PMID- 37918063
OWN - NLM
STAT- MEDLINE
DCOM- 20231120
LR  - 20231120
IS  - 1873-6750 (Electronic)
IS  - 0160-4120 (Linking)
VI  - 181
DP  - 2023 Nov
TI  - Zinc oxide nanoparticles-induced testis damage at single-cell resolution: 
      Depletion of spermatogonia reservoir and disorder of Sertoli cell homeostasis.
PG  - 108292
LID - S0160-4120(23)00565-2 [pii]
LID - 10.1016/j.envint.2023.108292 [doi]
AB  - The widespread application of zinc oxide nanoparticles (ZnO NPs) in our daily 
      life has initiated an enhanced awareness of their biosafety concern. An 
      incredible boom of evidence of organismal disorder has accumulated for ZnO NPs, 
      yet there has been no relevant study at the single-cell level. Here, we 
      profiled > 28,000 single-cell transcriptomes and assayed > 25,000 genes in 
      testicular tissues from two healthy Sprague Dawley (SD) rats and two SD rats 
      orally exposed to ZnO NPs. We identified 10 cell types in the rat testis. ZnO NPs 
      had more deleterious effects on spermatogonia, Sertoli cells, and macrophages 
      than on the other cell types. Cell-cell communication analysis indicated a sharp 
      decrease of interaction intensity for all cell types except macrophages in the 
      ZnO NPs group than in the control group. Interestingly, two distinct maturation 
      states of spermatogonia were detected during pseudotime analysis, and ZnO NPs 
      induced reservoir exhaustion of undifferentiated spermatogonia. Mechanically, ZnO 
      NPs triggered fatty acid accumulation in GC-1 cells through protein kinase B 
      (Akt)/mammalian target of rapamycin (mTOR) signaling and peroxisome 
      proliferator-activated receptor alpha (PPARalpha)/acyl-CoA oxidase 1 (Acox1) axis, 
      contributing to cell apoptosis. In terms of Sertoli cells, downregulated genes 
      were highly enriched for tight junction. In vitro and in vivo experiments 
      verified that ZnO NPs disrupted blood-testis barrier formation and growth factors 
      synthesis, which subsequently inhibited the proliferation and induced the 
      apoptosis of spermatogonia. As for the macrophages, ZnO NPs activated oxidative 
      stress of Raw264.7 cells through nuclear factor erythroid 2-related factor 2 
      (Nrf2)/heme oxygenase-1 (HO-1) pathway and promoted cell apoptosis through 
      extracellular signal-regulated kinase (ERK) 1/2 pathway. Collectively, our work 
      reveals the cell type-specific and cellularly heterogenetic mechanism of ZnO 
      NPs-induced testis damage and paves the path for identifying putative biomarkers 
      and therapeutics against this disorder.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Chen, Tong
AU  - Chen T
AD  - Department of Urology, The First Affiliated Hospital of Nanjing Medical 
      University, 210000 Nanjing, PR China.
FAU - Zhang, Lin
AU  - Zhang L
AD  - Clinical Medical Research Center for Women and Children Diseases, Key Laboratory 
      of Birth Regulation and Control Technology of National Health Commission of 
      China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to 
      Qingdao University, 250001 Jinan, PR China; Key Laboratory of Birth Defect 
      Prevention and Genetic Medicine of Shandong Health Commission, Shandong 
      University, 250001 Jinan, PR China.
FAU - Yao, Liangyu
AU  - Yao L
AD  - Department of Urology, The First Affiliated Hospital of Nanjing Medical 
      University, 210000 Nanjing, PR China.
FAU - Luan, Jiaochen
AU  - Luan J
AD  - Department of Urology, The First Affiliated Hospital of Nanjing Medical 
      University, 210000 Nanjing, PR China.
FAU - Zhou, Xiang
AU  - Zhou X
AD  - Department of Urology, The First Affiliated Hospital of Nanjing Medical 
      University, 210000 Nanjing, PR China.
FAU - Cong, Rong
AU  - Cong R
AD  - Department of Urology, The First Affiliated Hospital of Nanjing Medical 
      University, 210000 Nanjing, PR China.
FAU - Guo, Xuejiang
AU  - Guo X
AD  - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Qin, Chao
AU  - Qin C
AD  - Department of Urology, The First Affiliated Hospital of Nanjing Medical 
      University, 210000 Nanjing, PR China. Electronic address: qinchao@njmu.edu.cn.
FAU - Song, Ninghong
AU  - Song N
AD  - Department of Urology, The First Affiliated Hospital of Nanjing Medical 
      University, 210000 Nanjing, PR China. Electronic address: ninghongsong@sina.cn.
LA  - eng
PT  - Journal Article
DEP - 20231028
PL  - Netherlands
TA  - Environ Int
JT  - Environment international
JID - 7807270
RN  - SOI2LOH54Z (Zinc Oxide)
SB  - IM
MH  - Male
MH  - Rats
MH  - Animals
MH  - *Zinc Oxide/toxicity
MH  - Testis
MH  - Sertoli Cells
MH  - Spermatogonia
MH  - Rats, Sprague-Dawley
MH  - *Nanoparticles
MH  - Oxidative Stress
MH  - Homeostasis
MH  - Mammals
OTO - NOTNLM
OT  - Fatty acid accumulation
OT  - Sertoli cells
OT  - Spermatogonia
OT  - Testis damage
OT  - ZnO NPs
OT  - scRNA-seq
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/11/03 00:42
MHDA- 2023/11/20 06:55
CRDT- 2023/11/02 19:02
PHST- 2023/07/18 00:00 [received]
PHST- 2023/10/23 00:00 [revised]
PHST- 2023/10/25 00:00 [accepted]
PHST- 2023/11/20 06:55 [medline]
PHST- 2023/11/03 00:42 [pubmed]
PHST- 2023/11/02 19:02 [entrez]
AID - S0160-4120(23)00565-2 [pii]
AID - 10.1016/j.envint.2023.108292 [doi]
PST - ppublish
SO  - Environ Int. 2023 Nov;181:108292. doi: 10.1016/j.envint.2023.108292. Epub 2023 
      Oct 28.