Polygenic inheritance of cryptorchidism susceptibility in the LE/orl rat

Barthold, Julia Spencer; Pugarelli, Joan E.; MacDonald, Madolyn L.; Ren, Jia; Adetunji, Modupeore O.; Polson, Shawn W.; Mateson, Abigail B.; Wang, Yanping; Sol‐Church, Katia; McCahan, Suzanne M.; Akins, Robert E.; Devoto, Marcella; Robbins, A. K.

doi:10.1093/molehr/gav060

Cited by 11 publications

(14 citation statements)

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“…23 We observed strong nuclear expression of PAX7 and/or myogenin in scattered mesenchymal cells between muscle layers. EdU labeling showed that proliferation is robust in the myogenic zone, and many EdU+ cells also express PAX7, as shown previously in studies of striated muscle myogenesis.…”

Section: Discussionmentioning

confidence: 69%

Fetal Rat Gubernaculum Mesenchymal Cells Adopt Myogenic and Myofibroblast-Like Phenotypes

et al. 2016

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Purpose Gubernaculum-cremaster complex (GCC) development is hormonally-regulated and abnormal in a cryptorchid rat model. Using cell tracking techniques and imaging, we studied myogenic phenotypes and fates in the fetal rat GCC. Materials and methods E17 (embryonic day 17) GCCs were labeled with CellTracker™ or DNA synthesis marker 5-ethynyl-2′-deoxyuridine (EdU), or immobilized in Matrigel™ and grown in culture. E17-21 GCC sections and cells were imaged using widefield and deconvolution immunofluorescence microscopy and muscle- and/or myofibroblast-specific antibodies. Deconvolved image stacks were used to create a 3-dimensional (3D) model of E21 GCC muscle. Results Paired-box 7 (PAX7)+ and myogenin+ muscle precursors were visible in a desmin-rich “myogenic zone” between muscle layers that elongated and became thicker during development. GCC inner mesenchymal cells expressed desmin and alpha smooth muscle actin (αSMA) at lower levels than in the myogenic zone. After pulse-labeling with CellTracker™ or EdU, mesenchymal cells became incorporated into differentiated muscle. Conversely, mesenchymal cells migrated beyond Matrigel™-immobilized GCCs, expressed PAX7 and fused to form striated myotubes. Mesenchymal GCC cell lines proliferated >40 passages and exhibited contractile behavior, but did not form striated muscle. Our 3D GCC model showed 2 orthogonal ventral layers and an arcing inner layer of muscle. Conclusions Our data suggest that mesenchymal cells in the peripheral myogenic zone of the fetal GCC contribute to formation of a distinctively-patterned cremaster muscle. Non-myogenic, desmin- and αSMA-positive GCC mesenchymal cells proliferate and exhibit a myofibroblast-like phenotype in culture. Intrinsic mechanical properties of these divergent cell types may facilitate perinatal inversion of the GCC.

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Section: Discussionmentioning

confidence: 69%

Fetal Rat Gubernaculum Mesenchymal Cells Adopt Myogenic and Myofibroblast-Like Phenotypes

et al. 2016

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“…Two possible mechanisms may underlie the association between exposure to specific PBDEs and cryptorchidism: a ) competition at the androgen receptor level, to block the effects of endogenous androgens (e.g., in the gubernaculum muscle or inguinoscrotal fat pad) ( Barthold et al 2016 ; Kaftanovskaya et al 2012 ) and/or b ) effects on the Leydig cell in the fetal testes, resulting in endogenous androgen insufficiency ( Houk et al 2004 ; Wang et al 2009 ). Stoker et al ( Stoker et al 2005 ) reported that BDE-99 and -100 display antagonistic properties in the rat ventral prostate binding assay (

of 33 and

, respectively), while BDE-154 has a weak effect; they also found that BDE-100 is a true competitor at the androgen receptor level (

) and inhibits dihydrotestosterone-induced androgen receptor activation in a concentration-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

A Case–Control Study of Maternal Polybrominated Diphenyl Ether (PBDE) Exposure and Cryptorchidism in Canadian Populations

