Isolation and molecular characterization of spermatogonia from male Sprague-Dawley rats exposed<i>in utero</i>and postnatally to dibutyl phthalate or acrylamide

Souza, Nathália Pereira de; Arnold, Lora L.; Pennington, Karen L.; Pontes, Merielen Garcia Nascimento e; Miot, Hélio Amante; Camargo, João Lauro Viana de; Cohen, Samuel M.

doi:10.1080/15376516.2019.1611981

Cited by 8 publications

(8 citation statements)

References 67 publications

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“…In 1983, animal experiments conducted by Oishi S have shown that di-2-ethylhexyl phthalate (DEHP) can cause testicular atrophy in young male rats [3]. In vivo, DBP acts by reducing cell proliferation and impairing differentiation through reducing expression levels of Pou5f1 and Mki67 in prepubertal and pubertal testes [4]. In compare to other EDCs including other Phthalates and the mixture of EDCs, the main effect of DBP was decrease intratesticular testosterone, and steroid hormone enzymes [5].…”

Section: Introductionmentioning

confidence: 99%

Role of JNK and ERK1/2 MAPK signaling pathway in testicular injury of rats induced by di-N-butyl-phthalate (DBP)

et al. 2019

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Background Di- N -butyl-phthalate (DBP) is an endocrine disrupting substance. We investigated the adverse effect of DBP on testis of male rat and reveal its potential mechanism of MAPK signaling pathway involved this effect in vivo and in vitro. Gonadal hormone, sperm quality, morphological change and the activation status of JNK, ERK1/2 and p38 was determined in vivo. Primary Sertoli cell was established and cultivated with JNK, ERK1/2 inhibitors, then determine the cell viability, apoptosis and the expression of p-JNK, p-ERK1/2. Data in this study were presented as mean ± SD and determined by one-way analysis of variance (ANOVA) followed by Bonferroni’s test. Difference was considered statistically significant at P < 0.05. Results In vivo experiment, DBP impaired the normal structure of testicular tissue, reduced testosterone levels in blood serum, decreased sperm count and increased sperm abnormality, p-ERK1/2 and p-JNK in rat testicular tissue increased in a dose-dependent manner. In vitro studies, DBP could decrease the viability of Sertoli cells and increase p-ERK1/2 and p-JNK. Cell apoptosis in SP600125 + DBP group was significantly lower than in DBP group (P < 0.05). p-JNK was not significantly decreased in SP600125 + DBP group, while p-ERK1/2 was significantly decreased in U0126 + DBP group. Conclusions These results suggest that DBP can lead to testicular damage and the activation of ERK1/2 and JNK pathways, the JNK signaling pathway may be primarily associated with its effect.

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Section: Introductionmentioning

confidence: 99%

Role of JNK and ERK1/2 MAPK signaling pathway in testicular injury of rats induced by di-N-butyl-phthalate (DBP)

et al. 2019

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“…These dose levels were selected because they were able to induce testicular alterations when exposed in utero and induced dysgenetic areas in postnatal testes of rat 14,15,29,30 . Although these dose levels did not induce testicular lesions in rats not made cryptorchid in our previous short-term studies with SD rats 13,31 , the doses were kept at the same levels for the sake of comparison with other studies performed at the same laboratory. After birth, the pups were putatively exposed to AA or DBP through maternal milk until postna-tal day (PND) 21, when up to three male pups from each litter were allocated to their respective test groups and underwent surgical procedures for CPT.…”

