Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis

Alhasnani, Maha A.; Loeb, Skylar; Hall, Susan J.; Caruolo, Zachary; Simmonds, Faith; Solano, Amanda E.; Spade, Daniel J.

doi:10.1016/j.crtox.2022.100087

Cited by 4 publications

(1 citation statement)

References 99 publications

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“…SCs are believed to be the source of numerous essential growth factors, such as retinoic acid (RA), broblast growth factor 2 (FGF2), stem cell factor (SCF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), Wnt family member 5A (WNT5A), bone morphogenetic protein 4 (BMP4), KIT ligand (KITL), and glial cell line derived neurotrophic factor (GDNF), which play a crucial role in maintaining the balance of self-renewal in spermatogonial stem cells (SSCs) self-renewal and regulating the development of the testes [9][10][11] . Hence, SCs also known as "care" cells, ful ll their designated role by producing diverse factors and nutrients that support the successful SSCs into fully developed spermatozoa [10,12] . SCs play a crucial role in regulating testicular function; nevertheless, their role and underlying molecular mechanism in regulating spermatogenesis in prepubertal testes remains inadequately understood.…”

Section: Introductionmentioning

confidence: 99%

HnRNPK is essential for Sertoli cells development and male fertility in mice

Zheng,

Cheng,

Bai

et al. 2023

Preprint

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Background: Sertoli cells (SCs), a type of somatic supporting cells situated within the spermatogenic niche, play a crucial role in the maturation of germ cells. Nevertheless, the precise mechanisms governing the development of SCs and their impact on spermatogenesis remain incompletely understood. Results: In this study, we have identified hnRNPK, a multifunctional protein involved in signal transduction and gene expression regulation, as a significant novel regulatory factor in the development of neonatal SCs and pre-pubertal testicular growth in mice. In order to gain a deeper understanding of the roles played by hnRNPK in spermatogenesis, we conducted a thorough investigation utilizing SCs specific Hnrnpk knockout mice, which were obtained through the crossing of Hnrnpkflox/flox mice with Amh-Cre mice. The findings demonstrated that the absence of Hnrnpk in SCs had a significant impact on various aspects, including the proliferation and localization of SCs, the organization of seminiferous tubules, the occurrence of apoptotic cell death in both SCs and germ cells within the tubules, as well as the reduction in testis size and overall fecundity. Through the integration of RNA-seq and bioinformatics analysis, our study has unveiled the dysregulation of the transcriptome-wide expression of crucial genes involved in the control of SCs and germ cells fate. These genes encompass various processes, including cell-cell adhesion, cell proliferation and migration, piRNA processing, SC differentiation, and secretion. Conclusions: Our findings highlight the indispensable role of hnRNPK in SCs for the development of the testis and also shed light on a previously unknown function of hnRNPK in male germ cell survival and differentiation, specifically by modulating cell-cell communication.

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Section: Introductionmentioning

confidence: 99%

HnRNPK is essential for Sertoli cells development and male fertility in mice

Zheng,

Cheng,

Bai

et al. 2023

Preprint

View full text Add to dashboard Cite

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Editorial: New mechanistic insight into perinatal origins of reproductive disorders caused by chemical exposures

Svingen

2022

Current Research in Toxicology

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Reproductive toxicity following in utero and lactational exposure to a human-relevant phthalate mixture in rats

Curi,

Passoni,

Lima Tolouei

et al. 2023

Toxicological Sciences

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This rodent (Wistar rats) study examined reproductive effects of in utero/lactational exposure to a mixture of six antiandrogenic phthalates (PMix): diisobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP), diisopentyl phthalate (DiPeP), butylbenzyl phthalate (BBzP), di-2-ethylhexyl phthalate (DEHP), and diisononyl phthalate (DiNP). The PMix was defined based on exposure data from pregnant women in Brazil. Experimental groups were established by extrapolating the estimated human dose to rats (0.1 mg/kg/day), followed by up to three additional doses corresponding to 5, 1000 and 5000 times the starting rat dose: 0 (control), 0.1, 0.5, 100 and 500 mg/kg/day. The fetal experiment assessed gestational exposure effects on fetal gonads, while the postnatal experiment evaluated reproductive parameters in males and females after in utero and lactational exposure. Prenatal exposure decreased fetal testicular testosterone production at 0.5 and 500 mg/kg/day. PMix 500 also reduced mRNA expression of steroidogenesis-related genes, upregulated transcript expression of the retinoic acid-degrading enzyme Cyp26b1, and increased multinucleated gonocytes incidence in fetal testes. Postnatal assessment revealed antiandrogenic effects at the highest dose, including reduced anogenital distance, nipple retention, and decreased weight of reproductive organs. Early puberty onset (preputial separation) was observed at the lowest dose in males. In contrast, females did not show significant changes in fetal and adult endpoints. Overall, the PMix recapitulated early and late male rat phthalate syndrome phenotypes at the highest dose, but also induced some subtle changes at lower doses, which warrant confirmation and mechanistic assessments. Our data support the use of epidemiologically defined mixtures for exposure risk assessments over traditional toxicological approaches.

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Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis

Cited by 4 publications

References 99 publications

HnRNPK is essential for Sertoli cells development and male fertility in mice

HnRNPK is essential for Sertoli cells development and male fertility in mice

Editorial: New mechanistic insight into perinatal origins of reproductive disorders caused by chemical exposures

Reproductive toxicity following in utero and lactational exposure to a human-relevant phthalate mixture in rats

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