Defining the toxicological profile of 4-hydroxyphenylpyruvate dioxygenase-directed herbicides to Aedes aegypti and Amblyomma americanum

Authors: MCCOMIC, SARAH - University Of Florida; DUKE, STEPHEN - University Of Mississippi; BURGESS IV, EDWIN - University Of Florida; SWALE, DANIEL - University Of Florida

Submitted to: Pesticide Biochemistry and Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/11/2023
Publication Date: 7/13/2023
Citation: Mccomic, S.E., Duke, S.O., Burgess Iv, E.R., Swale, D.R. 2023. Defining the toxicological profile of 4-hydroxyphenylpyruvate dioxygenase-directed herbicides to Aedes aegypti and Amblyomma americanum. Pesticide Biochemistry and Physiology. https://doi.org/10.1016/j.pestbp.2023.105532.
DOI: https://doi.org/10.1016/j.pestbp.2023.105532

Interpretive Summary: Mosquitoes and ticks are highly relevant to human health and safety due to the pathogens they transmit during feeding. For instance, tick-borne diseases accounted for >75% of the nearly 650,000 cases of vector-borne disease reported in the United States during 2004–2016 and continue to rise. The potential to kill arthropod vectors through inhibition of enzymes essential for metabolism of components within the blood meal represents a unique approach for designing specific insecticides for hematophagous arthropods, which would be advantageous for beneficial pollinators. HPPD is a well-established herbicide target and a variety of structurally distinct chemical inhibitors of plant HPPD have been developed, which provides opportunities for repurposing the herbicidal chemistry to develop novel insecticides. The objective of this study was to characterize the toxicity and phenotypic effects of HPPD-inhibiting herbicides in blood-fed arthropods. In addition to mosquitoes, we assessed the toxicity of HPPD-inhibiting herbicides to the lone star tick, Amblyomma americanum, through ingestion and contact exposure. HPPD-inhibiting herbicides are novel in action and could lead to the development of hematophagous-specific arthropod control products.

Technical Abstract: Identification of novel target sites and chemical scaffolds for arthropod vector control has been a focal point within the field of insecticide science but seldom explores repurposing chemical classes not initially developed as insecticides. One such class are 4-hydroxyphenyl pyruvate dioxygenase (HPPD) inhibitors, which are well-established herbicides. Interestingly, HPPD is also a primary enzyme within the tyrosine degradation pathway in insects. When hematophagous arthropods digest a blood meal, excessive tyrosine is produced and must be metabolized to prevent tyrosine-mediated mortality. This aspect of hematophagous arthropod physiology warrants further investigation of HPPD inhibitor herbicides for control of hematophagous arthropods. Thus, the objective of this study was to characterize the toxicity and phenotypic effects of HPPD-inhibiting herbicides in blood-fed arthropods. Topical exposure of nitisinone, a pharmaceutical HPPD inhibitor, to blood-fed Aedes aegypti yielded high toxicity with an LD50 of 3.81 ng/insect (95% CI: 3.09 to 4.67 ng; Hillslope: 0.97, r2: 0.99) after blood feeding, yet was non-toxic to non-blood fed (NBF) individuals. HPPD-inhibitor herbicides were tested against Ae. Aegypti, and rank toxicity was tembotrione > pyrazoxyfen > tebuconazole > mesotrione against blood-fed female mosquitoes but were approximately 30-fold less toxic when compared to nitisinone. In addition to mosquitoes, we assessed the toxicity of HPPD-inhibiting herbicides to the lone star tick, Amblyomma americanum, through ingestion and contact exposure. Nitisinone was highly toxic to Am. americanum with a lethal time to kill 50% of subjects (LT50) of 23 h at 10 µM. RNA interference (RNAi) of the HPPD enzyme to Ae. aegypti and Am. americanum produced knockdown of 85% and 98%, respectively. A fluorescence assay for arthropods was developed to determine relative quantities of L-tyrosine in Ae. aegypti treated with HPPD inhibitors, and L-tyrosine levels enhanced by nitisinone correlated with knock down effects. HPPD-inhibiting herbicides are novel in action and could lead to the development of hematophagous-specific arthropod control products.