Gene × environment interaction between heterozygous deletion of the ADHD risk gene latrophilin-3 (adgrl3) and developmental deltamethrin exposure in Sprague Dawley rats

IF 2.6 3区医学 Q3 NEUROSCIENCES

Neurotoxicology and teratology Pub Date : 2025-03-01 DOI:10.1016/j.ntt.2025.107435

Charles V. Vorhees, Adam L. Fritz, Brooke M. Gollaway, Michael T. Williams

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引用次数: 0

Abstract

The prevalence of attention deficit hyperactivity disorder (ADHD) is 9.8 % in U.S. children. Several variants of Latrophiln-3 (LPHN-3) are associated with ADHD. Using CRISPR/Cas9 we deleted exon 3 in rats to create a global Lphn3 knockout. These rats are hyperactive, startle hyper-reactive, impulsive, and have impaired working, spatial, and egocentric learning and memory. Deltamethrin (DLM) is a widely used pyrethroid insecticide. Several epidemiological studies report an increase in ADHD prevalence in children exposed to pyrethroids. Developmental exposure to DLM in rats results in multiple behavioral deficits. The present experiment tested whether Lphn3 disruption interacts with developmental DLM exposure. Because Lphn3^−/− rats are severely impaired, we used Lphn3^+/− (Hets) because they have an intermediate phenotype. Rats were treated by gavage once/day from postnatal day 6–20 with DLM resulting in four groups: Lphn3-Het + DLM (1.0 mg/kg), Lphn3-Het + Corn Oil (CO), Lphn3^+/+ (wildtype: WT) + DLM, and WT + CO. From 31 litters, 19–27 offspring per genotype per treatment per sex were obtained with not more than 1 rat of each group and sex used from any one litter. Adult offspring were tested for exploration (open-field), 72-h home-cage activity, startle, novel object recognition (NOR), radial water maze (RWM), Morris water maze (MWM), and Cincinnati water maze (CWM). On MWM acquisition trials and the reversal probe trial, Lphn3-Het-DLM rats performed worse than other groups. This group also was impaired learning the CWM. No interactions were found for open-field, home-cage, startle, NOR, or RWM. The results show that the ADHD risk gene Lphn3 in combination with developmental DLM exposure has selective adverse effects compared with either factor alone.

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来源期刊

Neurotoxicology and teratology 医学-毒理学

CiteScore

5.60

自引率

10.30%

发文量

审稿时长

58 days

期刊介绍： Neurotoxicology and Teratology provides a forum for publishing new information regarding the effects of chemical and physical agents on the developing, adult or aging nervous system. In this context, the fields of neurotoxicology and teratology include studies of agent-induced alterations of nervous system function, with a focus on behavioral outcomes and their underlying physiological and neurochemical mechanisms. The Journal publishes original, peer-reviewed Research Reports of experimental, clinical, and epidemiological studies that address the neurotoxicity and/or functional teratology of pesticides, solvents, heavy metals, nanomaterials, organometals, industrial compounds, mixtures, drugs of abuse, pharmaceuticals, animal and plant toxins, atmospheric reaction products, and physical agents such as radiation and noise. These reports include traditional mammalian neurotoxicology experiments, human studies, studies using non-mammalian animal models, and mechanistic studies in vivo or in vitro. Special Issues, Reviews, Commentaries, Meeting Reports, and Symposium Papers provide timely updates on areas that have reached a critical point of synthesis, on aspects of a scientific field undergoing rapid change, or on areas that present special methodological or interpretive problems. Theoretical Articles address concepts and potential mechanisms underlying actions of agents of interest in the nervous system. The Journal also publishes Brief Communications that concisely describe a new method, technique, apparatus, or experimental result.