Section: Generalmentioning

confidence: 99%

Testicular alterations in cryptorchid/orchiopexic rats chronically exposed to acrylamide or di-butyl-phthalate

et al. 2022

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Exposure of Sprague-Dawley (SD) rats to acrylamide (AA) or di-butyl-phthalate (DBP) from the 12th gestational day to the 16th postnatal week (PNW) has been shown to reduce the effectiveness of orchiopexy in recovering the testicular alterations associated with experimental cryptorchidism established at weaning. Herein, we provide information about the long-term effects of AA or DBP on the testes of cryptorchid/orchiopexic rats. Male offspring exposed in utero to 10 mg/kg/day AA or 500 mg/kg/day DBP underwent bilateral surgical cryptorchidism at the 3rd PNW and orchiopexy at the 6th week, with continuous exposure to the chemicals through diet until the 58th week. Regardless of the test chemical, there were severe qualitative/quantitative alterations in the seminiferous tubules and increased numbers of Leydig cells. There was an increase and decrease in the number of tubules with c-Kit-and placental alkaline phosphatase-labeled germ cells, respectively, as compared to those in the control group, suggesting an imbalance between apoptosis and cell proliferation processes. The histological scores of the testicular lesions at the end of this one-year study were higher than those in the previous 16-week study, indicating that exposure of rats to the toxicants AA or DBP enhanced the testicular alterations induced by the chemicals beginning at the intra-uterine life, and impaired the effectiveness of orchiopexy in restoring the testes to normal morphology. Although the present experimental protocol does not completely replicate the natural human undescended testes, our findings may contribute to understanding the alterations occurring in cryptorchid/orchiopexic testes potentially exposed to exogenous chemicals for extended periods.

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“…For example, regions marked by both H3K4me1 and H3K27ac were connected to the promoters of Notch1 and Bmp7 , suggesting putative enhancers regulating their expression during the EMT-like process ( Figure 7C). Other examples included enhancers for Spry4 and Lin28a , which are both highly expressed in undifferentiated spermatogonia, including SSC ( Figure 7C) [69,70] .…”

Section: Gscmentioning

confidence: 99%

scATAC-Seq reveals epigenetic heterogeneity associated with an EMT-like process in male germline stem cells and its regulation by G9a

Liao

Suen

Luk

et al. 2020

Preprint

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Epithelial-mesenchymal transition (EMT) is a phenomenon in which epithelial cells acquire mesenchymal traits. It contributes to organogenesis and tissue homeostasis, as well as stem cell differentiation. Emerging evidence indicates that heterogeneous expression of EMT gene markers presents in sub-populations of germline stem cells (GSCs). However, the functional implications of such heterogeneity are largely elusive. Here, we unravelled an EMT-like process in GSCs by in vitro extracellular matrix (ECM) model and single-cell genomics approaches. Through modulating ECM, we demonstrated that GSCs exist in interconvertible epithelial-like and mesenchymal-like cell states. GSCs gained higher migratory ability after transition to a mesenchymal-like cell state, which was largely mediated by the TGF-β signaling pathway. Dynamics of epigenetic regulation at the single-cell level was also found to align with the EMT-like process. Chromatin accessibility profiles generated by single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) clustered GSCs into epithelial-like and mesenchymal-like states, which were associated with differentiation status. The high-resolution data revealed novel regulators in the EMT-like process, including transcription factors Zeb1 and Hes1. We further identified putative enhancer-promoter interactions and cis-co-accessibility networks at loci such as Tgfb1, Notch1 and Lin28a. Importantly, we demonstrated that histone methyltransferase G9a promoted the GSC EMT-like process in vitro and contributed to neonatal germ cell migration in vivo. Our work thus provides the foundation for understanding the EMT-like process and a comprehensive resource for future investigation of epigenetic regulatory networks in GSCs.

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Isolation and molecular characterization of spermatogonia from male Sprague-Dawley rats exposedin uteroand postnatally to dibutyl phthalate or acrylamide

Cited by 8 publications

References 67 publications

Role of JNK and ERK1/2 MAPK signaling pathway in testicular injury of rats induced by di-N-butyl-phthalate (DBP)

Role of JNK and ERK1/2 MAPK signaling pathway in testicular injury of rats induced by di-N-butyl-phthalate (DBP)

Testicular alterations in cryptorchid/orchiopexic rats chronically exposed to acrylamide or di-butyl-phthalate

scATAC-Seq reveals epigenetic heterogeneity associated with an EMT-like process in male germline stem cells and its regulation by G9a

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