Abstract
Paternal health cues are able to program the health of the next generation however the mechanism for this transmission is unknown. Reactive oxygen species (ROS) are increased in many paternal pathologies, some of which program offspring health, and are known to induce DNA damage and alter the methylation pattern of chromatin. We therefore investigated whether a chemically induced increase of ROS in sperm impairs embryo, pregnancy and offspring health. Mouse sperm was exposed to 1500 µM of hydrogen peroxide (H2O2), which induced oxidative damage, however did not affect sperm motility or the ability to bind and fertilize an oocyte. Sperm treated with H2O2 delayed on-time development of subsequent embryos, decreased the ratio of inner cell mass cells (ICM) in the resulting blastocyst and reduced implantation rates. Crown-rump length at day 18 of gestation was also reduced in offspring produced by H2O2 treated sperm. Female offspring from H2O2 treated sperm were smaller, became glucose intolerant and accumulated increased levels of adipose tissue compared to control female offspring. Interestingly male offspring phenotype was less severe with increases in fat depots only seen at 4 weeks of age, which was restored to that of control offspring later in life, demonstrating sex-specific impacts on offspring. This study implicates elevated sperm ROS concentrations, which are common to many paternal health pathologies, as a mediator of programming offspring for metabolic syndrome and obesity.
Highlights
There is increasing recognition that paternal health at conception can impact on the health of subsequent offspring
We determined that treatment of sperm with H2O2 resulted in poorer embryo development, reduced fetal growth, with the most pronounced effects observed in female offspring manifesting as altered body composition and glucose regulation
Analysis of the embryos that were generated with H2O2 treated sperm showed that embryo development was slowed at the 8-cell stage and blastocyst development was delayed after both 80 hours and 96 hours of development
Summary
There is increasing recognition that paternal health at conception can impact on the health of subsequent offspring. For example human studies have linked paternal smoking to an increase in the occurrence of childhood cancer [1,2], likely due to the direct impact of mutagenic xenobiotics found in cigarette smoke increasing the mutation load in sperm DNA [3]. Sperm are susceptible to oxidative damage due to their lack of cytoplasm which is mostly removed during the final stages of spermiogenesis [21,22]. This renders sperm vulnerable to oxidative damage due to diminished amounts of defensive enzymes, such as catalase and glutathione peroxidase, which are involved in protecting cells from ROS associated damage [23]
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