rising issue of RPL is due to the failure of prevention of ‘poor quality’ embryos to implant, which later presents clinically as miscarriage. Thus, pointing towards a failure of or impaired natural embryo selection (Quenby et al., 2002; Teklenberg et al., 2010). Various studies highlighted the role of different maternal causal factors and mechanisms underlying this extensive feto-maternal cross-talk. 

All this while little attention had been paid to paternal effects. While in the last two decades, evidences have suggested paternal contributions to  impaired fertilization and embryonic development. A shift in the current paradigm has focused on assessing the contribution of spermatozoa for the events underlying fertilization and embryogenesis. Apart from contributing the paternal haploid genome, the fertilizing spermatozoa also contributes the signal to initiate metabolic activity of oocyte (oocyte activation factor, OAF), and the centriole to direct the microtubule assembly for formation of mitotic spindle for subsequent cleavage divisions. Maternal centriole is fully degraded in order to avoid abnormal fertilization and only maintains the γ-tubulin for normal centrosome function (Wu et al., 2007). Any deficiency of OAF or centrosome dysfunction marks the ‘early paternal effects’ of embryonic development. These are marked by poor zygote and early embryo morphology and are seen before the activation of the embryonic genome which begins at the 4-cell stage in human embryo. On the other hand, the ‘late paternal effects’ are witnessed as poor developmental competence, implantation failure, pregnancy loss, developmental abnormalities (Tesarik et al., 2004; Barrosso et al., 2009) These “carried over” sublethal effects may be associated with sperm chromatin defects such as aneuploidies, sperm DNA damage, mitochondrial dysfunctions or even abnormal delivery of sperm mRNA (Barrosso et al., 2009). Defective spermatozoa not only affect the pregnancy outcome but also affect the health trajectory of the offspring resulting in an increase in dominant genetic disorders and neuropsychiatric disorders like autism and schizophrenia and even childhood carcinomas (Aitken, Baker & Sawyer, 2003; Kumar et al., 2015; Rima D et al, 2016; Dhawan et al., 2017).

The integrity of the sperm nuclear DNA is a vital determinant of semen quality as it not only correlates with successful fertilization but also normal embryonic development and subsequent health of the progeny. The highly polarized and stable sperm cells are characterized by a host of changes occurring during spermatogenesis and spermiogenesis. These highly differentiated cells undergo major morphological and molecular changes concerning acrosome and flagellar formation, cytoplasm elimination, mitochondrial rearrangement and finally nuclear reshaping. Sperm nuclear chromatin undergoes sixfold greater levels of compaction than the somatic cells where DNA is coiled around histone octamer including H2A, H2B, H3 and H4 histones into nucleosomes and then solenoids. The high level of nuclear compaction in sperm is comprised of step-wise replacement of histones by protamines. Protamines are the most abundant nuclear proteins, and highly basic in nature owing to high content of arginine. During the later stages of spermatogenesis both canonical histones and testicular histones in round spermatids are replaced by transition proteins (TP1 and TP2) which are subsequently replaced by protamines in elongated spermatids (Li et al., 2008; Hammoud et al., 2009; Miller, Brinkworth and Iles, 2010; Ioannou et al. 2016). ~85% of histones which are replaced by protamines form the central nucleoprotamine complex and ~15% remains as peripheral nucleohistones. The sperm DNA is compacted into doughnut-shaped toroids containing ~50kb of DNA in semicrystalline state (Ward, 2010). Both canonical histones and testicular histone variants in the sperm are replaced by protamine proteins (P1 and P2). While protamines bind to Alu repeats, histones are predominantly associated with telomeres and promoters of genes that regulate early embryonic development (Wykes & Krawetz 2003b). The condensation of the sperm chromatin facilitates the sperm motility, as decondensed sperm head may mechanically perturb the cell’s potential for motility (Carrell and Hammoud, 2010). The extensive creatin of inter- and intra- molecular disulfide bridges within the toroids is relatively resistant to DNA damage, while the peripheral nucleohistone compartment is particularly vulnerable to oxidative attack, attack by nucleases and DNA damage. Thus the condensed chromatin provides protection from the DNA damage to the vulnerable spermatozoa which is susceptible to damage at various stages of spermatogenesis, function and transport, and also post spermiogenesis. Along with the protection from DNA damage during compaction, the nuclear transcriptional machinery is also shut down, due to inability of polymerase enzymes to gain access to the DNA (Daduone P, 1995). In addition to the resumption of the oocyte’s cell cycle, the sperm chromatin is reorganized from its highly compacted and transcriptionally quiescent state after fertilization to generate a trancriptionally competent DNA which can contribute to embryonic development (McLay and Clarke, 2003). The sperm DNA is decondensed prior to DNA replication and mitosis and expands to approximately three times the size of the mature sperm nucleus, resulting in the formation of the paternal pronucleus (Nonchev and Tsanev, 1990). The majority of the protamines (~80%) are removed within 3hours post fertilization, and histone association with DNA begins to be completed by 4 hours. Transcription is initiated at 4- to 8-cell stage of embryonic genome.

