Oxidative Stress as a Common Key Event in Developmental Neurotoxicity.

Yuhei Nishimura,Yasunari Kanda,Hideko Sone,Hiroaki Aoyama,Ana Cipak Gasparovic

doi:10.1155/2021/6685204

Abstract

The developing brain is extremely sensitive to many chemicals. Perinatal exposure to neurotoxicants has been implicated in several neurodevelopmental disorders, including autism spectrum disorder, attention-deficit hyperactive disorder, and schizophrenia. Studies of the molecular and cellular events related to developmental neurotoxicity have identified a number of “adverse outcome pathways,” many of which share oxidative stress as a key event. Oxidative stress occurs when the balance between the production of free oxygen radicals and the activity of the cellular antioxidant system is dysregulated. In this review, we describe some of the developmental neurotoxins that target the antioxidant system and the mechanisms by which they elicit stress, including oxidative phosphorylation in mitochondria and plasma membrane redox system in rodent models. We also discuss future directions for identifying adverse outcome pathways related to oxidative stress and developmental neurotoxicity, with the goal of improving our ability to quickly and accurately screen chemicals for their potential developmental neurotoxicity.

Highlights

Many of these pathways share oxidative stress (OS) as a key common event associated with neurodevelopmental disorders [7, 8, 16, 17]
We describe how OS pathways are involved in Developmental neurotoxicity (DNT), describe representative examples of developmental neurotoxins (DTXs) and the mechanisms by which they affect cellular antioxidant and oxidant systems in rodent
Arsenic (As) is another element that inhibits antioxidant enzyme activity through modification of functional SH groups [44]. This has been demonstrated in rats, where perinatal exposure of dams to 2–100 mg/kg/day As from gestational day (GD) 6 to postnatal day (PND) 21 resulted in impaired superoxide dismutase (SOD), CAT, glutathione peroxidase (GPX), and glutathione reductase activities in various brain regions of the pups [45, 46]

Summary

Introduction

The high prevalence of neurodevelopmental disorders such as attention-deficit hyperactive disorder (5.3%), autism spectrum disorder (1%), and schizophrenia (1%) is a source of increasing concern worldwide [1,2,3]. Several molecular and cellular events leading to DNT, the so-called “adverse outcome pathways,” have been identified [14, 15] These adverse outcome pathways cover a wide range of molecular initiating events, including inhibition of receptors and enzymes such as Nmethyl-D-aspartate receptor and acetylcholinesterase and interruption of biosynthesis and bioavailability of thyroid hormone, which results in adverse outcomes such as impairment of cognitive functions, alteration of sensory functions, and impairment of motor functions [15]. Many of these pathways share oxidative stress (OS) as a key common event associated with neurodevelopmental disorders [7, 8, 16, 17]. Oxidative Medicine and Cellular Longevity models, and discuss future directions to increase our understanding of adverse outcome pathways as they relate to DNT induced by OS

The Role of Oxidative Stress in Developmental Neurotoxicity

Findings

Future Directions