Project of an Adverse Output Pathway (AOP) in Developmental Neurotoxicity

• Forschungsstelle: BAG
• Projektnummer: 13.005616

Schlüsselwörter (Englisch)

Adverse output pathway, AOP, development neurotoxicity, hippocampus-dependent functions, endocrine disruptor

Kurzbeschreibung (Englisch)

The aim of the project is to develop an AOP linking behavioral outcomes resulting from developmental exposure to chemicals, with molecular actions analyzed in in vitro cell systems. Learning and memory appear to represent a suitable adverse endpoint because (1) impairments are well documented in experimental animals after developmental exposure to different classes of chemicals, such as polychlorinated biphenyls (PCB5), pesticides, and bisphenol A (BPA) and because (2) cognitive functions are endpoints in OECD testing guidelines (e.g., TG426, Developmental Neurotoxicity Study). The model is relevant for humans, as exposure to a number of chemicals has been correlated with analogous cognitive deficiencies in epidemiological studies in humans. Since the hippocampus plays a central role in this type of behaviors, we propose to study chemical-induced changes in hippocampus as a possible link between adverse outcome and initiating events at the cellular level. Late effects at the molecular level have been identified in adult rodent hippocampus after exposure to chemicals during early development. Development and function of the hippocampus also depend on hormone actions (estrogens, androgens, thyroid hormones), which means that a hippocampus-based AOP could be expected to detect effects of endocrine disrupting chemicals on brain development (e.g., BPA).

Projektziele (Englisch)

Identify candidate signaling pathways and target genes from genome-wide analyses of rat developing hippocampus exposed to various chemicals (bisphenol A, chlorpyrifos and PCBs).

Link behavioral outcomes (such as learning and memory) resulting from exposure to chemicals at 2 different developmental stages, to the effects seen at the molecular level.

The information resulting from the AOP project are miscellaneous. AOP could potentially partially replace OECD test guidelines such asTG426 (Developmental Neurotoxicity Study) and the DNT Module (Developmental Neurotoxicity Study) of TG443 (Extended One-Generation Reproductive Toxicity Study). The model can also provide important information on the effects of endocrine disruptors on the brain development and to evaluate effects of mixtures of chemicals.

Abstract (Deutsch)

Ein Modell (ein sogenanntes AOP-adverse outcome pathway) wurde entwickelt, welches hilft die negativen Auswirkungen von bestimmten Chemikalien auf einen Organismus oder auf eine Population vorauszusagen. Exposition gegenüber gewissen Chemikalien während der Entwicklung kann zu kognitiven Störungen führen. Diese negativen Auswirkungen haben ihren Ursprung in Veränderungen auf molekularer Ebene im Hippocampus. Die Verbindung zwischen diesen molekularen Veränderungen im Hippocampus und dem Auftreten von kognitiven Störungen soll gefunden werden.

Umsetzung und Anwendungen (Englisch)

The present project led to the discovery of a new type of target genes of environmental chemicals affecting the development of hippocampus and learning and memory, i.e., several Sox and Pou genes. These genes are involved in cell-autonomous control of developmental processes, which means that they act within the cell, where they are expressed, rather than being secreted. In addition, neuregulin 1 (Nrg1), a repellent factor secreted by the pallium, and its receptor Erbb4, which control migration of cortical interneurons, were also affected. Several of the Sox and Pou genes, Sox6, Sox11, Pou2f2/Oct2, and Pou3f2/Brn2 showed analogous expression changes in response to all three chemicals. The study further revealed microRNAs as a target of these chemicals. Data from other cell systems suggest that the effect of the three chemicals on Sox6 may have been brought about by the downregulation of miR-24 observed in male hippocampus.

The gene expression changes were only seen in hippocampus of male offspring, but not in females. We are not sure whether this could reflect a basic sex difference. One reason for the difference might be sought in the considerable difference (3-4x) in cell proliferation rate in hippocampus of neonatal male and female rats.

Weiteres Vorgehen (Englisch)

The group of commonly affected genes in neonatal hippocampus might be used to construct a key event for an AOP; it could also be used as endpoints for the development of in vitro test guidelines or for the enhancement of existing in vivo test guidelines. However further experiments are needed. One information that would considerably help to specify a model that could be tested by additional in vitro and in vivo experiments, is the cellular location of the gene products in question, e.g., of Sox6. The evolution of the project will depend on the available resources.