Perinatal Exposure to the Cyanotoxin β-N-Méthylamino-l-Alanine (BMAA) Results in Long-Lasting Behavioral Changes in Offspring—Potential Involvement of DNA Damage and Oxidative Stress

Abstract

We recently demonstrated that perinatal exposure to the glutamate-related herbicide, glufosinate ammonium, has deleterious effects on neural stem cell (NSC) homeostasis within the sub-ventricular zone (SVZ), probably leading to ASD-like symptoms in offspring later in life. In the present study, we aimed to investigate whether perinatal exposure to another glutamate-related toxicant, the cyanobacterial amino acid β-N-methylamino-L-alanine (BMAA), might also trigger neurodevelopmental disturbances. With this aim, female mice were intranasally exposed to low doses of BMAA, 50 mg kg three times a week from embryonic days 7-10 to postnatal day 21. Behavioral analyses were performed during the offspring's early life and during adulthood. Developmental analyses revealed that perinatal exposure to BMAA hastened the appearance of some reflexes and communicative skills. BMAA-exposed offspring displayed sex-dependent changes in emotional cognition shortly after exposure. Later in life, the female offspring continued to express emotional defects and to display abnormal sociability, while males were less affected. To assess whether early exposure to BMAA had deleterious effects on NSC homeostasis, we exposed mice NSCs to 1 and 3 mM BMAA during 24 h. We found that BMAA-exposed NSCs produced high levels of ROS, highlighting the ability of BMAA to induce oxidative stress. We also showed that BMAA exposure increased the number of γH2AX/53BP1 foci per nucleus, suggesting that BMAA-induced DNA damage in NSCs. Collectively, this data strongly suggests that perinatal exposure to the cyanobacteria BMAA, even at low doses, results in neurobehavioral disturbances during both the postnatal period and adulthood. This is considered to be underpinned at the cellular level through dysregulation of NSC homeostasis in the developing brain.

Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors

“…It is a common neurotoxin utilized in the study of neurodegeneration in cellular and animal models, specifically those for the study of ALS/Parkinsonism-dementia complex. BMAA causes neuroinflammation, oxidative stress, apoptosis and cognitive impairment (Brownson et al, 2002; Lobner, 2009; Santucci et al, 2009; Zhou et al, 2010; Muñoz-Saez et al, 2013; Al-Sammak et al, 2015; Takser et al, 2016; Laugeray et al, 2017; Petrozziello et al, 2017). It elicits neurotoxicity by acting as an agonist for glutamate receptors such as AMPARs/KARs, NMDARs, and mGluR5 (Lobner, 2009; Delzor et al, 2014).…”

Mitotically heritable effects of BMAA on striatal neural stem cell proliferation and differentiation

“…It is widely accepted that the developing brain is more sensitive to the harmful effects of environmental contaminants than the adult brain 36 . It is important to mechanistically elucidate BMAA's effects on the developing brain, as this toxin has been detected in water and food chains all over the world 37–39 , and is shown to adversely affect the immature brain 25,27,40–42 . The present study revealed different susceptibilities of primary striatal neurons and NSC to BMAA-induced toxicity.…”

Angiopoietin-1 and ανβ3 integrin peptide promote the therapeutic effects of L-serine in an amyotrophic lateral sclerosis/Parkinsonism dementia complex model

“…The inflammatory environment in ALS changes with disease progression. Resident glial cells and infiltrating immune cells are considered among the major producers of ROS and reactive nitrogen species, which contribute to the pathological conditions of the CNS, including phagocytosis and apoptosis of the spinal cord motor neurons and neurons in the dentate gyrus (DG) region of the hippocampus [6,8,29]. The Alzheimer’s disease-like pathology is synergistic and dependent on oxidative stress and inflammation; thus, administration of anti-inflammatory agents might alleviate the disease outcome [30].…”