Search

DNA methylation is one of the most important epigenetic modifications and is closely related with several biological processes such regulation of gene transcription and the development of non-malignant diseases. The prevailing dogma states that DNA methylation in eukaryotes occurs essentially through 5-methylcytosine but recently adenine methylation, through 6-methyl adenine (6mA), was also found to be present in eukaryotes. In mouse embryonic stem cells it was shown to be associated with the repression and silencing of genes, particularly in the X-chromosome, known to play an important role in cell fate determination. Here, we have demonstrated that 6mA is a ubiquitous eukaryotic epigenetic modification that is put in place during epigenetically sensitive periods such as embryogenesis and foetal development. In somatic cells there are clear tissue specificity in 6mA levels, with, the highest 6mA levels being observed in the brain. In zebrafish, during the first 120h of embryo development, from a single pluripotent cell to an almost fully formed individual, 6mA levels steadily increase. An identical pattern was observed over embryonic days 7-21 in the mouse. Furthermore, exposure to a neurotoxic environmental pollutant during the same early life period led to a decrease in the levels of this modification. Our identification of the periods during which 6mA epigenetic marks are put in place and how they dynamically change in response to an early environmental stress, may shed a light on our understanding of the mammalian epigenetic modifications, and, as outlined in the developmental origins of health and disease, mechanistically contribute how a deviation from normal development can trigger disease phenotypes later in life., This manuscript has now been accepted for publication in Frontiers in Genetics DOI: http://doi.org/10.3389/fgene.2021.657171

The incidence of neurodevelopmental and neurodegenerative diseases worldwide has dramatically increased over the last decades. Although the aetiology remains uncertain, evidence is now growing that exposure to persistent organic pollutants during sensitive neurodevelopmental periods such as early life may be a strong risk factor, predisposing the individual to disease development later in life. Epidemiological studies have associated environmentally persistent organic pollutant exposure to brain disorders including neuropathies, cognitive, motor, and sensory impairments; neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD); and neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). In many ways, this expands the classical “Developmental Origins of Health and Disease” paradigm to include exposure to pollutants. This model has been refined over the years to give the current “three-hit” model that considers the individual’s genetic factors as a first “hit.” It has an immediate interaction with the early-life exposome (including persistent organic pollutants) that can be considered to be a second “hit.” Together, these first two “hits” produce a quiescent or latent phenotype, most probably encoded in the epigenome, which has become susceptible to a third environmental “hit” in later life. It is only after the third “hit” that the increased risk of disease symptoms is crystallised. However, if the individual is exposed to a different environment in later life, they would be expected to remain healthy. In this review, we examine the effect of exposure to persistent organic pollutants and particulate matters in early life and the relationship to subsequent neurodevelopmental and neurodegenerative disorders. The roles of those environmental factors which may affect epigenetic DNA methylation and therefore influence normal neurodevelopment are then evaluated.

International audience; Background: Dyslipidemia associated with obesity often manifests as increased plasma LDL and triglyceride-rich lipoprotein levels suggesting changes in hepatic lipoprotein receptor status. Persistent organic pollutants have been recently postulated to contribute to the obesity etiology by increasing adipogenesis, but little information is available on their potential effect on hepatic lipoprotein metabolism.Objective: The objective of this study was to investigate the effect of the common environmental pollutant, benzo[] pyrene (B[alpha]P) on two lipoprotein receptors, the LDL-receptor and the lipolysis-stimulated lipoprotein receptor (LSR) as well as the ATP-binding cassette transporter A1 (ABCA1) using cell and animal models. Results: LSR, LDL-receptor as well as ABCA1 protein levels were significantly decreased by 26-48% in Hepa1-6 cells incubated (, 2 h) in the presence of B[alpha]P (

International audience; Fluorene is one of the most abundant polycyclic aromatic hydrocarbons in air and may contribute to the neurobehavioral alterations induced by the environmental exposure of humans to PAHs. Since no data are available on fluorene neurotoxicity, this study was conducted in adult rats to assess the behavioral toxicity of repeated fluorene inhalation exposure. Male rats (n = 18/group) were exposed nose-only to 1.5 or 150 ppb of fluorene 6 hours/day for 14 consecutive days, whereas the control animals were exposed to non-contaminated air. At the end of the exposure, animals were tested for activity and anxiety in an open-field and in an elevated-plus maze, for short-term memory in a Y-maze, and for spatial learning in an eight-arm maze. The results showed that the locomotor activity and the learning performances of the animals were unaffected by fluorene. In parallel, the fluorene-exposed rats showed a lower level of anxiety than controls in the open-field, but not in the elevated-plus maze, which is probably due to a possible difference in the aversive feature of the two mazes. In the same animals, increasing blood and brain levels of fluorene monohydroxylated metabolites (especially the 2-OH fluorene) were detected at both concentrations (1.5 and 150 ppb), demonstrating the exposure of the animals to the pollutant and showing the ability of this compound to be metabolized and to reach the cerebral compartment. The present study highlights the possibility for a 14-day fluorene exposure to induce some specific anxiety-related behavioral disturbances, and argues in favor of the susceptibility of the adult brain when exposed to volatile fluorene.

