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A single, mild, transient scrotal heat stress causes DNA damage, subfertility and impairs formation of blastocysts in mice

C Paul, MRC Human Reproductive Sciences Unit, Queens Medical Research Institute, Edinburgh, United Kingdom
A Murray, Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
N Spears, Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
P Saunders, MRc Human Reproductive Sciences Unit, Queens Medical Research Institute, Edinburgh, EH164TJ, United Kingdom

Correspondence: Philippa Saunders, Email: p.saunders{at}ed.ac.uk

Abstract

Infertility represents a major clinical problem and 50% of cases are attributable to the male partner. Testicular function is temperature dependant and in both man and mouse the position of the testes in the scrotum ensures that they are kept at between 2°C and 8°C below core body temperature. We used a mouse model to investigate the impact of a single, transient, mild, scrotal heat stress (38°C, 40°C or 42°C for 30 min) on testicular function, sperm DNA integrity and embryo survival. We detected temperature-dependent changes in testicular architecture, numbers of apoptotic cells and a significant reduction in testis weight 7 and 14 days after heat stress at 42°C. We report for the first time that DNA strand breaks H2AX positive foci) were present in spermatocytes recovered from testes subjected to 40°C or 42°C. Fertility of heat-stressed males was tested 23-28d after treatment (sperm at this time would have been spermatocytes at time of heating). Paternal heat stress at 42°C resulted in reduced pregnancy rate, placental weight and litter size; pregnancies from the 40°C group had increased resorptions at e14.5. Abnormalities in embryonic development were detected at e3.5 and IVF with sperm recovered 16h or 23days after scrotal stress at 42°C revealed a block in development between the 4 cell and blastocyst stages. This study has provided evidence of temperature-dependent affects on germ cell DNA integrity and highlighted the importance of an intact paternal genome for normal embryo development.