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Di-(2-ethylhexyl) phthalate exposure induces premature testicular senescence by disrupting mitochondrial respiratory chain through STAT5B-mitoSTAT3 in Leydig cell

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Abstract

Di-(2-ethylhexyl) phthalate (DEHP), a prevalent plasticizer, is known to have endocrine-disrupting effects on males and cause reproductive toxicity. There were causal effects of DEHP on testosterone levels in the real world by Mendelian randomization analysis. Exposure to DEHP during the preadult stage might lead to premature testicular senescence, but the mechanisms responsible for this have yet to be determined. In this study, we administered DEHP (300 mg/kg/day) to male C57BL/6 mice from postnatal days 21 to 49. The mice were kept for 6 months without DEHP. RNA sequencing was conducted on testicular tissue at PNM6. The results indicated that DEHP hindered testicular development, lowered serum testosterone levels in male mice, and induced premature testicular senescence. TM3 Leydig cells were exposed to 300 μM of mono(2-ethylhexyl) phthalate (MEHP), the bioactive metabolite of DEHP, for 72 h. The results also found that DEHP/MEHP induced senescence in vivo and in vitro. The mitochondrial respiratory chain was disrupted in Leydig cells. The expression and stability of STAT5B were elevated by MEHP treatment in TM3 cells. Furthermore, p-ERK1/2 was significantly decreased by STAT5B, and mitochondria-STAT3 (p-STAT3 ser727) was significantly decreased due to the decrease of p-ERK1/2. Additionally, the senescence level of TM3 cells was decreased and treated with 5 mM NAC for 1 h after MEHP treatment. In conclusion, these findings provided a novel mechanistic understanding of Leydig cells by disrupting the mitochondrial respiratory chain through STAT5B-mitoSTAT3.

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Data availability

The data supporting the results of this study are available from the corresponding author upon any reasonable request.

Abbreviations

DEHP :

Di-(2-ethylhexyl) phthalate

MEHP :

Mono(2-ethylhexyl) phthalate

TD :

Testosterone deficiency

ROS :

Reactive oxygen species

RNS :

Reactive nitrogen species

MR :

Mendelian randomization

IV :

Instrumental variable

SNPs :

Single nucleotide polymorphisms

BAT :

Bioavailable testosterone

SHBG :

Sex hormone-binding globulin

DMRs :

Differentially methylated regions

LD :

Linkage disequilibrium

PND :

Postnatal day

PNM :

Postnatal month

DEGs :

Differentially expressed genes

AGD :

Anogenital distance

IHC :

Immunohistochemical

IF :

Immunofluorescence

DEGs :

Differentially expressed genes

FDR :

False discovery rate

GO :

Gene Ontology

GSEA :

Gene set enrichment analysis

CS :

Cell senescence

OXPHOS :

Oxidative phosphorylation

ssGSEA :

Single-sample gene set enrichment analysis

SAHF :

Senescence-associated heterochromatin foci

OCR :

Oxygen consumption rate

EDI :

Estimated daily intake

COIP :

Co-immunoprecipitation

CESTA :

Cellular thermal shift assay

NAC :

N-acetyl-cysteine

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Acknowledgements

We are grateful to all the teachers (Ruiqing Han, Peking Union Medical College, and so on) for their help.

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Author notes

  1. Haiming Cao, Qigen Xie, Peng Luo, and Jiaqi Chen contributed equally to this work.

Authors and Affiliations

  1. The Andrology Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China

    Haiming Cao, Qigen Xie, Peng Luo, Chunhua Deng & Zi Wan

  2. The Reproductive Andrology Clinic, the Seventh Affiliated Hospital of Sun Yat-Sen University, 628 Zhenyuan Road, 518000, Shenzhen, Guangdong, China

    Haiming Cao

  3. The Department of Pediatric Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China

    Qigen Xie

  4. The Urology Department, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, 365000, Fujian, China

    Jiaqi Chen

  5. Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China

    Kai Xia

  6. The Reproductive Center, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518000, Guangdong, China

    Lin Ma

  7. Translational Medicine Center, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China

    Demeng Chen

Authors
  1. Haiming Cao
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  2. Qigen Xie
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  3. Peng Luo
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  5. Kai Xia
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  6. Lin Ma
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  7. Demeng Chen
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  8. Chunhua Deng
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  9. Zi Wan
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Contributions

HMC and QGX: conceptualization, investigation, visualization, writing — original draft.

HMC and JQC: investigation, data curation, visualization, software.

HMC: methodology, visualization, writing — revised draft.

PL: investigation, validation, methodology, visualization, writing — revised draft.

KX: investigation, data curation.

LM: investigation, validation.

MDC: conceptualization, supervision, investigation.

ZW: conceptualization, funding acquisition, project administration, writing — review and editing.

CHD: conceptualization, supervision, writing — review and editing.

Corresponding author

Correspondence to Zi Wan.

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The authors declare no competing interests.

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Cao, H., Xie, Q., Luo, P. et al. Di-(2-ethylhexyl) phthalate exposure induces premature testicular senescence by disrupting mitochondrial respiratory chain through STAT5B-mitoSTAT3 in Leydig cell. GeroScience (2024). https://doi.org/10.1007/s11357-024-01119-x

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