What is minipuberty?
Can events you endured as an infant really impact your ability to have children yourself? What if we were going a step further, suggesting that infant life could in fact affect the overall neuroendocrine development, meaning really have an impact on our mental and non-mental health as adults?
Along with our birth comes the activation of the hypothalamic-pituitary-gonadal axis (HPG), resulting in hormonal changes (luteinizing and follicle stimulating hormones; LH, FSH) that set in motion the growth of the first wave of ovarian follicles set to ovulate at puberty in females and the development of the testes in males. Thus, the maturation and function of the HPG axis is actually a prerequisite for our own sexual maturation, thus the acquisition of fertility later on in life. Peculiarly enough, even though the HPG axis gets progressively activated from the first week of life, its activation is only transient since the system switches off around the 6th month of age, only to be re-activated once again at puberty onset. This short window of human sexual maturation, that is not continued till puberty, is named mini-puberty, and the mechanisms behind its regulation during infancy remain largely unknown.
How does prematurity affect minipuberty and the development of mental and non-mental disorders in later life?
Intriguingly, the amplitude of minipuberty (i.e. hormonal FSH levels) varies tremendously depending on gestational age at birth in both boys and girls, increasing up to 300-fold in preterm infants, comparing to the levels reported in fullterm newborns. Hyperandrogenism or altered follicular development, both occurring because of the aberrant minipuberty, could influence growth, neuronal network maturation, body composition, fat distribution, blood pressure, and lipid and glucose metabolism by altering their programming, thereby contributing to the risk of developing many noncommunicable diseases.
In fact, according to the WHO, preterm birth is one of the largest single conditions in the Global Burden of Disease analysis, due to its high mortality but also the considerable risk of lifelong morbidities, including neurodevelopmental disabilities (e.g. cerebral palsy, mental retardation, hearing loss, visual impairments), asthma, learning disabilities, attention deficit disorder, and emotional problems. As adults, preterm infants also have higher rates of insulin resistance and hypertension, thus being more prone to metabolic and cardiovascular disorders, compared to those born at term.
What is nitric oxide and how could it rescue the effects of premature birth?
Nitric oxide (NO) works as a signaling molecule in the nervous, cardiovascular and immune systems. NO has long been recognized as a key player in the central hormonal regulation of fertility but it was not until recently that we acquired some knowledge behind its role in the process of sexual maturation. Animal studies using mice deficient for NOS1 -the enzyme responsible for the production of NO in neurons- identified that NO deficiency is associated with aberrant minipuberty, with NOS1 deficient mice demonstrating exacerbated hormonal levels, similarly to what is seen in prematurely born infants. Further mouse but also human studies revealed that absence of NOS1, and thus altered minipuberty, results not only in defective sexual maturation, but also in comorbidities such as olfactory deficiency, hearing loss, cognitive impairments, metabolic abnormalities and reproductive disorders, in adulthood. Remarkably, we have shown that all the above reproductive and non-reproductive pathologies could be corrected by NO-replenishment therapy [inhaled NO (iNO) / sildenafil] specifically during minipuberty in NOS1-deficient mice.
APPROACH
The miniNO project ambitions to identify altered minipuberty as the key causative mechanism underlying multimorbidity associated with preterm birth. miniNO will be organized around seven main objectives and will provide a better understanding of the association between gestational age at birth and the various pathological phenotypes that come along. Hence, the project concept will be based on a systematic comparison of preterm and full-term patients in newly established cohorts to provide feedback on the influence of NO signaling on the minipuberty and their role on brain and body maturation. Those studies will also be complemented using pre-established cohorts of patients,
subjected or not to NO-replenishment therapy and followed since birth, to improve the prognosis of new-borns at hi gh-risk to develop mental and non-mental disorders. Finally, the complete understanding of the mechanisms underlying altered minipuberty will pave the way to develop novel diagnostic and preventive strategies to tackle altered minipuberty and associated developmental defects. This European project will help implement new approaches of prevention to alleviate the deleterious consequences of premature birth over lifetime and pave the way to personalized medicine.
Prevention & therapy development
METHODOLOGY
Genuine progress in developing effective preventive and therapeutic strategies to tackle neurodevelopmental disorders requires novel ideas and a multifaceted approach, only possible with an interdisciplinary and multinational consortium of clinical scientists, geneticists, and bioinformatician/genomic experts committed to the same goal as a single functional unit. The premise of miniNO is that the design of successfulunderstanding of developmentally-acquired brain
patient-management strategies will depend on a better understanding of developmentally-acquired brain malfunction caused by early life events, namely gestational age at birth and the shaping of minipuberty, that lead to multimorbidities combining mental (cognition and executive function, autism) and non-mental (anosmia, hearing loss, diabetes and infertility) disorders.
EXPECTED IMPACTS
In addition to preterm birth being responsible for 35% of the 3.1 million yearly deaths, its comorbidities continue throughout life, impairing normal neurodevelopment and increasing the chances of numerous noncommunicable diseases, thus inflicting a heavy burden on families, society and the health care system. As a matter of fact, the statistical data collected from various European countries demonstrate the enormous, and increasing, financial burden associated with prematurity in Europe reaching the amount of several billions per year. This lifetime cost estimates only include infants with major neurodevelopmental disabilities already diagnosed at birth, without taking into account other long-term morbidities or even its vast socio-economic consequences like the costs of the caregivers for individuals with
disabilities, out-of-pocket payments for education or loss of earnings during childhood, future lost productivity in the household and the labor force etc. Measures to prevent preterm birth on a global scale in a clinically significant way have so far been ineffective. It therefore becomes increasingly important to improve outcomes in those preterm infants currently being born. A better understanding of the association between gestational age at birth and various mental and non-mental pathological phenotypes could help us implement new approaches to prevention, restricting the deleterious effects of premature birth that burden preterm individuals throughout life, promoting a better quality of life for millions of people.
Concept and Objectives
MILESTONES
The miniNO project will be running from January 2020 to December 2026. During those 6 years, research teams will deliver several papers and results to advance knowledge about minipuberty and its comorbidities.
WORK PACKAGES
The miniNO project is organized in 8 work packages.
Through the WP1 to 5 and based on a strong European synergy, the partners will create a new cohort of premature infant and develop animal models (mouse) to expand the knowledge on the biological mechanisms of minipuberty. Completing those investigations with medical data from pre-existing European cohorts will lead to the proposition of new
clinical guidelines for the management of preterm infants as well as the development of early diagnosis test based on biomarker to improve the prognosis of altered minipuberty. WP6 to 8 consist in support activities: dissemination and communication, intellectual property management, exploitation, data management, ethical matters and coordination of the project.
