Di-n-butyl phthalate induced hypospadias relates to autophagy in genital tubercle via the PI3K/Akt/mTOR pathway

Li, Xiang; Li, Jinhao; Zhang, Ya; Zhou, Yun

doi:10.1539/joh.16-0089-oa

Cited by 22 publications

(17 citation statements)

References 47 publications

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“…Similarly, Li et al. also observed that the LC3II/LC3I ratio was significantly increased, and the expression of polyubiquitin‐binding protein p62 was significantly decreased in the GT from the hypospadias male fetuses [29], indicating that exposure to DBP during pregnancy inhibited cell apoptosis and promoted cell autophagy in the GT of fetal male rats, thereby resulting in the formation of hypospadias.…”

Section: Discussionmentioning

confidence: 81%

“…Another autophagic induction marker P62, a multifunctional ubiquitin-binding protein, was selectively degraded by autophagy, and its expression was negatively correlated with the autophagy activity [27,28]. Similarly, Li et al also observed that the LC3II/LC3I ratio was significantly increased, and the expression of polyubiquitinbinding protein p62 was significantly decreased in the GT from the hypospadias male fetuses [29], indicating that exposure to DBP during pregnancy inhibited cell apoptosis and promoted cell autophagy in the GT of fetal male rats, thereby resulting in the formation of hypospadias. Subsequently, expressions of PERK-eIF2a pathway-related proteins were examined in the GT of hypospadias fetal male rats, presenting an increased expression pattern of p-PERK, p-eIF2a and ATF4.…”

Section: Discussionmentioning

confidence: 86%

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Role of PERK‐eIF2α signaling pathway in fetal male rats with hypospadias induced by di‐n‐butyl phthalate

Zhao

Liu

2018

The Kaohsiung J of Med Scie

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This study aims to explore the role of PERK-eIF2α signaling pathway in fetal male rats with hypospadias induced by maternal exposure to di-n-butyl phthalate (DBP). DBP was used to treat pregnant SD rats by gastric intubation from gestation day (GD) 14-18 to construct a hypospadias rat model. The amount, weight, anogenital distance (AGD), and hypospadias incidence of rats were recorded and the genital tubercle (GT) of fetal male rats was collected on GD 19. Western blotting was performed to detect the expressions of PERK-eIF2α pathway- and autophagy-related proteins, and cell apoptosis was detected using TUNEL method. Then, GT fibroblasts of fetal rats were obtained and transfected with PERK-siRNA to detect cell apoptosis and autophagy in each transfected group. The incidence of hypospadias was 43.49% in fetal male rats induced by DBP. The fetal rats in DBP group presented the decreased birth weight and anogenital distance (AGD)/body weight ratio than the Control group (all P < 0.05). Further, p-PERK, p-eIF2α and ATF4 protein expressions and the ratio of LC3-II/LC3-I were greatly increased in the GTs of fetal rats, while apoptosis index (AI) and P62 protein expression were evidently decreased (all P < 0.05). In addition, the apoptosis rate was increased in GT fibroblasts after transfection of PERK-siRNA with the increased P62 and reduced LC3-II/LC3-I ratio (all P < 0.05). Activation of PERK-eIF2α signaling pathway can influence the GT development of fetal male rats with hypospadias induced by DBP through activation of autophagy and inhibition of apoptosis.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 86%

Role of PERK‐eIF2α signaling pathway in fetal male rats with hypospadias induced by di‐n‐butyl phthalate

Zhao

Liu

2018

The Kaohsiung J of Med Scie

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“…Furthermore, apoptosis plays a key role during the development of the male genitalia ( 51 , 69 , 70 ). Previous studies have proposed that the suppression of apoptotic-related genes can give rise to hypospadias ( 71 , 72 ). For instance, reduced apoptosis is observed in finasteride-induced hypospadiac rats through the MAPK/ERK signaling pathway ( 73 ).…”

Section: Discussionmentioning

confidence: 99%

A Proteomics Signature of Mild Hypospadias: A Pilot Study

et al. 2020

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Background and Objective: Mild hypospadias is a birth congenital condition characterized by the relocation of the male urethral meatus from its typical anatomical position near the tip of the glans penis, to a lower ventral position up to the brim of the glans corona, which can also be accompanied by foreskin ventral deficiency. For the most part, a limited number of cases have known etiology. We have followed a high-throughput proteomics approach to study the proteome in mild hypospadias patients.Methods: Foreskin samples from patients with mild hypospadias were collected during urethroplasty, while control samples were collected during elective circumcision (n = 5/group). A high-throughput, quantitative proteomics approach based on multiplexed peptide stable isotope labeling (SIL) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was used to ascertain protein abundance changes in hypospadias patients when compared to control samples.Results: A total of 4,815 proteins were quantitated (2,522 with at least two unique peptides). One hundred and thirty-three proteins from patients with mild hypospadias showed significant abundance changes with respect to control samples, where 38 proteins were increased, and 95 proteins were decreased. Unbiased functional biological analysis revealed that both mitochondrial energy production and apoptotic signaling pathways were enriched in mild hypospadias.Conclusions: This first comprehensive proteomics characterization of mild hypospadias shows molecular changes associated with essential cellular processes related to energy production and apoptosis. Further evaluation of the proteome may expand the search of novel candidates in the etiology of mild hypospadias and could also lead to the identification of biomarkers for this congenital urogenital condition.

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“…Autophagy is a key cellular process for maintaining homeostasis, and involves Open Journal of Apoptosis the degradation of subcellular components [16] [17]. During this process, cellular components reach lysosomes for degradation [18]. It has been documented that phthalates can cause autophagic cell death with mitochondrial effects [19].…”

Section: Autophagymentioning

confidence: 99%

Cell Death Effects of the Phthalate 2-Ethyl-1-Hexanol on Human Linfoblast Cells

Rios¹,

Vélez²,

Zayas³

2019

OJApo

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Phthalates have been used in a wide variety of consumer goods. Their versatility as plasticizers has translated into worldwide use in a vast array of consumer products. These compounds can leach into matrices, such as food and liquids that can be routed for human exposure. One of the most used phthalates is Diethylhexyl phthalate (DEHP). Diethylhexyl phthalate and its metabolite 2-ethyl-1-hexanol (2-EH) have demonstrated biological effects which merit further evaluation. In this work, we expand on our previous work with DEHP and screen the 2-EH metabolite for different cell death endpoints such as growth inhibition, apoptosis, autophagy, caspase activation, DNA fragmentation, and cell cycle arrest using fluorophores and the NC3000 instrument. Significant results (p < 0.05) revealed higher toxicity for the 2-EH metabolite when compared to DEHP. Also, 2-EH presented apoptosis induction with characteristic hallmarks, such as loss of mitochondrial membrane potential, caspase activation, DNA fragmentation and cell cycle arrest at the S phase. In addition, the presence of autophagosome was detected through L3CB protein staining. We conclude that 2-EH presents differences in cell death endpoints that interestingly differ from the DEHP parent compound. Further studies are needed to establish the molecular pathways responsible for the observed effects.

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Di-n-butyl phthalate induced hypospadias relates to autophagy in genital tubercle via the PI3K/Akt/mTOR pathway

Cited by 22 publications

References 47 publications

Role of PERK‐eIF2α signaling pathway in fetal male rats with hypospadias induced by di‐n‐butyl phthalate

Role of PERK‐eIF2α signaling pathway in fetal male rats with hypospadias induced by di‐n‐butyl phthalate

A Proteomics Signature of Mild Hypospadias: A Pilot Study

Cell Death Effects of the Phthalate 2-Ethyl-1-Hexanol on Human Linfoblast Cells

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