Progetto Trambigen

  • MINISTERO DELLA SALUTE - RICERCA FINALIZZATA
    Bando Progetti di Ricerca Giovani Ricercatori - Ricerca Finalizzata
  • STUDIES ON THE INVOLVEMENT OF GENETIC, EPIGENETIC AND ENVRINOMENTAL FACTORS IN THE PATHOGENESIS OF CONGENITAL HYPOTHYROIDISM. NOVEL PERSPECTIVES FOR THE MANAGEMENT OF A LARGELY UNEXPLAINED DISORDER

Congenital Hypothyroidism (CH) is the most common congenital endocrine disease and avoidable cause of severe mental retardation. The most important reviews on CH report an incidence of 1:3-4000 newborns and the large majority of cases (about 75%) being due to defects in thyroid organogenesis, collectively called thyroid dysgenesis. A very recent study conducted in Lombardy by the Coordinator and several collaborators of this proposal indicates that the incidence of permanent CH is at least double than currently thought (about 1:1400 newborns) and that >60% of the cases appear as due to functional defects of a normally developed thyroid gland.

Such a significant increment in the diagnosis of permanent CH has an obvious important socio-economical impact, due to the increased workload for Screening Labs and Pediatric Centers, and raises uncertainty on the most appropriate management for many CH babies.

The CH pathogenesis is still largely unknown and may include the contribution of individual and environmental factors. Causal genetic mutations have been found in <10% of CH cases, suggesting the involvement of still unidentified genes or alternative mechanisms. In this context, the RUs of Milan (Prof. L. Persani) and Padova (Dr. N. Tiso) investigated the role of Notch pathway and of the ligand Jagged1 in the process of thyroid development in the zebrafish model. Since the Notch pathway is involved in the development of other endoderm derivatives as well as of cardiac bud, alterations in this pathway may contribute mainly to the pathogenesis of CH cases combined with defects in other organs or tissues.

The existence of alternative mechanisms for CH pathogenesis is supported by the elevated frequency of discordance for CH phenotype between monozygotic (MZ) twins. This latter finding suggests the involvement of non-mendelian mechanisms that might predispose to or protect from the full expression of a CH genetic background. We hypothesize that a disturbed gestation, possibly affected by undernutrition as in the case of premature birth or multiple pregnancies, or a premature adaptation to extra-uterine life might result in an abnormal methylation state including that of genes involved in thyroid hormone production/metabolism or action. Such an abnormal methylation might lead to a resetting of HPT axis and sustain the increased risk for CH in these conditions.

Additional evidence points to a possible influence of environmental factors able to interfere with newborn thyroid function. Many EDCs, including polychlorinated biphenyls (PCBs) and dioxins, have been described to interfere with thyroid function in vitro. However, the molecular mechanisms underlying their activity in hypothyroidism development have never been extensively investigated and most of all no data are available about a possible interference by EDCs on the in vivo processes leading to thyroid development.

In the light of all these unsolved biological questions, the aim of this collaborative study is thus to expand our knowledge on the genetic, epigenetic and environmental factors contributing to CH pathogenesis.

Principal investigator

  • Prof. Luca Persani - Fondazione Istituto Auxologico Italiano, Milano (coordinatore)

Scientist in charge of the local Unit

Partnership

  • Unità  Operativa n.  1 (Istituto Capofila) - ISTITUTO AUXOLOGICO ITALIANO, Istituto di Ricovero e Cura a Carattere Scientifico
  • Unità  Operativa n. 2 - OSPEDALE SAN RAFFAELE S.r.l
  • Unità Operativa n. 3 - DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE,   UNIVERSITA' DEGLI STUDI DI BOLOGNA
  • Unità  Operativa n. 4 - DIPARTIMENTO DI BIOLOGIA, UNIVERSITA' DEGLI STUDI DI PADOVA
  • Unità  Operativa n. 5 - ISTITUTO SUPERIORE DI SANITA'
  • Unità Operativa n. 6 - BIOGEM s.c.a.r.l
  • Unità Operativa n. 7 - DIPARTIMENTO DI MEDICINA CLINICA E SPERIMENTALE, UNIVERSITA' DEGLI STUDI DI PISA

Keywords

Zebrafish, thyroid, congenital hypothyroidism (CH), hypothalamic-pituitary-thyroid (HPT) axis, EDCs (endocrine disrupting chemicals)