Effect of radiation on neural tube closure and related congenital abnormalities

Craenen Kai

Promoter

Moons Lieve, (KUL), lieve.moons@bio.kuleuven.be

SCK•CEN Mentor

Benotmane Rafi
rafi.benotmane@sckcen.be
+32 14 33 27 31

SCK•CEN Co-mentor

Verslegers Mieke
mieke.verslegers@sckcen.be
+32 14 33 28 67

Expert group

Radiobiology

PhD started

2014-10-01

Short project description

The neural tube defects or NTDs, which represent the second most common birth defect in humans, can be induced spontaneously and by chemical agents. Several reports indicate a high incidence of neural tube defects "NTDs" (up to 27 per 10.000 compared to 3-4 in U.S) in Ukrain Ceasium- most contaminated areas such as Polissia (highest Chernobyl impacted region) establishing a strong link between occurrence of NTDs and exposure to radiation (Werteleki et al, 2010). NTDs have also been shown to be induced by prenatal exposure to ionising radiation "IR", with a spatiotemporal heterogeneity of molecular mechanisms leading to the folding and the closure of the neural tube (Harris and Juriloff, 1999). It is well known that exposure to ionizing radiation (IR) during gestation can lead to deleterious effects in foetuses such as teratogenicity effects or even lethality in case of high doses (De Santis et al., 2005). However the loss of an unexpected embryo is considered as of minor importance compared to the risk to have a new born affected by a malformation, and then it’s particularly interesting to study medium and low doses radiation, which can induce these malformations such as anencephaly and/or exencephaly. Failure to complete the process of fusion to form the neural tube leads to NTDs, which are among the most disabling human birth defects.

Objective

Preliminary animal data at the Radiobiology Unit have shown an increase (about 20 to 30% per Gy) in the rate of exencephalies and more than 30% of eyes deffect when irradiating the pregnant mother at the organogenesis period (E8-E10). In some mice models, these malformations include mainly anencephaly, exencephaly, spina bifida and rachitisis (Juriloff and Harris, 2000). The more frequent NTDs is the exencephaly, where the foetus hasn’t a correct closure of the neural tube at the cranial area, which results in an absence of closure of the skull and an overgrowth of neural tissue in the region of the mid-brain. The link between NTDs and eye defect remain unknown.

Our investigations will essentially focus on radiation-induced teratogenicity effects and congenital anomalies (morphological and histopathological analyses). The ultimate objective is to illustrate the potential mechanisms (molecular pathways, metabolic processes and regulatory networks and epigenetics) leading to NTDs and brain anomalies and eyes defect resulting from an irradiation at the early post gastrula stages. Several microarray data have been generated the previous years after irradiation at the gastrula stage (within the FANC and NOTE EU project), and will be valorised by the PhD candidate to elucidate the early effects of radiation at the organogenesis period. The role of low vs. high folate diet will be studied, with particular emphasis on the early events just after the exposure and the late consequences leading to external malformations such as exencephaly/anencephaly and eyes defect.