Kynurenine Pathway as a New Target of Cognitive Impairment Induced by Lead Toxicity During the Lactation

Daniela Ramirez Ortega,Saul Gómez Manzo,Benjamín Pineda,Jaime Marcial Quino,Paulina Ovalle Rodríguez,Camilo Ríos,Verónica Pérez De La Cruz,Gabriel Roldán Roldán,Gonzalo Pérez De La Cruz,Gustavo I Vázquez Cervantes,Marisela Méndez Armenta,Lucio Antonio Ramos Chávez,Araceli Díaz Ruiz,Dinora F González Esquivel

doi:10.1038/s41598-020-60159-3

Abstract

The immature brain is especially vulnerable to lead (Pb2+) toxicity, which is considered an environmental neurotoxin. Pb2+ exposure during development compromises the cognitive and behavioral attributes which persist even later in adulthood, but the mechanisms involved in this effect are still unknown. On the other hand, the kynurenine pathway metabolites are modulators of different receptors and neurotransmitters related to cognition; specifically, high kynurenic acid levels has been involved with cognitive impairment, including deficits in spatial working memory and attention process. The aim of this study was to evaluate the relationship between the neurocognitive impairment induced by Pb2+ toxicity and the kynurenine pathway. The dams were divided in control group and Pb2+ group, which were given tap water or 500 ppm of lead acetate in drinking water ad libitum, respectively, from 0 to 23 postnatal day (PND). The poison was withdrawn, and tap water was given until 60 PND of the progeny. The locomotor activity in open field, redox environment, cellular function, kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) levels as well as kynurenine aminotransferase (KAT) and kynurenine monooxygenase (KMO) activities were evaluated at both 23 and 60 PND. Additionally, learning and memory through buried food location test and expression of KAT and KMO, and cellular damage were evaluated at 60 PND. Pb2+ group showed redox environment alterations, cellular dysfunction and KYNA and 3-HK levels increased. No changes were observed in KAT activity. KMO activity increased at 23 PND and decreased at 60 PND. No changes in KAT and KMO expression in control and Pb2+ group were observed, however the number of positive cells expressing KMO and KAT increased in relation to control, which correlated with the loss of neuronal population. Cognitive impairment was observed in Pb2+ group which was correlated with KYNA levels. These results suggest that the increase in KYNA levels could be a mechanism by which Pb2+ induces cognitive impairment in adult mice, hence the modulation of kynurenine pathway represents a potential target to improve behavioural alterations produced by this environmental toxin.

Highlights

Lead (Pb2+) is one of the main environmental neurotoxins that represents a health problem due to its multiple industrial, domestic, medical and technological applications[1]
The developing brain is especially vulnerable to Pb2+ neurotoxicity since this heavy metal crosses through the placenta during pregnancy and is able to pass into milk during the lactation period, reaching the developing brain impacting its functionality and morphology[6,7]
Our results support that kynurenine pathway (KP) metabolites, the high levels of kynurenic acid (KYNA), are correlated with long-term cognitive impairment induced by Pb2+ during the lactation period

Summary

Introduction

Lead (Pb2+) is one of the main environmental neurotoxins that represents a health problem due to its multiple industrial, domestic, medical and technological applications[1]. There are reports showing that even low doses of Pb2+ cause cognitive and motor functions impairment in humans and animal models[8], mainly when the exposure occurs during brain development, where there are intense cellular proliferation, differentiation and synaptogenesis In this regard, it has been shown that Pb2+, at low micromolar concentrations, inhibits in an age-dependent manner the N-methyl-D-aspartate receptor (NMDAr) activation, being more harmful in the neonatal than in adult brain and producing long-term cognitive impairment[3,9,10]. It has been suggested that the high KYNA levels found in fetal brain as well as its rapid decline during the postnatal period, are involved in NMDAr modulation, necessary for the normal brain development[19,20] In this context, it has been shown that the fluctuation in brain KYNA levels can cause impairment in working memory, sensorimotor gating and in the attention process in adult rodents[21,22,23]. Our results support that KP metabolites, the high levels of KYNA, are correlated with long-term cognitive impairment induced by Pb2+ during the lactation period

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