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J Pediatr Genet 2020; 09(02): 145-148
DOI: 10.1055/s-0039-1700974
Letter to the Editor
Georg Thieme Verlag KG Stuttgart · New York

8-Hydroxy-2'-Deoxyguanosine in Sperm DNA and Increased Risk of Nonfamilial Sporadic Heritable Retinoblastoma in the Child

Shilpa Bisht
1   Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
,
Bhavna Chawla
2   Ocular Oncology Service, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
,
Rima Dada
1   Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
› Author Affiliations
Further Information

Publication History

16 July 2019

04 December 2019

Publication Date:
13 January 2020 (online)

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Retinoblastoma (RB) is the most common eye cancer affecting children below 5 years of age.[1] Its incidence is 1 in every 15,000 to 20,000 live births, which translates to approximately 9,000 newly diagnosed RB cases each year worldwide.[2] The incidence of RB is very high in Indian children, where approximately 1,400 to 1,800 new cases are diagnosed every year.[3] Alfred G. Knudson proposed a two-hit hypothesis in RB pathogenesis, where he defined loss-of-function mutation in both alleles of RB1 tumor suppressor gene as the main cause for RB initiation.[4] Nonfamilial sporadic heritable RB (NFSHRB) is either unilateral or bilateral and associated with a negative family history. Zhu et al proposed that the constitutional mutation (i.e., first hit in the RB1 gene) in NFSHRB mainly occurs as a de novo paternal germ line mutation which mainly occur during spermatogenesis.[5] [6]

Previous studies have highlighted that oxidative stress and oxidative DNA damage (ODD) leads to higher rates of genetic and epigenetic variations in the sperm DNA that influences the outcomes of pregnancy and the health of offspring resulting from a paternally-mediated increased disease risk.[7] [8] Previously, we have also reported that oxidative stress and polymorphism in the paternal sperm DNA in two essential SNPs (single nucleotide polymorphism) of MTHFR (677 and 1298) are associated with an increased risk of NFSHRB in their offspring.[9] We now propose that higher levels of ODD in paternal sperm, due to unhealthy social habits and advanced paternal age, plays a role in the pathogenesis of NFSHRB.[5] [6]

RB shows autosomal dominant pattern of inheritance but is recessive at the cellular level.[10] Paternal sperm ODD is the underlying cause of infertility, recurrent spontaneous abortions, congenital malformations, other autosomal dominant disorders, and neuropsychiatric ailments, such as schizophrenia and bipolar disorders.[11] The majority of high-risk autism spectrum disorder cases are associated with paternal sperm differentially methylated regions.[12] Accumulation of the oxidative base adduct 8-hydroxy-2'-deoxyguanosine (8-OHdG) predisposes to mutations, epimutations, and de novo germ line mutations in the male germ line.[13] [14] Sperm harbors highly truncated DNA damage detection and repair mechanisms and depends upon the oocyte to repair the oxidative base lesion, that is, 8-OHdG.[15] Extensive ODD in the sperm leads to persistence of this mutagenic base postfertilization and predisposes to genetic and epigenetic abnormalities in the offspring.[13] [16]

We have measured the 8-OHdG levels in the seminal plasma of the fathers of children affected with NFSHRB and the fathers of healthy children using the DNA/RNA Oxidative Damage ELISA Kit (Cayman Chemical, Ann Arbor, Michigan, Unites States). We have found elevated seminal 8-OHdG levels (126.25 ± 13.67 ng/mL) in the fathers (n = 103) of children affected with NFSHRB, as compared with the seminal 8-OHdG levels (34.13 ± 5.99 ng/mL) in the fathers of healthy children (n = 105). The mean age of the fathers of these children was 32.61 ± 5.67 years. We have further categorized the fathers of children affected with NFSHRB into various groups depending upon their lifestyle habits (smokers, alcohol consumers, both smokers and alcohol consumers, and both nonsmokers and alcohol nonconsumers). To determine the impact of ODD (measured by 8-OHdG), we have performed t-test in each of the subgroups to determine the impact of the lifestyle factors ([Table 1]). A higher level of 8-OHdG (134.56 ± 12.79 ng/mL) was also found in the blood plasma of children with NFSHRB (n = 103), as compared with the blood plasma 8-OHdG levels (31.70 ± 8.99 ng/mL) in healthy children (n = 105).

Table 1

Impact of the lifestyle factors

Determinants of ODD

p-Value

Median of differences

ROS in smokers vs. 8-OHdG in smokers (n = 43)

<0.0001

−794.9

ROS in alcohol consumers vs. 8-OHdG in alcohol consumers (n = 41)

<0.0001

−512.3

ROS in smokers + alcohol consumers vs. 8-OH in smokers + alcohol consumers (n = 72)

<0.0001

−738.2

ROS in nonsmokers+ alcohol nonconsumers vs. 8-OH in nonsmokers + alcohol nonconsumers (n = 19)

<0.0001

−527.2

Abbreviations: 8-OHdG, 8-hydroxy-2'-deoxyguanosine; ODD, oxidative DNA damage.


8-OHdG is the most potent biomarker of ODD, and elevated levels are implicated as a major factor in causation of several genetic and epigenetic disorders, including cancers.[13] [17] This evidence highlights the paternal contribution to offspring health and strongly suggests a preconception origin of disease and that paternal exposures have life-long impacts on the offspring health through genetic and epigenetic mechanisms.[18] [19] Elevated 8-OHdG levels have been shown to cause methylation alterations. The present study indicates that elevated levels of seminal 8-OHdG are indicative of oxidative stress induced ODD and predispose to mutations, epimutations, and de novo germ line mutations. Male germ line mutations may lead to postzygotic mutations, increasing the risk for NFSHRB in offspring.

Most factors contributing to oxidative stress are modifiable with adoption of simple lifestyle interventions. For example, we have previously shown that the yoga-based lifestyle intervention (YBLI) leads to a significant decline in seminal oxidative stress and ODD. We have reported that 6 months' practice of YBLI by fathers of children affected with RB is associated with a significant decline in oxidative stress, ODD, and an improvement in sperm DNA integrity. These improvements may further reduce disease burden in the next generation and reduce incidence of childhood cancers.[14] We have also reported the impact of YBLI on several other clinical conditions, such as male partners of couples with recurrent pregnancy losses, congenital malformations,[20] rheumatoid arthritis and comorbid depression,[21] and major depressive disorder.[22] We have also reported that 12 weeks of YBLI by parents of children affected with RB is associated with reduction in the severity of psychological stress and resulted in improvement in overall quality of life and elevation in the levels of systemic biomarkers of neuroplasticity and neurotrophins, including brain derived neurotrophic factor, dehydroepiandrosterone sulfate, sirtuin1, cortisol, and melatonin.[23] YBLI also appears to exert some helpful influence on the expression of genes which maintain DNA integrity, engage in DNA repair, and genes of anti-inflammatory pathways.[14] [24] [25] As sperm has a highly truncated repair mechanism, it is important for potential fathers to be educated to remember that biological parenting begins long before conception, it begins when themselves are conceived. This emphasizes the need for potential fathers to adopt a healthy and stress-free lifestyle to improve sperm health and the well-being of future generations.