A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation

Dalgaard, Marlene Danner; Weinhold, Nils; Edsgärd, Daniel; Silver, Jeremy D.; Pers, Tune H.; Nielsen, John; Jørgensen, Niels; Juul, Anders; Gerds, Thomas Alexander; Giwercman, Aleksander; Giwercman, Yvonne Lundberg; Cohn‐Cedermark, Gabriella; Virtanen, Helena E.; Toppari, Jorma; Daugaard, Gedske; Jensen, Thomas Skøt; Brunak, Søren; Meyts, Ewa Rajpert‐De; Skakkeb˦k, Niels Erik; Leffers, Henrik; Gupta, Ramneek

doi:10.1136/jmedgenet-2011-100174

Cited by 96 publications

(70 citation statements)

References 44 publications

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“…In this perspective, epigenetic (de)regulation is a tempting bridge between genetics and environment [94,176,181], even trans-generationally [180,182]. Genvironmental disturbance results in a spectrum of clinical manifestations associated with increased risk of TGCC that has been baptized testicular dysgenesis syndrome (TDS) [183,184] (Fig. 2B).…”

Section: The Genvironmental Hypothesis and Its Clinical Manifestationsmentioning

confidence: 97%

An oncofetal and developmental perspective on testicular germ cell cancer

Rijlaarsdam

Looijenga

2014

Seminars in Cancer Biology

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Section: The Genvironmental Hypothesis and Its Clinical Manifestationsmentioning

confidence: 97%

An oncofetal and developmental perspective on testicular germ cell cancer

Rijlaarsdam

Looijenga

2014

Seminars in Cancer Biology

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“…Instead, it was a comparatively narrow category of male reproductive conditions followed by a larger category of metabolic-dysfunctions that suggested the benefits of examining the landscape of chronic diseases and conditions from a more holistic perspective. One of the initial characterizations linking chronic diseases and conditions keyed to early life environmental conditions was in the area of testicular dysgenesis syndrome [68,69]. With this syndrome, testicular germ cell cancer, cryptorchidism and some cases of hypospadias and male infertility have been linked with impaired development of the testis.…”

Section: Chronic Diseases Are Connected As Interlinked Patternsmentioning

confidence: 99%

The Completed Self: An Immunological View of the Human-Microbiome Superorganism and Risk of Chronic Diseases

Dietert

Dietert²

2012

Entropy

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Abstract:In this review, we discuss an immunological-driven sign termed the Completed Self, which is related to a holistic determination of health vs. disease. This sign (human plus commensal microbiota) forms the human superorganism. The worldwide emergence of an epidemic of chronic diseases has caused increased healthcare costs, increased premature mortality and reduced quality of life for a majority of the world's population. In addition, it has raised questions concerning the interactions between humans and their environment and potential imbalances. Misregulated inflammation, a host defensehomeostasis disorder, appears to be a key biomarker connecting a majority of chronic diseases. We consider the apparent contributors to this disorder that promote a web of interlinked comorbid conditions. Three key events are suggested to play a role: (1) altered epigenetic programming (AEP) that may span multiple generations, (2) developmental immunotoxicity (DIT), and (3) failure to adequately incorporate commensal microbes as a newborn (i.e., the incomplete self). We discuss how these three events can combine to determine whether the human superorganism is able to adequately and completely form during early childhood. We also discuss how corruption of this event can affect the risk of later-life diseases.

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“…This association, sometimes referred to as "testicular dysgenesis syndrome," suggests shared genetic and environmental origins for TGCTs and abnormalities in urogenital development (24)(25)(26).…”

mentioning

confidence: 99%

Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

Carouge

Blanc

Knoblaugh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Testicular tumors, the most common cancer in young men, arise from abnormalities in germ cells during fetal development. Unconventional inheritance for testicular germ cell tumor (TGCT) risk both in humans and mice implicates epigenetic mechanisms. Apolipoprotein B mRNA-editing enzyme complex 1 (APOBEC1) cytidine deaminase and Deadend-1, which are involved in C-to-U RNA editing and microRNA-dependent mRNA silencing, respectively, are potent epigenetic modifiers of TGCT susceptibility in the genetically predisposed 129/Sv inbred mouse strain. Here, we show that partial loss of either APOBEC1 complementation factor (A1CF), the RNA-binding cofactor of APOBEC1 in RNA editing, or Argonaute 2 (AGO2), a key factor in the biogenesis of certain noncoding RNAs, modulates risk for TGCTs and testicular abnormalities in both parent-of-origin and conventional genetic manners. In addition, non-Mendelian inheritance was found among progeny of A1cf and Ago2 mutant intercrosses but not in backcrosses and without fetal loss. Together these findings suggest nonrandom union of gametes rather than meiotic drive or preferential lethality. Finally, this survey also suggested that A1CF contributes to long-term reproductive performance. These results directly implicate the RNA-binding proteins A1CF and AGO2 in the epigenetic control of germ-cell fate, urogenital development, and gamete functions.he germline is the only cell lineage that transmits genetic and epigenetic information across generations. Early in mammalian development, primordial germ cells (PGCs) escape a somatic fate to become unipotent precursors of gametes, the highly specialized cells that give rise to the totipotent zygote upon fertilization (1). Various molecular mechanisms regulate pluripotency by modulating gene expression and protein activity throughout development (2). Failure of pluripotency control can lead to infertility, carcinoma in situ, gamete dysfunctions, and unusual modes of inheritance. Carcinoma in situ anomalously express markers of pluripotency and can give rise to testicular germ cell tumors (TGCTs) (3-7). Studying the genetics, epigenetics, and biology of germ cells (GCs) and TGCTs can provide unique insights about GC development, pluripotency control, tumorigenesis, and unconventional inheritance.TGCTs are the third most heritable cancer and are the most common cancers in young men 15-35 y old (8). Genome-wide association studies (GWAS) in humans identified susceptibility loci such as KIT ligand (KITL), Sprouty 4 (SPRY4), Bcl2 antagonist killer (BAK1), Doublesex-and Mab3-related transcription factor (DMRT1), Deleted in azoospermia RNA-binding protein (DAZL), PRDM transcriptional regulator (PRDM14), the telomerase reverse transcriptase TERT, and its cofactor AFT7IP (9-15). Individually and collectively, however, these susceptibility genes account for only a modest portion of inherited risk. Many genes and inherited factors remain to be discovered, their functions in normal development characterized, and the ways that dysfunction leads to TGCTs inve...

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A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation

Cited by 96 publications

References 44 publications

An oncofetal and developmental perspective on testicular germ cell cancer

An oncofetal and developmental perspective on testicular germ cell cancer

The Completed Self: An Immunological View of the Human-Microbiome Superorganism and Risk of Chronic Diseases

Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

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