Is the Exposome Involved in Brain Disorders through the Serotoninergic System?

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine acting as a neurotransmitter in the central nervous system (CNS), local mediator in the gut, and vasoactive agent in the blood. It has been linked to a variety of CNS functions and is implicated in many CNS and psychiatric disorders. The high comorbidity between some neuropathies can be partially understood by the fact that these diseases share a common etiology involving the serotoninergic system. In addition to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumor cells, including glioma cells, in vitro. The developing CNS of fetus and newborn is particularly susceptible to the deleterious effects of neurotoxic substances in our environment, and perinatal exposure could result in the later development of diseases, a hypothesis known as the developmental origin of health and disease. Some of these substances affect the serotoninergic system and could therefore be the source of a silent pandemic of neurodevelopmental toxicity. This review presents the available data that are contributing to the appreciation of the effects of the exposome on the serotoninergic system and their potential link with brain pathologies (neurodevelopmental, neurodegenerative, neurobehavioral disorders, and glioblastoma).

Androgen-dependent sexual dimorphism in pituitary tryptophan hydroxylase expression: relevance to sex differences in pituitary hormones

Serotonin is a biogenic monoamine conserved across phyla that is implicated in diverse physiological and behavioural functions. On examining the expression of the rate-limiting enzymes in serotonin synthesis, tryptophan hydroxylases (TPHs), in the teleost medaka ( Oryzias latipes ), we found that males have much higher levels of tph1 expression as compared with females. This robust sexual dimorphism was found to probably result from the direct stimulation of tph1 transcription by androgen/androgen receptor binding to canonical bipartite androgen-responsive elements in its proximal promoter region. Our results further revealed that tph1 expression occurs exclusively in pro-opiomelanocortin ( pomc )-expressing cells and that the resulting serotonin and its derivative melatonin inhibit the expression of the pituitary hormone genes, fshb , sl and tshb . This suggests that serotonin and/or melatonin synthesized in pomc -expressing cells act in a paracrine manner to suppress pituitary hormone levels. Consistent with these findings and the male-biased expression of tph1 , the expression levels of fshb , sl and tshb were all higher in females than in males. Taken together, the male bias in tph1 expression and consequent serotonin/melatonin production presumably contribute to sex differences in the expression of pituitary hormones and ultimately in the physiological functions mediated by them.

Inhibition of Yeast Growth by Tryptamine and Recovery with Tryptophan

Background: Tryptamine, a biogenic monoamine that is present in trace levels in the mammalian central nervous system, has probable roles as a neurotransmitter and/or a neuromodulator and may be associated with various neuropsychiatric disorders. One of the ways tryptamine may affect the body is by the competitive inhibition of the attachment of tryptophan to tryptophanyl tRNA synthetases. Methods: This study has explored the effects of tryptamine on growth of six yeast species (Saccharomyces cerevisiae, Candida glabrata, C. krusei, C. dubliniensis, C. tropicalis and C. lusitaniae) in media with glucose or ethanol as the carbon source, as well as recovery of growth inhibition by the addition of tryptophan. Results: Tryptamine was found to have an inhibitory effect on respiratory growth of all yeast species when grown with ethanol as the carbon source. Tryptamine also inhibited fermentative growth of Saccharomyces cerevisiae, C. krusei and C. tropicalis with glucose as the carbon source. In most cases the inhibitory effects were reduced by added tryptophan. Conclusion: The results obtained in this study are consistent with tryptamine competing with tryptophan to bind mitochondrial and cytoplasmic tryptophanyl tRNA synthetases in yeast: effects on mitochondrial and cytoplasmic protein synthesis can be studied as a function of growth with glucose or ethanol as a carbon source. Of the yeast species tested, there is variation in the sensitivity to tryptamine and the rescue by tryptophan. The current study suggests appropriate yeast strains and approaches for further studies.

A genetically encoded fluorescent sensor for rapid and specific in vivo detection of norepinephrine

Norepinephrine (NE) and epinephrine (Epi), two key biogenic monoamine neurotransmitters, are involved in a wide range of physiological processes. However, their precise dynamics and regulation remain poorly characterized, in part due to limitations of available techniques for measuring these molecules in vivo. Here, we developed a family of GPCR Activation-Based NE/Epi (GRABNE) sensors with a 230% peak ΔF/F0 response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second rapid kinetics, high specificity to NE vs. dopamine. Viral- or transgenic- mediated expression of GRABNE sensors were able to detect electrical-stimulation evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRABNE sensors are a robust tool for rapid and specific monitoring of in vivo NE/Epi transmission in both physiological and pathological processes.

Mediation of inducible nitric oxide and immune-reactive lysozymes biosynthesis by eicosanoid and biogenic amines in flesh flies

Nitric oxide (NO) plays various roles in insect immunity: as a cytotoxic component and as a signalling molecule; and immune-reactive lysozymes (IrLys) provide a first line of humoral immune functions against invading bacteria. Although there is considerable literature on eicosanoid and biogenic monoamine actions on insect immunity, there is no information on the role(s) of these chemicals in inducing NO and IrLys. We addressed this gap by challenging third instarSarcophaga(Liopygia)argyrostoma(Robineau-Desvoidy) with the Gram-positive bacteriumMicrococcus luteus. Here, we report that bacterial challenge induces elevation of NO and IrLys concentrations in haemocytes and in the fat body. The plasma pool content is comparatively low. Eicosanoid biosynthesis inhibitors (EBIs) lead to suppression of both NO and IrLys levels. Control larvae have low constitutive levels of NO and lysozyme concentrations. Octopamine (OA) elicits elevation of NO and IrLys concentrations. A similar effect is obtained by 5-hydroxytryptamine (5-HT) for NO. These data indicate immune-mediating roles of eicosanoids, OA and 5-HT in NO and IrLys activities.

Biogenic Monoamine Disorders

Biogenic monoamine disorders are a group of inherited diseases characterized by a defect in the synthesis, transport, or degradation of catecholamines and serotonin. The phenotype mostly reflects the pattern and severity of the monoamine deficiency. Movement disorders due to cerebral dopamine deficiency are almost always prominent, mostly in the form of dystonia and/or parkinsonism. These disorders are potentially devastating yet treatable. Early diagnosis and treatment are crucial to prevent ongoing brain dysfunction. Detection of hyperphenylalaninemia in a neonate could be a good clue to the diagnosis. Final diagnosis is often based on a detailed biochemical investigation of the cerebrospinal fluid and can be confirmed by molecular analysis. Treatment is aimed at restoring neurotransmitter homeostasis using monoamine precursors, monoamine agonists, and inhibitors of monoamine degradation. It also comprises the control of hyperphenylalaninemia and the prevention of cerebral folate deficiency, when applicable.