Academic Journal
Prenatal dexamethasone exposure programs male offspring subfertility via GR/HDAC6/CTSL-mediated spermatogonial autophagic flux blockade.
| Title: | Prenatal dexamethasone exposure programs male offspring subfertility via GR/HDAC6/CTSL-mediated spermatogonial autophagic flux blockade. |
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| Authors: | Jin S; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China., Yao Y; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China., Zhu L; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China., Zhao X; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China., Li M; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China., Jiang P; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China., Kong Z; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China., Liu Y; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China., Ao Y; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. Electronic address: ay0085@126.com., Wang H; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. Electronic address: wanghui19@whu.edu.cn. |
| Source: | Chemico-biological interactions [Chem Biol Interact] 2026 Oct 01; Vol. 438, pp. 112300. Date of Electronic Publication: 2026 Aug 06. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: Ireland NLM ID: 0227276 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7786 (Electronic) Linking ISSN: 00092797 NLM ISO Abbreviation: Chem Biol Interact Subsets: MEDLINE |
| Imprint Name(s): | Publication: Limerick : Elsevier Original Publication: Amsterdam, Elsevier. |
| MeSH Terms: | Cathepsin L*/metabolism , Cathepsin L*/genetics , Autophagy*/drug effects , Dexamethasone*/pharmacology , Dexamethasone*/toxicity , Receptors, Glucocorticoid*/metabolism , Histone Deacetylase 6*/metabolism , Spermatogonia*/drug effects , Spermatogonia*/metabolism , Infertility, Male*/chemically induced , Infertility, Male*/metabolism , Infertility, Male*/pathology , Prenatal Exposure Delayed Effects*, Signal Transduction/drug effects ; Epigenesis, Genetic/drug effects ; Animals ; Male ; Pregnancy ; Female ; Rats ; Rats, Sprague-Dawley ; Acetylation |
| Abstract: | Background: Male infertility is significant, and part of it is associated with prenatal drug exposure. While prenatal glucocorticoid treatment is widely used, its long-term effects on male offspring fertility and the underlying programming mechanisms remain unclear. Methods: Based on a clinical-based PDE rat model (0.4 mg/kg dexamethasone, b.i.d.) during late pregnancy (gestational day 18-19), the fertility of male offspring was evaluated. Transcriptome sequencing was employed to identify potential targets. The epigenetic regulation of lysosomal protease Cathepsin L (CTSL) was analyzed using chromatin immunoprecipitation (Ch-IP) and co-immunoprecipitation (co-IP). Rescue experiments were performed using the TRPML1 agonist ML-SA1 and genetic CTSL overexpression to validate the signaling pathway. Multiple prenatal exposure models were used to verify the generalizability of this mechanism. Results: The subfertility of PDE male offspring originated in the fetal period. Then, a specific autophagic flux blockade in spermatogonia was identified, and was driven by the persistent downregulation of CTSL. Mechanistically, the activated Glucocorticoid Receptor (GR) recruited Histone Deacetylase 6 (HDAC6) to the Ctsl promoter, leading to reduced H3K27 acetylation and subsequent transcriptional silencing. Importantly, reactivating lysosomal signaling via ML-SA1 or genetically restoring CTSL expression reversed the autophagic flux blockade and rescued fertility outcomes. Furthermore, this GR/HDAC6/CTSL axis might be a shared pathway underlying a subset of other glucocorticoid-related prenatal exposures. Conclusions: These findings provide potential intervention targets for the early prevention and treatment of fetal-origin male subfertility and offer a theoretical basis for guiding rational drug use and healthy lifestyles during pregnancy. (Copyright © 2026 Elsevier B.V. All rights reserved.) |
| Competing Interests: | 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. |
| Contributed Indexing: | Keywords: Autophagy-lysosome; Cathepsin L; Epigenetics; Glucocorticoids; Male fertility |
| Substance Nomenclature: | EC 3.4.22.15 (Cathepsin L) 7S5I7G3JQL (Dexamethasone) 0 (Receptors, Glucocorticoid) EC 3.5.1.98 (Histone Deacetylase 6) |
| Entry Date(s): | Date Created: 20260806 Date Completed: 20260903 Latest Revision: 20260903 |
| Update Code: | 20260904 |
| DOI: | 10.1016/j.cbi.2026.112300 |
| PMID: | 42562296 |
| Database: | MEDLINE |
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