Goodyer

Poon

Aleksa

et al. 2017

Environ Health Perspect

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Background:Polybrominated diphenyl ethers (PBDEs) are flame retardants found in North American household products during the past four decades. These chemicals leach out in dust as products age, exposing individuals daily through inhalation and ingestion. Animal studies suggest that PBDEs disrupt sex hormones and adversely affect development of the reproductive system.Objectives:In the present study, we examined whether there is a link between maternal hair PBDE concentrations and the risk of cryptorchidism (undescended testes) in male infants; testis descent is known to be dependent on androgens.Methods:Full-term male infants were recruited through clinics in Montreal, Toronto, and London, Canada. Boys with cryptorchidism at 3–18 months of age (n=137) were identified by pediatric urologists and surgeons; similar-aged controls (n=158) had no genitourinary abnormalities as assessed by pediatricians. Eight BDE congeners (BDE-28, -47, -99, -100, -153, -154, -183, -209) were measured by GC-MS (gas chromatography–mass spectrometry) in maternal hair samples collected at the time of recruitment.Results:The ∑PBDE geometric mean for maternal hair was 45.35 pg/mg for controls and 50.27 pg/mg for cases; the concentrations of three BDEs (BDE-99, -100, and -154) were significantly higher in cases than controls in unadjusted models. In adjusted models, every 10-fold increase in the concentration of maternal hair BDE-99 [OR=2.53 (95% CI: 1.29, 4.95)] or BDE-100 [OR=2.45 (95% CI: 1.31, 4.56)] was associated with more than a doubling in the risk of cryptorchidism. BDE-154 [OR=1.88 (95% CI: 1.08, 3.28)] was also significant.Conclusions:Our results suggest that maternal exposure to BDE-99, -100, and -154 may be associated with abnormal migration of testes in the male fetus. This may be due to the anti-androgenic properties of the PBDEs. https://doi.org/10.1289/EHP522

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“…Approximately 20% of NS patients have HCM (Nishikawa et al ., ), of these 95% have a RAF1 mutation which results in increased kinase activity (Pandit et al ., ; Razzaque et al ., ). On the other hand, breeding studies in cryptorchid rat strains have shown an altered expression of genes that participate in muscle development, and in the contraction of tissues that participate in testicular descent (Barthold et al ., ). There is evidence which indicate that the Ras/MAPK pathway participates in muscle cell differentiation both with negative (Yang et al ., ; Yokoyama et al ., ) and positive effects (Li & Johnson, ; Cho et al ., ).…”

Section: Discussionmentioning

confidence: 97%

“…It is possible that some of the 57 patients without any CNV detected in this study harbor RIT1 CNVs. On the other hand, recent evidence from breeding studies of a cryptorchid rat strain (Barthold et al ., ); and from association studies in both pigs (Elansary et al ., ) and man (Barthold et al ., ) have suggested that cryptorchidism is inherited as a polygenic trait, whit different variants contributing to susceptibility. Therefore, we suggest that the RAF1 microduplication detected in this study represents one of these variants.…”

Section: Discussionmentioning

confidence: 99%

Copy number variants of Ras/MAPK pathway genes in patients with isolated cryptorchidism

et al. 2017

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Cryptorchidism is the most common congenital disorder in boys, but the cause for most cases remains unknown. Patients with Noonan Syndrome are characterized by a typical face, growth retardation, congenital heart defects, learning disabilities and cryptorchidism. Copy number variations of Ras/MAPK pathway genes are unusual in patients with several clinical features of Noonan Syndrome; however, they have not been studied in patients with only one feature of this condition, such as cryptorchidism. Our aim was to determine whether patients with isolated cryptorchidism exhibit Ras/MAPK pathway gene copy number variations (CNVs). Fifty-nine patients with isolated cryptorchidism and negative for mutations in genes associated with Noonan Syndrome were recruited. Determination of Ras/MAPK pathway gene CNVs was performed by Comparative Genome Hybridization array. A CNV was identified in two individuals, a ~175 kb microduplication at 3p25.2, partially including RAF1. A similar RAF1 microduplication has been observed in a patient with testicular aplasia. This suggests that some patients with isolated cryptorchidism may harbor Ras/MAPK pathway gene CNVs.

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Polygenic inheritance of cryptorchidism susceptibility in the LE/orl rat

Cited by 11 publications

References 86 publications

Fetal Rat Gubernaculum Mesenchymal Cells Adopt Myogenic and Myofibroblast-Like Phenotypes

Fetal Rat Gubernaculum Mesenchymal Cells Adopt Myogenic and Myofibroblast-Like Phenotypes

A Case–Control Study of Maternal Polybrominated Diphenyl Ether (PBDE) Exposure and Cryptorchidism in Canadian Populations

Copy number variants of Ras/MAPK pathway genes in patients with isolated cryptorchidism

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