DNA damage in spermatozoa is multifactorial due to both intrinsic and extrinsic factors. It is the result of poor protamination, excessive production of reactive oxygen species (ROS) levels, abortive apoptosis, infections and varicocele increase in the number of immature sperm cells which lack antioxidant protection. Advancing paternal age at conception, lifestyle factors like smoking, alcohol, overwhelming psychological stress, consumption of fatty foods and various environmental exposures, electromagnetic radiations, radiotherapy and chemotherapy are various other extrinsic factors. The spermatozoon is particularly vulnerable to attack by oxidants due to its propensity to produce reactive oxygen species (ROS) during physiological processes as sperm capacitation, its lack of antioxidant protection as a result of minimal cytoplasmic volume, high polyunsaturated fatty acid (PUFA) content , a paucity of DNA damage detection and repair machinery and very little capacity for transcription or translation [Shamsi et al., 2008; Aitken et al., 2010; Aitken & Baker 2013; Aitken 2014; Kumar et al., 2015; reviewed by Aitken and De Iuliis 2010; Aitken et al., 2013; Rima D. et al., 2016; Bisht et al. 2017].

Oxidative stress (OS), the main culprit for sperm DNA damage is mediated by an imbalance in reactive oxygen species production and scavenging mechanisms, when oxidants like superoxide anion (O2.), nitric oxide (NO • ), peroxyl (ROO.), hydroxyl radicals (OH •), hydrogen peroxide (H2O2) or peroxynitrite (ONOO-) outweigh the number of antioxidants. It has a negative effect on sperm function by disrupting the integrity of the DNA as a result of concurrent damage to proteins and lipids present in the sperm cell plasma membrane, particularly docosahexaenoic acid with six double bonds per molecule, therefore affecting cell membrane fluidity and permeability (Aitken 2013). The lipid peroxidation reaction cascades further result in the generation of small molecular mass electrophilic lipid aldehydes such as 4-hydroxynonenal (4HNE), acrolein, and malondialdehyde (De Lamirande & Gagnon, 1992; Aitken, De Iuliis & McLachlan, 2009). Though mild to moderate levels of oxidative stress are beneficial for several physiological processes associated with sperm capacitation and maintainance of telomere length, thus playing a pivotal role in maintenance of genomic integrity but supraphysiological levels of ROS impede sperm membrane fluidity and permeability (Aitken et al., 2012; Aitken 2014). Increasing levels of ROS also targets the telomeres, the tandemly repeating hexameric units (5’TTAGGG3’) as these are histone bound, located in periphery of sperm nucleus and are rich in guanine. Both the location and guanine content of telomeres make them highly susceptible to oxidative damage (Thilagavathy et al., 2013b; Mishra  et al., 2016). It is also witnessed to modulate the sperm epigenome by altered methylation patterns, and may have significant adverse effects on developing embryo. 