National audience; Environmental pollutants such as benzo(a)pyrene (BaP) produce numerous deficits related to central deficiencies, including decreased motor activity, neuromuscular and autonomic abnormalities. While the carcinogenicity of BaP is well established, its neurotoxic effects have received less attention. Recently, some authors predicted the neurotoxic potential of polycyclic aromatic hydrocarbon particles deposited within the brain, and their subsequent adverse effects on development. Currently, the relationship between BaP, the cerebral metabolism of xenobiotics, and behaviour has received little attention. Therefore, we focused the present study on the effects of an oral subacute BaP administration (0.02, 0.2, 2, 20 and 200 mg/kg/day, 10 days) on the regional expression of CYP1A1 gene in the brain, and the anxiety-related behaviour in adult mice. The results showed that the subacute exposure to BaP induced significant increases in the CYP1A1 expression in the hippocampus, the frontal cortex, and the temporal cortex at the two highest doses administered (20 and 200 mg/kg) whereas the lowest BaP concentrations did not. At the same doses, the animals exhibited a reduction of their anxiety level, as reflected by significant increases in the time spent in the central part of the elevated plus maze correlated with reductions in the time spent in the closed arms. Concomitantly, significant increases in the number of head dipping were observed with the same animals in the hole board apparatus. The present study suggests that there is a dose-dependent relationship between the level of BaP exposure, the cerebral metabolism of this xenobiotic, and the modulation of anxiety-related behaviour.

National audience; Human activities produce polluting compounds such as the Persistent Organic Pollutants group (POP) which may interact with agriculture. These molecules have raised concern about risk of transfer through the food chain via the animal product. The POP are characterised by a strong persistence in the environment, a high volatility and a lipophilicity, which lead to their accumulation in fat tissues. These compounds are enlisted in international conventions so that the information about their potential toxicity for humans and the environment may be organised. The aim of this paper was to study transfer through the food chain of three groups of POP: the dioxins-furans (PCDD/F), the polychlorobiphenyls (PCB) and the Polycyclic Aromatic Hydrocarbons (PAH). The results show that the contamination of fodder by these compounds is observed when they are exposed to emission sources as compared to those in remote areas. They also show that a differential transfer of the molecules is detected towards biological matrices (milk).; Les activités humaines produisent des composés polluants tels que les Polluants Organiques Persistants (POP) qui peuvent dans certains cas entraîner des risques de contamination des activités agricoles. Ces molécules posent des problèmes de transfert dans la chaîne alimentaire, notamment vers les produits animaux. Les POP sont caractérisés par une forte rémanence, une volatilité élevée et une lipophilie marquée entraînant leur accumulation potentielle dans les tissus adipeux. Ce groupe de molécules potentiellement toxiques pour l’homme et l’environnement fait l’objet d’une attention internationale. L’objectif de cette synthèse est d’aborder le devenir de trois familles de composés POP, de type hydrocarbures polycycliques : les dioxines-furanes (PCDD/F), les polychlorobiphényles (PCB) et les hydrocarbures aromatiques polycycliques (HAP). Les résultats de recherche montrent une contamination significative des fourrages situés en zones exposées aux polluants par comparaison avec des zones isolées. Ils mettent également en évidence un transfert différentiel de ces molécules toxiques vers les matrices biologiques dont le lait.

Polycyclic Aromatic Hydrocarbons (PAHs) are lipophilic, persistant and ubiquitous compounds in the environment. Exposed fodder becomes a PAHs route for lactating ruminants. A first experiment was aimed to evaluate the influence of feeding system on PAHs levels in cows' milk. The results showed that grass generals a more important PAHs exposition than maize fodder. A second experiment was focused on PAHs transfer from feed to milk in controlled conditions. Among the 16 PAHs of the US-EPA list, only light compounds with less than 5 aromatic rings were detected in milk. Their transfer levels decreased from 30 % to 1 %., Les Hydrocarbures Aromatiques Polycycliques sont des composés lipophiles, persistants et ubiquistes dans l' environnement. Suite à leurs dépôts sur les végétaux et le sol, le fourrage devient une voie d'exposition potentielle des ruminants laitiers aux HAP. Nos travaux sur l'influence du mode d'alimentation sur les teneurs en HAP du lait ont révélé qu'un système d'élevage de type herbager engendrait une exposition du troupeau aux HAP supérieure à celui de type maïs fourrage. Le transfert des HAP du fourrage vers le lait chez la vache laitière a été étudié en conditions de terrain contrôlées. Sur les 16 HAP inscrits comme polluants prioritaires par l'US-EPA, seuls les composés à moins de 5 cycles aromatiques ont été détectés dans les laits. Les coefficients de transferts apparents établis pour 6 HAP étaient compris entre 1 % et 30 %.