Abstract
Clothianidin is a widely used neonicotinoid insecticide, which is a potent agonist of the nicotinic acetylcholine receptor in insects. This neurotoxic compound has a negative impact on insect immunity, as it down-regulates the activation of the transcription factor NF-κB. Given the evolutionary conserved role of NF-κB in the modulation of the immune response in the animal kingdom, here we want to assess any effect of Clothianidin on vertebrate defense barriers. In presence of this neonicotinoid insecticide, a pro-inflammatory challenge with LPS on the human monocytic cell line THP-1 results both in a reduced production of the cytokine TNF-α and in a down-regulation of a reporter gene under control of NF-κB promoter. This finding is corroborated by a significant impact of Clothianidin on the transcription levels of different immune genes, characterized by a core disruption of TRAF4 and TRAF6 that negatively influences NF-κB signaling. Moreover, exposure to Clothianidin concurrently induces a remarkable up-regulation of NGFR, which supports the occurrence of functional ties between the immune and nervous systems. These results suggest a potential risk of immunotoxicity that neonicotinoids may have on vertebrates, which needs to be carefully assessed at the organism level.
Highlights
Neonicotinoids are among the most widely used insecticides in agriculture, which are effective at low dosage and show poor affinity for the nicotinic acetylcholine receptor of mammalian species[1,2]
Insect immune response is negatively modulated by Clothianidin, which disrupts nuclear factor-κB (NF-κB) signaling by up-regulating a negative modulator of this transcription factor[14]
Because NF-κB signaling underpins the modulation of several immune reactions in animals, we wanted to assess if this alteration induced by Clothianidin occurred in humans
Summary
Neonicotinoids are among the most widely used insecticides in agriculture, which are effective at low dosage and show poor affinity for the nicotinic acetylcholine receptor of mammalian species[1,2]. The molecular mechanism underlying the negative effect of the neonicotinoid Clothianidin on insect immune response has been recently reported[14] This insecticide is able to exert a negative effect on the activation of the nuclear factor-κB (NF-κB) and of the downstream immune barriers, which promotes uncontrolled viral replication in honeybees bearing covert infections[14]. NF-κB has a central role in the immune response by animals[20], and, any defense pathway, conserved across distant evolutionary lineages, under control of this transcription factor could be influenced by a shared negative regulation of its activation This could account for the proposed link between the use of neonicotinoids and the increasing incidence of pathologies in different animal groups[4,19]. Comprehensive effort towards a thorough characterization of neonicotinoid impact on human health, which, surprisingly, is still in its infancy[21,22]
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