In 2009, Elizabeth Blackburn, Carol Greider and Jack Szostak were awarded the Physiology or Medicine Nobel Prize for discovering the fundamental processes whereby chromosome ends are protected by telomeres and the enzyme telomerase. Telomeres are regions of non-coding, but highly structured DNA at the end of linear eukaryotic chromosomes, consisting of tandem repeated highly conserved DNA sequence. Telomeres shorten at each cell division or when cells are exposed to oxidative stress (OS), resulting in telomere shortening with aging in most animals. A permanent arrest in the cell cycle occurs through cellular senescence when telomeres are shortened to a critical length, thereby increasing risk factors in a large number of diseases. Consequently, telomere length (TL) appears to predict remaining lifespan in humans and wild animals, with individuals with the shortest telomeres displaying the poorest survival prospects. Telomere erosion is therefore now considered an essential component of the ageing phenotype.
While gradual telomere attrition is a normal component of the aging process, accelerated telomere erosion and premature senescence occur in individuals that are exposed to stressors. Several cross-sectional studies in humans and experimental studies in wild and captive animals have reported associations between telomere erosion and high levels of psychosocial stress or stress biomarkers. For example, an experimental exposure to the stress hormone cortisol has been shown to dampen telomerase activity, whereas behavioral interventions that reduce stress have been shown to increase telomerase activity and slow down telomere erosion. This suggests that stress-related changes in telomere integrity is a mechanism linking stress and disease susceptibility.
Exposure to stressors is also well known to have transgenerational effects, with stress levels in the parental line having long-term negative consequences on offspring health. Recent studies show that these transgenerational effects might be mediated, at least in part, by telomere attrition. Babies from mothers who experienced stress during pregnancy had shorter telomere at birth and birds experimentally stressed during egg production produced chicks with shorter telomeres than controls. These negative effects of maternal stress levels on offspring TL should not be mediated by changes in gamete TL because the pool of ova is established in utero and TL in ova are thought to be very stable. These negative maternal effects may instead rely on the complex maternal–fetal/neonatal interaction and be mediated by an increased transfer of glucocorticoid hormones from the mother to the developing embryo. This would in turn activate the production of reactive oxygen species (ROS), as well as decrease telomerase activity in the offspring, potentially leading to telomere erosion.
Despite having long been overlooked, paternal effects (the influence of fathers on offspring traits via mechanisms other than the transmission of alleles) are now increasingly recognized as affecting a broad range of phenotypic traits in the next generation in a variety of organisms. Paternal effects can negatively impact their offspring and there is increasing evidence for transgenerational effects of paternal stress levels at the time of reproduction with long-term consequences on offspring health. In most cases, the proximate mechanism mediating paternal influence on offspring remains unknown. This question is intriguing because in most species fathers do not interact with their offspring beyond transferring the ejaculate and mechanisms of paternal effects in these species might be widespread.
Sperm cells are highly vulnerable to OS due to the high proportion of polyunsaturated fatty acids in their membrane, their condensed DNA and reduced transcription machinery, and it is already known that stress exposure entails costs in terms of reduced sperm quality (i.e. sperm number and motility) through systemic OS levels and oxidative damage to sperm cells. Telomeres are very sensitive to damage induced by OS and paternal exposure to stressors may thus affect TL in sperm before fertilization as well as inherited by the offspring, with consequences on offspring TL and for aging and disease susceptibility. Given that TL at birth is a good predictor of age-related disease onset, this hypothesis, not hitherto investigated in any species, might explain, at least in part, the long-term effects of paternal stress on offspring health observed in humans and several model species.
In the proposed research, I will use a multidisciplinary approach at the interface of physiology, evolutionary biology and molecular biology to experimentally test this hypothesis and to investigate the role of sperm TL in paternal effects within the timeframe of a grant. Specifically, I propose to perform two experiments with the following aims:
• Aim 1: Measure the effect of stress exposure on sperm TL
• Aim 2: Determine links between sperm TL and offspring TL at birth
• Aim 3: Elucidate the effects of sperm TL on offspring development and disease susceptibility during growth
Anthropogenic changes in land-use has accelerated in recent decades. To understand the current and future viability of wild populations, we need to understand the underlying mechanisms for how species evolve, acclimatize or cope with these stressful human-modified environments. In addition, the explosive growth of human population brings along increasing number of contacts between humans and wildlife, increasing the risk of outbreak of zoonotic diseases. This leads to a growing need of studies that help to understand evolutionary changes in immune function and parasite susceptibility of animals living in stressful environments. The results of this project might be essential to understand the impact of stress on animal reproduction, aging and immune capacity and predict how human activities might impact wild population dynamics. In addition, this project might be of high interest for the biomedical community interested to predict how sperm telomere length influence fertility and then pre/post-birth development.
