Manoj Kumar

Bio: Manoj Kumar is an academic researcher from All India Institute of Medical Sciences. The author has contributed to research in topics: Docking (molecular) & Mitochondrial DNA. The author has an hindex of 18, co-authored 110 publications receiving 1047 citations. Previous affiliations of Manoj Kumar include AIIMS, New Delhi.

Epigenetics and its role in male infertility

Abstract: Male infertility is a common and complex problem affecting 1 in 20 men. Despite voluminous research in this field, in many cases, the underlying causes are unknown. Epigenetic factors play an important role in male infertility and these have been studied extensively. Epigenetic modifications control a number of processes within the body, but this review will concentrate on male fertility and the consequences of aberrant epigenetic regulation/modification. Many recent studies have identified altered epigenetic profiles in sperm from men with oligozoospermia and oligoasthenoteratozoospermia. During gametogenesis and germ cell maturation, germ cells undergo extensive epigenetic reprogramming that involves the establishment of sex-specific patterns in the sperm and oocytes. Increasing evidence suggests that genetic and environmental factors can have negative effects on epigenetic processes controlling implantation, placentation and fetal growth. This review provides an overview of the epigenetic processes (histone-to-protamine exchange and epigenetic reprogramming post-fertilization), aberrant epigenetic reprogramming and its association with fertility, possible risks for ART techniques, testicular cancer and the effect of environmental factors on the epigenetic processes.

Mutation screening and genotype phenotype correlation of α-crystallin, γ-crystallin and GJA8 gene in congenital cataract

Abstract: Purpose To screen α-crystallin (CRYAB), γ-crystallin (CRYGC and CRYGD), and Connexin 50 (Cx-50 or GJA8) genes in congenital cataract patients and controls.

Chromosomal abnormalities & oxidative stress in women with premature ovarian failure (POF).

Abstract: Background & objectives: Premature ovarian failure (POF) is defined as the cessation of ovarian function under the age of 40 yr and is characterized by amenorrhoea, hypoestrogenism and elevated serum gonadotrophin levels. The cause of POF remains undetermined in majority of the cases. This study was aimed to investigate the type and frequency of cytogenetic abnormalities in patients with idiopathic POF and also to study the role of oxidative stress in such cases. Methods: Seventy five women with idiopathic POF were included in this study. Chromosome analysis was done in peripheral blood lymphocytes by conventional GTG banding to identify numerical or structural abnormalities. Cytogenetically normal cases were investigated for reactive oxygen species (ROS) levels in their blood by luminol-chemiluminescence assay. Results: Eighteen chromosomal anomalies were identified in POF patients (24%). Majority of the cases were found to have X-chromosome abnormalities (28%). Overall median ROS range was found to be significantly higher (P Interpretation & conclusions: X-chromosome anomalies were found to be the major contributor of POF. Oxidative stress may be the underlying aetiology in idiopathic premature ovarian failure. Thus the results of this study highlight the role of cytogenetic abnormalities and supraphysiological levels of ROS in causation of idiopathic POF. But the role of oxidative stress needs to be confirmed by other studies on patients from different geographical areas and from different ethnicities.

In silico structure-based design of a novel class of potent and selective small peptide inhibitor of Mycobacterium tuberculosis Dihydrofolate reductase, a potential target for anti-TB drug discovery

Abstract: The worldwide TB structural genomics initiative has identified several new drug targets for Mycobacterium tuberculosis (M tb) Dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate that is essential for DNA synthesis Inhibition of its activity leads to arrest of DNA synthesis and hence cell death Thus, M tb DHFR (mtDHFR) is an attractive novel drug target for developing anti-TB drugs Structural comparison of mtDHFR and human DHFR (hDHFR) reveals key differences in the active sites These differences can be exploited for the design of selective inhibitors for mtDHFR Based on the recently determined high resolution crystal structure of mtDHFR complexed with known inhibitor methotrexate (MTX) and cofactor NADPH, a tri-peptide inhibitor has been identified using a structure-based drug design approach Docking studies indicate that the designed tripeptide inhibitor has a high potency (K (d) = 178 nM) and is a selective (approximately 120 fold over hDHFR) inhibitor for mtDHFR Hence, the tripeptide is a suitable lead compound for the development of novel anti-TB drugs

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Abstract: Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Oxidative stress and male infertility

Abstract: Male infertility accounts for up to half of the infertility cases and affects 13–15% couples worldwide. An optimal level of reactive oxygen species is crucial for maintaining spermatogenesis and sperm functions. However, excessive production of reactive oxygen species may cause oxidative stress. Oxidative stress has been identified as one of the major risk factors which affects the fertilizing potential of spermatozoa. Oxidative stress occurs due to excessive production of ROS and causes germ cell DNA damage, sperm fragility and defects in motility, culminating in infertility. Poor sperm quality and DNA damage may also result in pregnancy loss. This article highlights the significance of ROS in human male fertility and that of oxidative stress in infertility.

A paternal environmental legacy: Evidence for epigenetic inheritance through the male germ line

Abstract: Literature on maternal exposures and the risk of epigenetic changes or diseases in the offspring is growing. Paternal contributions are often not considered. However, some animal and epidemiologic studies on various contaminants, nutrition, and lifestyle-related conditions suggest a paternal influence on the offspring's future health. The phenotypic outcomes may have been attributed to DNA damage or mutations, but increasing evidence shows that the inheritance of environmentally induced functional changes of the genome, and related disorders, are (also) driven by epigenetic components. In this essay we suggest the existence of epigenetic windows of susceptibility to environmental insults during sperm development. Changes in DNA methylation, histone modification, and non-coding RNAs are viable mechanistic candidates for a non-genetic transfer of paternal environmental information, from maturing germ cell to zygote. Inclusion of paternal factors in future research will ultimately improve the understanding of transgenerational epigenetic plasticity and health-related effects in future generations.

Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring

Abstract: Over the last decade, there has been a significant increase in average paternal age when the first child is conceived, either due to increased life expectancy, widespread use of contraception, late marriages and other factors. While the effect of maternal ageing on fertilization and reproduction is well known and several studies have shown that women over 35 years have a higher risk of infertility, pregnancy complications, spontaneous abortion, congenital anomalies, and perinatal complications. The effect of paternal age on semen quality and reproductive function is controversial for several reasons. First, there is no universal definition for advanced paternal ageing. Secondly, the literature is full of studies with conflicting results, especially for the most common parameters tested. Advancing paternal age also has been associated with increased risk of genetic disease. Our exhaustive literature review has demonstrated negative effects on sperm quality and testicular functions with increasing paternal age. Epigenetics changes, DNA mutations along with chromosomal aneuploidies have been associated with increasing paternal age. In addition to increased risk of male infertility, paternal age has also been demonstrated to impact reproductive and fertility outcomes including a decrease in IVF/ICSI success rate and increasing rate of preterm birth. Increasing paternal age has shown to increase the incidence of different types of disorders like autism, schizophrenia, bipolar disorders, and childhood leukemia in the progeny. It is thereby essential to educate the infertile couples on the disturbing links between increased paternal age and rising disorders in their offspring, to better counsel them during their reproductive years.