Role of parental age on offspring health.
Associate Professor Rebecca Robker
The University of Adelaide
Evidence linking advanced age of both mothers and fathers to autism spectrum disorders in children is becoming impossible to ignore. This project will elucidate the defects that occur in eggs and sperm with aging and test whether reversing them with a novel therapeutic can mitigate anxiety-like behaviours in offspring. This research is essential as more couples choose to have children later in life. The outcomes will improve our understanding of the consequences of parental aging on child health and provide evidence of improving gamete quality prior to pregnancy as a preventative therapy.
Associate Professor Rebecca Robker, Associate Professor Cheryl Shoubridge.
As they age, women and men face infertility and increased risk of developmental problems in their children. We have found a candidate drug that restores eggs and sperm health in aged mice and so tested whether it could improve embryo development. Embryo development was poor when either the mother or father was older; however, treatment of the older animals resulted in improved pregnancy rates and healthier embryo development. In particular, offspring from older fathers were born smaller and had increased risk of neonatal death; but these problems were avoided when the male mice were treated prior conceiving with females. We are confirming that offspring conceived from eggs and sperm treated with the drug are healthy and normal through adulthood. This preclinical research is an essential step towards the development of a new human fertility treatment that is necessary to ensure that intending parents of all ages have the healthiest children possible.
Accumulating evidence links advanced parental age at conception to subsequent childhood neurological disorders, such as autism spectrum disorders (ASDs), which are diagnosed as delayed cognitive or communication abilities, repetitive behaviours and social impairment. The reason(s) that increased parental age at conception increases offspring susceptibility to ASDs is not known. However, because autism spectrum disorders are associated with increasing age of both mothers and fathers, it suggests that changes to eggs and sperm with aging contribute to neurological issues in children.
Mitochondria are the structures within cells that produce essential cellular energy; and they are known to decline during ageing. We recently discovered that eggs and sperm from older female and male mice exhibit poor mitochondrial activity (ie metabolism) and generate embryos with impaired development. In addition we have previously discovered that a novel therapeutic molecule (called BGP-15) improves mitochondrial activity in mouse oocytes that are damaged by obesity, and normalises their development. Our latest data suggests that directly treating oocytes and sperm from older animals with BGP-15 can also improve the mitochondria. BGP-15 is a niacin-derivative, which stabilises the proteins of the mitochondria, increasing their metabolism and the production of more mitochondria. BGP-15 has been tested in humans in multiple Phase 2 trials for Type 2 diabetes, which indicates that it is safe for human use and could be developed as a therapeutic pharmaceutical.
In this project we sought to determine whether administration of BGP-15 to older mice could restore the health of eggs and sperm and improve early embryo development and fetal health. Subsequently, we would examine the adult health of the offspring, specifically focussing on neurological testing. Mice that were ‘older’ ie ~1 year old were untreated or treated with BGP-15 for 4 days, and their eggs, sperm and embryos were compared to those of young (6 week old) mice. Older female mice ovulate very few eggs, similar to older women, but older mice treated with BGP-15 had improved ovulation rates. Further, eggs of older female mice had increased levels of stress markers that were alleviated in the females treated with BGP-15. Lastly, treatment of older females resulted in improved embryo development when their eggs were fertilised. Older male mice exhibit declines in fertility and fetal health similar to those of older men. Older male mice have reduced sperm motility and high levels of stress markers in their sperm. Using our time-lapse embryo monitoring system we found that sperm from older males leads to poor embryo development, namely reduced capacity for the fertilised egg to form a 2 cell embryo and when it does there is delayed development to the blastocyst stage. Older males are less capable of initiating a pregnancy following mating. When pregnancies do result, both the placenta and the fetus are reduced in weight. Subsequently, at birth the neonates from older males have reduced weight and increased neonatal mortality. In older males that were treated with BGP-15 for 4 days prior to mating many of these detrimental issues were reversed. Sperm motility was increased in the treated males but most importantly, embryo development was improved. Sperm from older males that were treated led to normal fertilisation and embryo development at the 2 cell stage and blastocyst stage. Pregnancy rates were improved in the older males that were treated compared to those that were untreated. Further, the high incidence of neonatal mortality observed in older males was negated in the males that were treated with BGP-15. We are continuing to examine the post-natal and adult phenotypes, particularly the metabolic and behavioural phenotypes, in these offspring.
These experiments have provided the first detailed examination of early embryo development from advanced age parents, and proof-of-concept preclinical data on the effectiveness of BGP-15. From this there have been two major outcomes.
- We were able to patent our findings that BGP-15 improves sperm quality. This enabled us to expand our research into clinical investigations of whether BGP-15 is able to protect human sperm (and eggs). For these studies we are now collaborating with a local fertility clinic (Fertility SA) and an interstate clinic (Monash IVF).
- This Channel 7 grant underpinned our NHMRC Project Grant application which was awarded $1.1M in funding (2019-2022). This will allow us to complete the offspring assessments and to expand our clinical studies. The findings from the completed NHMRC grant will facilitate the attraction of a commercial partner to support a clinical trial.
Our ultimate goal is to see BGP-15 developed as new pharmaceutical for reproductive medicine that can restore health to both eggs and sperm and thereby provide the greatest assurance of child health. The Channel 7 Research Grant support has played an essential role in the development of this potential therapy.
Manuscript in preparation: Mitochondrial function in gametes is reversible with BGP-15.
Poster presentation: The Channel 7 Children’s Research Foundation was acknowledged in all instances.
- Australian Society for Medical Research SA Division Annual Scientific Meeting 2018. Title: Advanced parental age is associated with decreased gamete quality and altered early embryonic development. Authors: Macarena B. Gonzalez, Rebecca Robker.
- Society for Reproductive Biology Annual Conference 2018. Reversing decreased gamete quality and altered embryogenesis caused by advanced paternal age. Authors: Macarena B. Gonzalez, Rebecca Robker. *** this presentation was a finalist in the Oozoa Award Symposium.
- ANZ Society for the Developmental Origins of Health and Disease (DoHaD) Annual Conference 2018. Title: Advanced age of mothers and fathers is associated with altered early embryonic development. Authors: Macarena B. Gonzalez, Rebecca Robker
We filed International Patent Application PCT/AU2018/051040 ‘Methods and products for improving sperm quality’ September 2018. It details our discoveries on the novel effects of BGP-15 on improving sperm quality and developmental competence. This IP will be used to develop an IVF media that can protect damaged sperm, particularly that from older men, from DNA damage and thereby improve embryo development and ensure better fetal and child health. We are working in collaboration with Fertility SA to validate the effects of BGP-15 on human sperm. We are seeking commercial partners to develop the technology and support clinical trials.
This Channel 7 Children’s Research Foundation grant underpinned our NHMRC Project Grant application, which was awarded $1.1M in funding (2019-2022). This will allow us to complete the offspring assessments and to expand our clinical studies. The findings from the completed NHMRC grant will facilitate the attraction of a commercial partner to support a clinical trial.