The oxidative DNA damage (ODD) observed in spermatozoa attacks the backbone of the sperm DNA helix and includes single-strand and double-strand breaks and DNA fragmentation. The damage primarily occurs at the guanine bases and results in the introduction of abasic sites, purine, pyrimidine and deoxyribose modifications and DNA cross linking, The base adducts primarily formed are 8-hydroxy-2′-deoxyguanosine (8OHdG) and 8–oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) (Aitken & De Iuliis 2009; Aitken et al., 2010; Aitken & Baker, 2013; Lord & Aitken, 2015). Repair of 8OHdG lesions is primarily conducted by the base excision repair (BER) pathway enzymes: oxoguanine glycosylase (OGG1), apurinic/apyrimidinic endonuclease (APE1) and X-ray repair cross complementing protein (XRCC1). The damage can also be repaired by nucleotide excision repair (NER) pathway, but this complex, multistep repair process is reserved for lesions that are causing structural distortion of the DNA (Brierley and Martin, 2013). Spermatozoa has a very limited capacity of repair as it only possess the first enzyme in the BER pathway, 8‑oxoguanine glycosylase 1 (OGG1), which removes 8-OHdG (51) and liberates it to the cell exterior (Smith etal., 2013). As sperm lacks the downstream enzymes in BER pathway, APE1 and XRCC1, it is dependent on oocyte repair mechanisms post fertilization.. The oocyte thus accumulates an abundance of mRNA and proteins involved in DNA repair within its vast cytoplasm during oogenesis (Menezo et al., 2007), as the new DNA repair genes cannot be transcribed by the embryo until the 4-cell stage in humans. Thus aging oocytes experiencing genome fatigue with an aberrant/incomplete repair mechanism may result in persistence of the highly mutagenic bases and predispose embryo to higher rate of mutations.

Various studies have previously investigated the link between pregnancy loss and high DNA damage in sperm (Carrell et al., 2003; Lewis & Aitken , 2005; Lin et al., 2008; Robinson et al., 2012). Paternal age has also been linked with miscarriage as the trend of older parenthood has witnessed an increase in western countries with a large no. of men fathering children above the age of 50 years (Kidd SA et al., 2001). Though maternal age is an obvious contributor to poor fecundity, the effect of advancing paternal age cannot be negated (Hassold T, 2001). Population based studies conducted to assess the effect of paternal age on the pregnancy outcomes in spontaneous conceptions reported significantly higher spontaneous abortion rate in women with male partners older than 45 years compared to those whose partners were less than 25 years of age (de la Rochebrochard and Thonneau, 2002; Slama et al., 2005; Kleinhaus et al, 2006). The role of sperm aneuploidies as a contributor to pregnancy loss among partners of aging men has also been hypothesized. Approximately 50-70% of spontaneous abortions in normal conceptions can be accounted to aneuploidies, and remaining 30-50% remained unexplained and attributed to unknown genetic and epigenetic factors (Lewis SEM & Aitken RJ, 2005). 

As discussed previously due to the shutdown of nuclear transcription in spermatozoa, the oocyte provides large quantities of previously transcribed RNA for embryonic development. Sperm provide a host of novel mRNA to the oocyte at fertilization which are critical for embryonic development. These paternally derived mRNAs were seen to be unique to sperm cell and were detected in the zygote following fertilization and contribute extragenomically to early embryonic development. From various transcriptomic studies it was seen that these mRNA reflect the fertility and quality of sperm. Ostermeier et al. identifies six candidate genes (clusterin, AKAP4, protamine 2, CDH13, FOXG1B and WNT5A) present in human spermatozoa, but not in unfertilized human oocytes out of a rough estimate of a total of 18,000 RNA molecules which were delivered to the oozyte upon fertilization. They further demonstrated that mRNAs of two of these genes, namely protamine 2 and clusterin, were delivered from spermatozoa to the oocyte at fertilization using a zona-free hamster egg and human sperm penetration assay. They thus highlighted the role of spermatozoal mRNA in pronuclear formation, orchestration of events leading to oocyte activation, the transition from maternal to embryonic gene control and the establishment of imprints in early embryos (Ostermeir et al., 2002). These transcripts are supportive of implantation, early embryogenesis and contribute to the transcriptome of embryo prior to the activation of embryonic genome (Ostermeier et al., 2002; Lambard et al., 2004; Krawetz 2005; Boerke et al., 2007; Lalancette et al., 2008a; Kumar et al, 2013; Kumar et al., 2016). Any dysregulation in the transcript levels along with deranged OS parameters can point towards the causes of infertility, RPL,  congenital malformations and even childhood carcinomas (Rima D et al., 2016; Dhawan et al., 2016; Kumar et al., 2012; Kumar et al., 2016).

