The herbicides glyphosate and glufosinate and the cyanotoxin ß-N-methylamino-l-alanine induce long-term motor disorders following postnatal exposure: the importance of prior asymptomatic maternal inflammatory sensitization.

Background: Prenatal maternal immune activation (MIA) and/or perinatal exposure to various xenobiotics have been identified as risk factors for neurological disorders, including neurodegenerative diseases. Epidemiological data suggest an association between early multi-exposures to various insults and neuropathologies. The "multiple-hit hypothesis" assumes that prenatal inflammation makes the brain more susceptible to subsequent exposure to several kinds of neurotoxins. To explore this hypothesis and its pathological consequences, a behavioral longitudinal procedure was performed after prenatal sensitization and postnatal exposure to low doses of pollutants. Methods: Maternal exposure to an acute immune challenge (first hit) was induced by an asymptomatic lipopolysaccharide (LPS) dose (0.008 mg/kg) in mice. This sensitization was followed by exposing the offspring to environmental chemicals (second hit) postnatally, by the oral route. The chemicals used were low doses of the cyanotoxin ß-N-methylamino-l-alanine (BMAA; 50 mg/kg), the herbicide glufosinate ammonium (GLA; 0.2 mg/kg) or the pesticide glyphosate (GLY; 5 mg/kg). After assessing maternal parameters, a longitudinal behavioral assessment was carried out on the offspring in order to evaluate motor and emotional abilities in adolescence and adulthood. Results: We showed that the low LPS immune challenge was an asymptomatic MIA. Even though a significant increase in systemic pro-inflammatory cytokines was detected in the dams, no maternal behavioral defects were observed. In addition, as shown by rotarod assays and open field tests, this prenatal LPS administration alone did not show any behavioral disruption in offspring. Interestingly, our data showed that offspring subjected to both MIA and post-natal BMAA or GLA exposure displayed motor and anxiety behavioral impairments during adolescence and adulthood. However, this synergistic effect was not observed in the GLY-exposed offspring. Conclusion: These data demonstrated that prenatal and asymptomatic immune sensitization represents a priming effect to subsequent exposure to low doses of pollutants. These double hits act in synergy to induce motor neuron disease-related phenotypes in offspring. Thus, our data strongly emphasize that multiple exposures for developmental neurotoxicity regulatory assessment must be considered. This work paves the way for future studies aiming at deciphering cellular pathways involved in these sensitization processes.

Haslea ostrearia Pigment Marennine Affects Key Actors of Neuroinflammation and Decreases Cell Migration in Murine Neuroglial Cell Model.

Haslea ostrearia, a cosmopolitan marine pennate diatom, produces a characteristic blue pigment called marennine that causes the greening of filter-feeding organisms, such as oysters. Previous studies evidenced various biological activities of purified marennine extract, such as antibacterial, antioxidant and antiproliferative effects. These effects could be beneficial to human health. However, the specific biological activity of marennine remains to be characterized, especially regarding primary cultures of mammals. In the present study, we aimed to determine in vitro the effects of a purified extract of marennine on neuroinflammatory and cell migratory processes. These effects were assessed at non-cytotoxic concentrations of 10 and 50µg/mL on primary cultures of neuroglial cells. Marennine strongly interacts with neuroinflammatory processes in the immunocompetent cells of the central nervous system, represented by astrocytes and microglial cells. An anti-migratory activity based on a neurospheres migration assay has also been observed. These results encourage further study of Haslea blue pigment effects, particularly the identification of molecular and cellular targets affected by marennine, and strengthen previous studies suggesting that marennine has bioactivities which could be beneficial for human health applications.

ß-N-Methyl-Amino-L-Alanine cyanotoxin promotes modification of undifferentiated cells population and disrupts the inflammatory status in primary cultures of neural stem cells.

ß-N-Methyl-Amino-L-Alanine (BMAA) produced by 95% of cyanobacteria is in constant augmentation with cyanobacteria worldwide proliferation due to global warming and eutrophication. Previously, it has been shown that this contaminant induced neurological disorders, notably by acting as a developmental toxin. However, very few studies focus on the impact of BMAA on neuroglial cells, like astrocytes and microglial cells, in a developmental context. In the present study, we investigated whether BMAA disturbs neurogenesis from mice subventricular zone (SVZ) cells and whether this neurotoxin induces neuroinflammation. We show that BMAA at 100 µM disturbs the population of undifferentiated cells (B1 and C cells) and promotes their proliferation. Further, BMAA affects the organization of neuroblasts, indicating that SVZ function could be impaired. BMAA affects neuroinflammatory processes by increasing the release of proinflammatory cytokines IL-1ß, IL-6 and TNFα. Our study adds to evidence that BMAA may disturb the central nervous system homeostasis by targeting glial cells. We highlighted that BMAA may impair SVZ niches and drives astrocytes and microglial cells into a proinflammatory status, with an ameboid shape for microglia.

Fucoxanthin, a Marine-Derived Carotenoid from Brown Seaweeds and Microalgae: A Promising Bioactive Compound for Cancer Therapy.

Fucoxanthin is a well-known carotenoid of the xanthophyll family, mainly produced by marine organisms such as the macroalgae of the fucus genus or microalgae such as Phaeodactylum tricornutum. Fucoxanthin has antioxidant and anti-inflammatory properties but also several anticancer effects. Fucoxanthin induces cell growth arrest, apoptosis, and/or autophagy in several cancer cell lines as well as in animal models of cancer. Fucoxanthin treatment leads to the inhibition of metastasis-related migration, invasion, epithelial-mesenchymal transition, and angiogenesis. Fucoxanthin also affects the DNA repair pathways, which could be involved in the resistance phenotype of tumor cells. Moreover, combined treatments of fucoxanthin, or its metabolite fucoxanthinol, with usual anticancer treatments can support conventional therapeutic strategies by reducing drug resistance. This review focuses on the current knowledge of fucoxanthin with its potential anticancer properties, showing that fucoxanthin could be a promising compound for cancer therapy by acting on most of the classical hallmarks of tumor cells.