Abstract
Rationale
Methamphetamine (METH) exposure has toxicity in sperm epigenetic phenotype and increases the risk for developing addiction in their offspring. However, the underlying transgenerational mechanism remains unclear.
Objectives
The current study aims to investigate the profiles of sperm epigenetic modifications in male METH-exposed mice (F0) and medial prefrontal cortex (mPFC) transcriptome in their male first-generation offspring (F1).
Methods
METH-related male F0 and F1 mice model was established to investigate the effects of paternal METH exposure on reproductive functions and sperm DNA methylation in F0 and mPFC transcriptomic profile in F1. During adulthood, F1 was subjected to a conditioned place preference (CPP) test to evaluate sensitivity to METH. The gene levels were verified with qPCR.
Results
METH exposure obviously altered F0 sperms DNA methylated profile and male F1 mPFC transcriptomic profile, many of which being related to neuronal system and brain development. In METH-sired male F1, subthreshold dose of METH administration effectively elicited CPP, along with more mPFC activation. After qPCR verification, Sort1 and Shank2 were at higher levels in F0 sperm and F1 mPFC.
Conclusions
Our findings put new insights into paternal METH exposure-altered profiles of F0 sperm DNA methylation and male F1 mPFC transcriptomics. Several genes, such as Sort1 and Shank2, might be used as potential molecules for further research on the transgenerational vulnerability to drug addiction in offspring by paternal drug exposure.
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Abbreviations
- BP:
-
Biological process
- CASA:
-
Computer assisted semen analyzer
- CC:
-
Cellular component
- CPP:
-
Conditioned place preference
- F0:
-
Male father mice
- F1:
-
Male first-generation offspring mice
- METH:
-
Methamphetamine
- MF:
-
Molecular function
- mPFC:
-
Medial prefrontal cortex
- PBS:
-
Phosphate buffer saline
- PFA:
-
Paraformaldehyde
- PFC:
-
Prefrontal cortex
- P21:
-
Postnatal day 21
- SAL:
-
Saline
- WT:
-
Wild type
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Acknowledgements
This work is supported by National Natural Science Foundation of China (82271531 and 82071495) and Natural Science Foundation of Jiangsu Province, China (BK20201398).
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LZ and LD performed behavioral tests and morphological tests. WG, ZY, CL, CZ, ZZ, CQ, and GF assist with the data analysis. FY and LD performed data analysis. GX and FY wrote the manuscript. GX developed the overall concept.
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Li, Z., Liu, D., Wang, G. et al. METH exposure alters sperm DNA methylation in F0 mice and mPFC transcriptome in male F1 mice. Psychopharmacology 241, 897–911 (2024). https://doi.org/10.1007/s00213-023-06516-2
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DOI: https://doi.org/10.1007/s00213-023-06516-2