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Childhood disease burden: Is father to blame?: Beyond the Abstract

Poor lifestyles and paternal preconception health are strong determinants of health of the offspring. During the last decade, there has been a decline in human semen quality and sperm health. From conception of father, adverse childhood events, psychological stress, and poor social habits impact sperm epigenome and may lead to increased risk of genetic and epigenetic diseases in the offspring.

Environmental pollutants, exposure to occupational hazardous chemicals and lifestyle factors (oxidative and psychological stress, sedentary lifestyle, smoking, excessive alcohol intake) can exert direct toxic effects on sperm. Reactive oxygen species (ROS) participate in many cellular and reproductive processes and a critical balance is required to maintain cellular homeostasis. Oxidative stress (OS) may disrupt redox sensitive reaction and lead to impaired fertilization, infertility, recurrent pregnancy loss, congenital malformations, complex neuropsychiatric disorders, and childhood cancers. It can also result in increased mutational load in germ cells and increased risk of autosomal dominant disorders in offspring (Figure 1).

Majority of lifestyle factors are modifiable such as intake of nutritionally depleted fast and processed food, psychological stress, environmental and occupational exposures, cigarette smoking, drug abuse, and excess alcohol and caffeine consumption have significant impact on reproductive potential. OS results in free radical mediated damage to bio-membranes, especially PUFAs of lipid bilayer and essential cellular components. OS disrupts sperm plasma membrane by lipid peroxidation which generates a variety of reactive electrophiles like malondialdehydes (MDA), propanal, hexanal, 4-hydroxy-2-nonenal (4-HNE), isoprostane (8-IP) etc.

High levels of MDAs lead to formation of MDA-MDA dimers, which are highly mutagenic and cause leakage of electrons and mitochondrial dysfunction by binding to electrophillic proteins of electron transport chain. Formation of MDA-DNA adducts cause mutations in tumour suppressor genes and oncogenes leading to loss of cell cycle control and altered gene expression (1). 4-HNE appears to be the most toxic product of lipid peroxidation and plays an important role as signaling molecule stimulating gene expression with protective functions that can enhance cellular antioxidant capacity. Cells can survive when 4-HNE levels are low, but there is damage to organelle and protein leading to induction of autophagy, senescence and cell cycle arrest when 4-HNE levels increase. At high levels of 4-HNE, there is induction of apoptosis/necrosis programmed cell death which eventually lead to molecular damage (2). Such mutagenic and toxic secondary lipid peroxidation products can also react with proteins and DNA to form adducts resulting in a variety of cytotoxic and genotoxic consequences.

Severe OS results in sperm DNA damage both single strand and double strand breaks and nucleotide modifications in the DNA. The oxidizing capacity of ROS results in accumulation of mutagenic base, 8-hydroxy-2’-deoxyguanosine (8-OHdG) and also causes dysregulation in levels of mRNAs/transcripts. Paternal dysregulated sperm transcripts alter sperm methylation pattern, affect the sperm epigenome and after fertilization contribute to the transcriptome of embryo prior to activation of embryonic genome which may affect lifelong health of the offspring or may result in various childhood diseases. Dysregulation of various mRNA transcripts such as FOXG1, WNT5A, SOX3, and STAT4 which play a critical role in embryogenesis may prove fatal for the growing embryo and result in implantation failure, recurrent pregnancy losses, congenital malformations and even childhood cancers (3, 4). Oxidative damage may also result in accelerated telomere shortening and contribute to loss of genomic integrity, chromosome instability, and aberrations in the chromatin packaging which expose the genome to further oxidative insult (5, 6). The contribution of the paternal genome to offspring viability and health depends on sperm DNA integrity and highlights the impact of preconception paternal habits. 

OS is caused by various endogenous and exogenous factors which leads to defects in sperm function resulting impairing the functional and structural integrity of the spermatozoa. Sperm possesses an inefficient/ incomplete repair system against oxidative DNA damage. It is dependent on oocyte to repair the DNA lesions. However aging oocyte or oocyte with suboptimal repair system fails to repair the damage post fertilization.  Thus, offspring harbor increased load of mutagenic bases (1). Majority of de novo germ line mutations are paternal in origin and the frequency increases with advanced paternal age, oxidative DNA damage and accumulation of highly mutagenic bases. Environmental and lifestyle factors like smoking, excessive intake of non-veg (high levels of endocrine disrupting chemicals in animal meat), fast and processed food, excessive alcohol intake, tobacco consumption, psychological stress and excessive use of mobile phones influence the highly sensitive male epigenome. An important feature of childhood cancer development is the change in DNA methylation patterns, characterized by the hypermethylation of tumour suppressor genes and hypomethylation of repetitive elements causing genome instability and hypermutability. OS also results in increased levels of oxidative DNA damage, high DNA fragmentation Index and low concentrations of antioxidant in the semen, which are detrimental to the health and wellbeing of the embryo.

Figure 1: Lifestyle & Environmental factors which affect sperm & impact on offspring 
(Abbreviations: EDCs- Endocrine Disrupting Chemicals, DNMT- DNA methyltransferase) 
Surabhi
The differentially methylated regions of candidate genes in aged paternal spermatozoa might contribute to the increased incidence of neuropsychiatric disorders, schizophrenia, autism-spectrum-disorder and bipolar disorders in the offspring of older fathers (7, 8, 9). Alterations in gamete methylation may serve as earlier developmental exposure to the growing fetus and contribute to the intergenerational transmission of environmentally induced disease (10). Increased life expectancy, advanced age of marriage, various socio-economic factors, and access to assisted reproductive techniques like IVF, ICSI has increased the chance of older parents with poor sperm parameters to conceive children, hence, increasing the average paternal age at first childbirth (11).

