The Role of Genetics and Oxidative Stress in the Etiology of Male Infertility-A Unifying Hypothesis?
The Role of Genetics and Oxidative Stress in the Etiology of Male Infertility-A Unifying Hypothesis?
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DOI：
10.3389/fendo.2020.581838
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发表时间：
2020
影响因子：
5.2
通讯作者：
Baker MA
中科院分区：
文献类型：
--
作者：
Aitken RJ;Baker MA
尽管男性不育的发病率很高，但人们对其病因知之甚少。然而，近年来基因测序技术的进步使我们能够识别出大量罕见的单点突变，这些突变通过精子发生的内分泌调节、生殖细胞分化和精子功能，从胚胎起源起阻碍男性生殖的方方面面。撇开这些单基因突变不谈，男性不育最常见的遗传原因是非整倍体，如Klinefelter综合征和Y染色体突变，它们加在一起约占所有非梗阻性无精子症病例的20%-25%。氧化应激也已成为男性生育的主要原因，至少40%的患者表现出一些氧化还原攻击的证据，导致高水平的脂质过氧化和以8-羟基-2‘-脱氧鸟苷(8OHdG)形式的氧化性DNA损伤。后者是高度诱变的，可能导致我们物种的从头突变，其中75%已知发生在男性生殖系中。对人类精子基因组中8OHdG损伤的检查发现，精子中约有9000个基因组区域容易受到氧化攻击。虽然这些被氧化的碱基通常广泛分布在整个基因组中，但15号染色体上的一个特定区域似乎是氧化攻击的热点。这个基因座定位于一个与男性不育症、癌症、印记障碍和各种行为状况(自闭症、躁郁症、自发性精神分裂症)有关的遗传位置，这些情况与怀孕时父亲的年龄有关。我们提出了一种假说，即许多环境、生活方式和临床因素共同诱导雄性生殖系中的氧化DNA损伤，然后触发从头开始的突变的形成，这可能对后代的健康包括随后的生育产生重大影响。
Despite the high prevalence of male infertility, very little is known about its etiology. In recent years however, advances in gene sequencing technology have enabled us to identify a large number of rare single point mutations responsible for impeding all aspects of male reproduction from its embryonic origins, through the endocrine regulation of spermatogenesis to germ cell differentiation and sperm function. Such monogenic mutations aside, the most common genetic causes of male infertility are aneuploidies such as Klinefelter syndrome and Y-chromosome mutations which together account for around 20–25% of all cases of non-obstructive azoospermia. Oxidative stress has also emerged as a major cause of male fertility with at least 40% of patients exhibiting some evidence of redox attack, resulting in high levels of lipid peroxidation and oxidative DNA damage in the form of 8-hydroxy-2'-deoxyguanosine (8OHdG). The latter is highly mutagenic and may contribute to de novo mutations in our species, 75% of which are known to occur in the male germ line. An examination of 8OHdG lesions in the human sperm genome has revealed ~9,000 genomic regions vulnerable to oxidative attack in spermatozoa. While these oxidized bases are generally spread widely across the genome, a particular region on chromosome 15 appears to be a hot spot for oxidative attack. This locus maps to a genetic location which has linkages to male infertility, cancer, imprinting disorders and a variety of behavioral conditions (autism, bipolar disease, spontaneous schizophrenia) which have been linked to the age of the father at the moment of conception. We present a hypothesis whereby a number of environmental, lifestyle and clinical factors conspire to induce oxidative DNA damage in the male germ line which then triggers the formation de novo mutations which can have a major impact on the health of the offspring including their subsequent fertility.