Establishment of Adverse Outcome Pathway (AOP) Networks for Cognitive Dysfunction
Master's Thesis Project

Background:
Developmental neurotoxicity (DNT) testing of chemicals is not yet required by current legislation, despite the rising prevalence of neurodevelopmental disorders like autism and ADHD and the unknown role of chemical exposure in these conditions. However, the discussion about a classification of neurotoxic substances within the framework of the European chemicals legislation REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) is ongoing.

Conventional animal models are largely unsuitable for precise DNT assessments because they are too costly and too slow and the data is difficult to interpret. There is therefore a great need for alternative test systems that provide relevant results for humans. New Approach Methodologies (NAMs) that integrate in vitro, in silico and non-mammalian models will provide the necessary mechanistic information to enable rapid, cost-effective and human-centred DNT testing.

Adverse Outcome Pathway (AOP) frameworks that describe the sequence of biological events, link chemical exposure to an adverse health outcome and provide a structured approach to interpret mechanistic data from NAMs.

Project description:
While neurons are often the focus of DNT research, glial cells, particularly oligodendrocytes, are crucial in brain development and are highly vulnerable to chemical exposure, highlighting the need for more precise DNT assessments.

This project aims to identify missing Key Events (KEs) and Key Event Relationships (KERs) within a proposed AOP network connecting impaired oligodendrocyte differentiation to cognitive decline. Specifically, it focuses on defining not yet described KEs and KERs in an AOP initiated by the Molecular Initiating Event (MIE) of voltage-gated sodium channel binding.

Figure 1: Putative AOP network for impaired oligodendrocyte development.

Techniques used in the master thesis include semi-systematic literature review, data mining of data bases like the US-EPA ToxCast dashboard and other relevant sources for making use of already published data.

Our offer:

• We offer a well-structured research topic with a clear research question and hypothesis that is essential to address contemporary problems in toxicology to advance current risk assessment.
• We provide you with advisors with expertise in your chosen field to ensure the project scope is manageable within your time frame and resources and is publishable in peer-reviewed journals.
• We offer insights into novel methods that are currently on the rise in regulatory toxicology.
• We provide you with international exposure through our involvement in international research projects.
• This project will help you prepare for your next career step- whether pursuing a PhD or working in industry or regulatory authorities.

What is asked of you:

• Self-motivated and pro-active problem-solving skills
• High affinity for data evaluation and writing of scientific texts
• Strong team spirit and good communication skills
• Openness to learn and adopt

Contact:

Ellen.fritsche@clutterunibas.ch

Lothar.aicher@clutterunibas.ch

Lidwina.gerner@clutterunibas.ch