These factors have a negative effect on fertility and reproductive outcomes in older couples, contributing to higher incidence of congenital malformations, childhood cancers, fetal deaths and increased risk of genetic/epigenetic disorders (12). The increased incidence of childhood diseases in parents with advanced age is due to accumulation of DNA damage in sperm.  This is due to accumulation of replicative errors and environmental factors which may modulate the epigenome. In sharp contrast oocyte is only susceptible to dysjunction errors and may result in chromosomal abnormalities, however aging oocyte experience genomic fatigue and may inefficiently repair sperm DNA lesions at time of fertilization. Advanced paternal age has also been associated with numerous disorders like autosomal dominant disorders like achondroplasia, developmental disorders like cleft palate, cardiovascular malformations, diaphragmatic hernia etc. and complex neuro-psychiatric disorders like schizophrenia, autism, epilepsy, bipolar disorders etc. in children born to older fathers (9, 13, 14). 

It is well established that for the normal development and functioning of the human brain, the regulation of epigenetic landscape is critical. Neurodevelopmental disorders (NDs) such as autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD) are characterized by a complex etiology, which involves multiple genes and gene-environment interactions. There are a number of maternal factors influencing epigenetic pathways (chromatin reorganization, histone modifications, DNA methylation, and miRNA regulation) such as lifestyle, including diet, obesity, alcohol consumption, and smoking, alter epigenetic mechanisms, thereby contributing to NDs such as embryonic neural tube defects (NTDs), autism, Down’s syndrome, Rett syndrome, and later onset of neuropsychological deficits (15).  The occurrence and severity of phenotypes associated with neurodevelopmental disorders are associated with the genes that control specific stages of neural development like PAX3, PAX7, NKX2.2 and NKX6.1. Recent studies highlighted the role of paternal aging on the onset of behavioral abnormalities in mice carrying a mutation of Pax6, a gene with neurodevelopmental regulatory functions (16). Exposure to environmental tobacco smoke and alcohol during pregnancy increases the risk of ADHD (maternal smoking during pregnancy by 2.64 times (95% CI 1.45-4.80), and paternal smoking during pregnancy by 1.17 times (95% CI 1.98-1.39) (17).

Studies from our laboratory have demonstrated that unhealthy lifestyle and social habits contribute to generation of seminal free radicals leading to oxidative stress and DNA damage and culminate in early testicular aging. Fathers of children with Non familial sporadic heritable retinoblastoma (NFSHRb) when compared with the fathers of healthy children showed high levels of ROS (56.7 ±46.3 RLU/s/ million sperm; 21.6 ± 7.9 RLU/s/million sperm; p < 0.0001*), DFI (30.3 ± 5.9%; 23.2 ± 9.4%; p = 0.0017*) and 8OHdG (72.5 (12.8–631.1) pg/ml; 32.7 (5.6–89) pg/ml; <0.0001***) respectively (18). Moreover, smoking and tobacco consumption increases oxidative DNA damage and accumulation of highly mutagenic bases in sperm which may be a possible etiology for childhood cancer as it increases incidence of de novo germline mutation and predisposes to mutations post fertilization. Kumar SB and colleagues in 2015 reported the odds ratio (OR) of NFSHRb for smokers was 7.29 (95%CI 2.9-34.5, p<0.01), for tobacco chewers 4.75 (2.07-10.9, p<0.05) and for both 9.11 (3.79-39.2; p<0.01) (19). A recent study from our laboratory, there was a significant reduction in oxidative stress markers such as ROS, DFI and 8-OHdG after yoga and meditation based lifestyle intervention (YMLI) (1). Tolahunase et al. have shown that practice of YMLI can significantly reduce the rate of cellular aging as there was significant reduction in DNA damage, mutagenic base 8-OHdG, oxidative stress markers ROS and increase in total antioxidant capacity (TAC). Telomerase activity (p>0.05), anti-inflammatory and cell cycle repair genes have also shown an increase after 4 weeks of YMLI in apparently healthy individuals (1, 20).

Hence, poor lifestyle factors such as smoking, alcohol consumption, tobacco use, excessive use of mobile phone usage, a stressful life and lack of exercise and regular intake of nutritionally depleted processed foods result in oxidative stress. Recent studies have recommended that to combat such high levels of free radical above ten servings of fruits and vegetables are recommended. However these are also loaded with insecticides and pesticides and with constraints of time and space in majority of developing nations, YMLI is ideal for integrating into our daily routine. Adopting a healthy life style by reversal of the poor social habits like quitting smoking, minimizing excessive alcohol intake, minimizing exposure to endocrine disrupting channels (Bisphenol A, insecticides, pesticides), minimizing usage of cell phone, increased intake of fruits and vegetables, maintaining optimal weight, increasing physical activity and adopting yoga and meditation as an integral part of our lifestyle will not only minimize OS and its associated sequealae but also significantly improve quality of life and promote physical, mental and reproductive health (5, 21, 22, 23). Yoga and meditation is a holistic approach which includes combination of asanas (postures), breathing practices (pranayamas) and meditation to attain the highest level of consciousness leading to improvement of spiritual, physical, mental and reproductive health of an individual. So as couples delay parenthood and resort to assisted reproductive technology, YMLI is the way to reduce the rate of testicular and biological aging and thus reduce disease burden in next generation.


Written by: Surabhi Gautam1, Manoj Kumar1, Rima Dada1

1Laboratory for Molecular Reproduction & Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, India

References

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