Developmental, behavioral, cellular and molecular evaluation of a embryo-fetal and juvenile toxicity induced by the chronic exposure during gestational and lactational phases to a mixture of the 6 NDL-PCB indicators in a mouse model – NEURODEVETOX

The raise of anthropogenic activities has led to a large release of various chemicals in the environment. These pollutants can affect the animal and human health via food chain contamination. Actually, epidemiological studies reveal a significant raise of mental and neurological disorders among children such as autism or kinetic disorders. Environmental pollutants are highly suspected to induce such pathologies when exposition occurs at early stages. Thus, it becomes extremely relevant to study their mechanisms of action through some interdisciplinary approaches, in functional and molecular biology, in genomic and transcriptomic analyses.
Our project, divided into eleven tasks, aims to develop such an approach to increase our knowledge on some ubiquitous pollutants.
This project has already been submitted to a previous evaluation (CES 2010). Thus, the criticisms and recommendations of the experts have been carefully taken into account in this new version. It also joins the perspectives of PNSE researches, evenly focuses on risks induced by food contaminants such as ALIA, ANSES and also REACH program objectives (CD 2I).
This project would lead to the elaboration of a European consortium, dedicated to the assessment of the neurotoxic risk.
The choice of the 6 Non-Dioxin-Like PolyChloroBiphenyls indicators (6 NDL-PCBi) is motivated by their strong occurrence in food matrices as well as the great rarity of the results in literature relative to their neurotoxicity (AFSSET, AFSSA-ANSES, EFSA). The exposure to these xenobiotics is incontestable, since they are indicators of the food chain contamination for the NDL-PCBs sub-family, and secondly, they are highly detected in several human tissues, including brain.
We wish to investigate the neurotoxicity of a relevant mixture of the 6 NDL-PCBi, which proportions of each congener and doses are carefully argued. It is divided in two parallel approaches:
The first part is a neurotoxicological investigation performed with pure compounds. It will allow to characterize the effects and the mechanistical aspects of the neurotoxicity induced by these hazardous pollutants.
In the second part, a new neurotoxicological investigation will be carried out in animals exposed to the same equivalent doses of the 6 NDL-PCBi, but via a contaminated food matrice containing other environmental contaminants, that types and levels will be previously determined. The goal of this second part is to mimic the real exposure resulting from polluted food matrices consumption. It will allow to verify the persistence and reproducibility of the results previously obtained with pure compounds, or to observe and characterize any deviation due to other pollutants (cocktail effects). Among the several food matrices, fish is the most contaminated by PCBs. It is responsible for the largest transfer of these pollutants to humans. In the fish flesh, the 6 NDL-PCBi may vary in quantity, but they always show equivalent proportions. Although this matrices is also contaminated by other various pollutants (metals, pesticides, PBDEs, HAPs…), it seems extremely relevant to reproduce the first part of the study, with a real food matrice whom degree of contamination directly results from a real environmental exposure. The actual regulatory thresholds about the 6 NDL-PCBi daily intake do not constitute a protection of the consumer regarding chronic and early exposures.
Indeed, the brain, during the stages of prenatal and juvenile development, is highly susceptible to the action of these xenobiotics which are significantly transferred from the mother to its offspring. Consequently, an early exposure may lead to persistent impairments in developmental/behavioural/cognitive functions in juveniles or at adult stage. Consequently, we submit this project focusing on the assessment of the neurotoxicity induced in mice pups by the chronic exposure of gestating and lactating dams to the ingestion of the 6 NDL-PCBi at relevant environmental doses.