An Invertebrate Model of the Developmental Neurotoxicity of Insecticides: Effects of Chlorpyrifos and Dieldrin in Sea Urchin Embryos and Larvae

Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target?

“…In turn, cholinergic effects influence AC and cAMP formation. Resolution of these issues thus ultimately requires simplified systems such as cell cultures or lower organisms (Buznikov et al 2001;Schuh et al 2002;Song et al 1998). …”

“…Although originally all organophosphates were thought to elicit neurodevelopmental damage through inhibition of cholinesterase (Mileson et al 1998;Pope 1999), it is now apparent that other mechanisms play an important, perhaps predominating role, involving concentrations below the threshold for the systemic toxicity associated with cholinergic hyperstimulation Das and Barone 1999;Pope 1999;Schuh et al 2002;Slotkin 1999, In press). CPF itself, as distinct from CPF oxon, the active metabolite that inhibits cholinesterase, disrupts the fundamental processes of brain development, such as DNA synthesis (Dam et al 1998;Whitney et al 1995), expression and function of macromolecular constituents and transcription factors that control cell differentiation (Crumpton et al 2000;Garcia et al 2001;Johnson et al 1998;Schuh et al 2002), and expression and function of neurotransmitters and their receptors that act as neurotrophins in the developing brain (Buznikov et al 2001;Dam et al 1999aDam et al , 1999bHoward and Pope 2002;Huff et al 2001;Liu et al 2002;Yanai et al 2002;Zhang et al 2002).…”

Amyloid precursor protein 96–110 and β-amyloid 1–42 elicit developmental anomalies in sea urchin embryos and larvae that are alleviated by neurotransmitter analogs for acetylcholine, serotonin and cannabinoids

“…Here, we performed a comparative study for APP [96][97][98][99][100][101][102][103][104][105][106][107][108][109][110] , adopting the same strategy used to identify its role in neurodevelopment in higher organisms [45], namely to add soluble, exogenous peptide so as to preempt the role of endogenous, full-sequence, membrane-anchored APP. As in our earlier work [13], we evaluated the protective effects of ACh, 5HT and cannabinoids by using analogs synthesized with arachidonoyl moieties to enhance lipophilicity as required to penetrate into the embryo, focusing on agents whose biological activities against more classical neurotoxicants were verified in earlier work [2,6,7,[11][12][13]. These were compared to other neurotransmitter-related chemicals and in addition, we evaluated agents acting through other mechanisms that could impact neurotrophic effects or downstream neurotoxic consequences of APP 96-110 : cholinesterase inhibitors, phosphodiesterase inhibitors, α-adrenergic and NMDA receptor antagonists, and antioxidants.…”

“…The sea urchin embryo, develops the ability to synthesize, store and release ACh and other neurotransmitters, and possesses the analogous receptors and downstream signaling cascades, all of which appear rapidly over a defined developmental period and act as morphogens that control cell differentiation and assembly of the embryo and larva [10,13,20,26]. Agents that target specific neurotrophic mechanisms or signaling cascades in the mammalian brain, produce structural anomalies during sea urchin morphogenesis that are readily characterized with routine light microscopy [4,5,[9][10][11][12][17][18][19]36,41]. Further, normal sea urchin development is well characterized at both structural and biochemical levels; consequently, the mechanisms of action and consequences of exposure for a wide variety of embryotoxins, teratogens and neurotoxicants have been evaluated with this system [5,9,11,12,16,19,27,36].…”

“…Agents that target specific neurotrophic mechanisms or signaling cascades in the mammalian brain, produce structural anomalies during sea urchin morphogenesis that are readily characterized with routine light microscopy [4,5,[9][10][11][12][17][18][19]36,41]. Further, normal sea urchin development is well characterized at both structural and biochemical levels; consequently, the mechanisms of action and consequences of exposure for a wide variety of embryotoxins, teratogens and neurotoxicants have been evaluated with this system [5,9,11,12,16,19,27,36]. Unlike mammalian models, each sea urchin produces thousands to millions of offspring that develop rapidly and simultaneously, with a coordinated and highly specific sequence of morphological events, so that toxicant exposures produce uniform phenotypes for any given critical exposure period [11,12,19,36].…”