In utero and lactational exposure to low-doses of the pyrethroid insecticide cypermethrin leads to neurodevelopmental defects in male mice—An ethological and transcriptomic study

Abstract

Accumulating evidence suggests that developmental exposure to environmental chemicals may modify the course of brain development, ultimately leading to neuropsychiatric / neurodegenerative disorders later in life. In the present study, we assessed the impact of one of the most frequently used pesticides in both residential and agricultural applications − the synthetic pyrethroid cypermethrin (CYP) − on developmental neurotoxicity (DNT). Female mice were perinatally exposed to low doses of CYP (5 and 20 mg/kg body weight) from gestation to postnatal day 15. Behavioral analyses were performed during the offspring’s early life and during adulthood. Postnatal analyses revealed that perinatal exposure to CYP disturbed motor development without modifying sensory and communicative skills. We found that later in life, CYP-exposed offspring expressed maladaptive behaviors in response to highly challenging tasks and abnormal sociability. Transcriptomic analyses performed in the offspring’s brain at the end of the exposure, highlighted mitochondrial dysfunction as a relevant pathomechanism underlying CYP-induced DNT. Interestingly, several genes involved in proteostasis maintenance were also shown to be dysregulated suggesting that alterations in biogenesis, folding, trafficking and degradation of proteins may significantly contribute to CYP-related DNT. From a regulatory perspective, this study highlights that behavioral and transcriptomic analyses are complementary tools providing useful direction for better DNT characterization, and as such, should be used together more systematically.

Influence of Nanomolar Deltamethrin on the Hallmarks of Primary Cultured Cortical Neuronal Network and the Role of Ryanodine Receptors

“…2012). Consistent with these findings, prenatal mice receiving low doses (5mg/kg) of cypermethrin exposure were recently shown to develop abnormal social and adaptive responses that were correlated with changes in brain transcriptional profiles (Laugeray et al. 2017).…”

“…Evidence for age-dependent susceptibility to pyrethroids was also indicated by subchronic and chronic exposure studies in rodent and zebrafish models. Prenatal mice receiving low doses (5mg/kg) of cypermethrin exposure developed abnormal motor activity and social and adaptive responses (Laugeray et al. 2017), while adults were much less sensitive (Singh et al.…”

Relationship between Autism Spectrum Disorder and Pesticides: A Systematic Review of Human and Preclinical Models

“…That is, most of the studies included in the present review are concerned with OP exposure (13 out of 16, 81.3%). Of the remaining articles, two used Glufosinate ammonium (GLA) (12.5%) [ 43 , 44 ], and one exposed their animals to the synthetic Pyrethroid cypermethrin (CYP) (6.3%) [ 45 ]. From all of these studies, only one [ 42 ] did not administer the pesticide during development; thus, most of the studies included in this systematic review present good examples of developmental neurotoxicity (15 out of 16, 93.8%).…”

“…Concerning the quality of the preclinical studies, three out of the 16 were labeled as H (18.8%) [ 30 , 37 , 38 ], 10 as MH (62.5%) [ 31 , 32 , 33 , 34 , 35 , 36 , 40 , 43 , 44 , 45 ], and the remaining three as ML-quality (18.8%) [ 39 , 41 , 42 ]. In a similar vein, 37 out of 45 human studies were classified as VH (82.2%) [ 46 , 48 , 49 , 50 , 51 , 52 , 53 , 56 , 57 , 58 , 59 , 61 , 63 , 64 , 65 , 66 , 67 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 80 , 81 , 82 , 83 , 84 , 85 , 87 , 88 , 89 , 90 , 91 ], 7 as H (15.6%) [ 47 , …”

Current Research on the Safety of Pyrethroids Used as Insecticides

“…Animal studies show that cypermethrin at a dose 5 to 20 mg/kg for two weeks can permeate the mother-child barrier, causing mitochondrial and neuronal dysfunction, and affecting communication skills in fetuses [ 71 , 72 ]. Alfa-cypermethrin at a dose 0.02 mg/kg/day of pregnancy may have toxic effects on the development of both the fetus and the parent organism [ 71 ].…”