OS induced damage is one of the main causes of the loss of structural and functional integrity of sperm cells. This ODD in the spermatozoa is marked by the generation of single-strand and double strand breaks, mutagenic base adducts, electrophillic aldehydes, DNA fragmentation and DNA cross-linking (Aitken et al., 2009; Aitken et al., 2012, Bisht et al., 2017). This can further result in arrest or induction of gene transcription, accelerated telomere attrition (Thilagavathy et al., 2013b), aberrant sperm DNA methylation patterns resulting in global hypomethylation and genomic instability (Rima D et al., 2016; Bisht et al., 2017). Shorter sperm telomere length may result in impaired cleavage. Though inheritance of telomere length is a complex trait but paternal telomere length is a major determinant. Shorter telomere may not disrupt genomic integrity and result in chromosomal instability but also result in slowed and impaired cleavage and poor blastocyst development. OS and the resultant high levels of DNA damage to the sperm highlight the need for an early diagnosis and prompt treatment. 

A delicate balance between the pro-oxidant and antioxidant levels is very essential for regulating various reproductive processes. Spermatozoa possess their own natural antioxidant system including both enzymatic (superoxide dismutase, catalase) and non-enzymatic (pyruvate, ascorbic acid) antioxidants to regulate the deleterious impact of harmful ROS. Other non-enzymatic antioxidants are vitamins C and E, carotenoids, omega-3 and -6 fatty acids, reduced glutathione (GSH), coemyme Q10, L-arginine ettc. Various dietary sources of antioxidants include vitamins C and E, carotenois and flavonoids (Sen & Chakraborty 2011; Birben et al., 2012; Bisht et al., 2017; Bisht et al., 2017). Deficiency of the antioxidant defense leads to accumulation of excessive ROS and causes degradation of sperm DNA. These antioxidants reduce the cellular levels of ROS by both decreasing the levels of enzymatic ROS production as well as inactivating the ROS produced by sperm metabolic pathways (Bisht et al., 2017). 

However, over the counter prescriptions and indiscriminate use of antioxidants without regular monitoring of ROS levels, may cause the sperm cells to go into a state of reductive stress causing a disruption in cellular homeostasis (Bauersachs & Widder, 2012). Effect of the majority of antioxidant regimes has been cited only on sperm motility and ROS levels, and not on the genomic integrity. Such conflicting reports highlight the importance of alleviating the various lifestyle related modifiable causative factors of OS and ODD. Lifestyle interventions like adoption of regular practice of yoga and meditation has been previously reported to substantially improve sperm DNA integrity  by regulating oxidative stress and reducing oxidative DNA damage (Kumar et al., 2015, Rima D eu al., 2016, Tolahunase et al, 2017, Mohanty et al., 2016). Antioxidant therapy can certainly decrease ROS levels but doesn’t regulate them and high levels may cause premature DNA decondensation and disrupt pronuclei formation; while yoga and meditation based lifestyle intervention (YBLI) not only lowers but regulates ROS levels. YBLI has also been seen to show long term effects on gene expression patterns by histone modification. It helps in normalization of dysregulated sperm transcripts, increasing the expression of genes involved in DNA repair, downregulation of proinflammatory genes, thus aiding in maintenance of genomic integrity and chromosomal stability (Kumar et al., 2015, Dada et al., 2015, Dada et al., 2016; Rima D et al., 2016, Dhawan et al., 2017, Bisht et al., 2017; Tolahunase et al., 2017).

Spermatozoa is thus a very critical and dynamic participant in normal embryogenesis and its role  extends beyond the fertilization process. An attempt can further be made to unveil the molecules responsible for sperm-oocyte interaction, regulation of fertilization and subsequent post-fertilization events underlying a successful pregnancy. We also highlight the various sublethal effects that can be “carried over” after implantation resulting in untoward embryonic/fetal defects and affect the health trajectory of the offspring. Furthermore, the impact of simple lifestyle modifications  like yoga and meditation into our daily routine may aid in  alleviation of deranged sperm dynamicsand improve the carry home live birth rate.

Written by: Rima Dada, MD, PhD and Vidhu Dhawan, MD, PhD Scholar, All India Institute of Medical Sciences, New Delhi, India


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