Periodic Reporting for period 1 - neurOmics (Novel Methods to Identify Endocrine Disruption Induced Neurotoxicity)
Reporting period: 2023-05-01 to 2024-08-31
By using cutting-edge methods within developmental neurotoxicity and endocrine disruption, neurOmics will use exploratory omics in a powerful alterative model system to form novel hypotheses on how endocrine disrupting chemicals affect the brain. The project will utilize a representative of true frogs, the cosmopolitan tadpole model American bullfrog (Rana [Lithobates] catesbeiana), to understand the causes of developmental neurotoxicity (DNT) and exploit this gained knowledge to establish adverse outcome pathways (AOPs) applicable for risk assessment of chemicals — a European Commission priority focus area and supporting the Green Deal ‘a toxic-free environment.
Currently, the incidence of neurodevelopmental disorders such as attention deficit hyperactivity disorders and autism spectrum disorders are increasing among children; a trend that has been linked to man-made chemicals suspected of causing developmental neurotoxicity. Thyroid hormone signaling is well-known for playing an essential role in brain development in all vertebrates. Hence, thyroid hormone system disrupting chemicals are likely candidates for causing developmental toxicity. Despite this, the current guidelines are insufficient to properly identify chemicals that are toxic for the developing brain and scientists across the world have recently called for better testing methods. The proposed project aims to develop novel testing strategies that will have a far-reaching impact and contribute to breaking down the wall between human and environmental toxicology. This will enable for a better and more feasible identification and safety assessment of hazardous chemicals, ultimately reducing the neurodevelopmental
disorders observed among children today.
Currently, the incidence of neurodevelopmental disorders such as attention deficit hyperactivity disorders and autism spectrum disorders are increasing among children; a trend that has been linked to man-made chemicals suspected of causing developmental neurotoxicity. Thyroid hormone signaling is well-known for playing an essential role in brain development in all vertebrates. Hence, thyroid hormone system disrupting chemicals are likely candidates for causing developmental toxicity. Despite this, the current guidelines are insufficient to properly identify chemicals that are toxic for the developing brain and scientists across the world have recently called for better testing methods. The proposed project aims to develop novel testing strategies that will have a far-reaching impact and contribute to breaking down the wall between human and environmental toxicology. This will enable for a better and more feasible identification and safety assessment of hazardous chemicals, ultimately reducing the neurodevelopmental
disorders observed among children today.
Neurodevelopment is highly conserved across animal species and is an elegant choreography of neuronal differentiation, cell migration and network formation that unfolds to construct an organ of uppermost complexity. Equal in magnitude is, however, the vulnerability. Failure in the spatial and temporal organization can have detrimental effects.
Amphibians are exceptional alternative models because the action of thyroid hormones on the re-organization of a tadpole brain during metamorphosis has direct parallels to the developing human brain during the last trimester and the first weeks of life where a surge of thyroid hormones is essential for proper development. Using mass spectrometry imaging we initially developed a methodology to examine a whole developmental series of tadpoles throughout metamorphosis to establish a critical developmental baseline and produce a brain developmental atlas applicable to other vertebrate species as well.
Subsequently, we exposed tadpoles to the thyroid hormone system disrupting contaminant PFOS and the model chemical perchlorate. This study allowed us to look at brain metabolites that change due to chemical exposure. Even more importantly however, these molecules can now also be linked to the developmental baseline. This means that we can look at the biological significance of the changes in the brain lipidome of tadpoles when they are exposed to thyroid hormone system disrupting chemicals.
Amphibians are exceptional alternative models because the action of thyroid hormones on the re-organization of a tadpole brain during metamorphosis has direct parallels to the developing human brain during the last trimester and the first weeks of life where a surge of thyroid hormones is essential for proper development. Using mass spectrometry imaging we initially developed a methodology to examine a whole developmental series of tadpoles throughout metamorphosis to establish a critical developmental baseline and produce a brain developmental atlas applicable to other vertebrate species as well.
Subsequently, we exposed tadpoles to the thyroid hormone system disrupting contaminant PFOS and the model chemical perchlorate. This study allowed us to look at brain metabolites that change due to chemical exposure. Even more importantly however, these molecules can now also be linked to the developmental baseline. This means that we can look at the biological significance of the changes in the brain lipidome of tadpoles when they are exposed to thyroid hormone system disrupting chemicals.
Mass spectrometry imaging MSI combines microscopic imaging with mass spectrometry to interrogate surfaces and in that way unites mass spectrometry and histology. This opportunity to gain spatial and chemical information has allowed us to make a developmental atlas of vertebrate brain development
Additionally, applying mass spectrometry imaging of the tadpole sensory system including brain, olfactory system and eyes after exposure to the legacy contaminant PFOS allowed an unprecedented scientific discovery as we found this contaminant to localize to a specific neuroendocrine gland and to the olfactory epithelium.
Additionally, applying mass spectrometry imaging of the tadpole sensory system including brain, olfactory system and eyes after exposure to the legacy contaminant PFOS allowed an unprecedented scientific discovery as we found this contaminant to localize to a specific neuroendocrine gland and to the olfactory epithelium.