The cellular basis of fetal endoplasmic reticulum stress and oxidative stress in drug-induced neurodevelopmental deficits

Abstract

Prenatal substance exposure is a growing public health concern worldwide. Although the opioid crisis remains one of the most prevalent addiction problems in our society, abuse of cocaine, methamphetamines, and other illicit drugs, particularly amongst pregnant women, are nonetheless significant and widespread. Evidence demonstrates prenatal drug exposure can affect fetal brain development and thus can have long-lasting impact on neurobehavioral and cognitive performance later in life. In this review, we highlight research examining the most prevalent drugs of abuse and their effects on brain development with a focus on endoplasmic reticulum stress and oxidative stress signaling pathways. A thorough exploration of drug-induced cellular stress mechanisms during prenatal brain development may provide insight into therapeutic interventions to combat effects of prenatal drug exposure.

Maternal Calorie Restriction Induces a Transcriptional Cytoprotective Response in Embryonic Liver Partially Dependent on Nrf2

“…In our mouse model, which is based on calorie deprivation by restricting access to food, it is impossible to distinguish whether the effects seen are due to calorie restriction per se or due to the lack of specific nutrients such as proteins, vitamins etc. The ISR is known to be implicated in the pathogenesis of preeclampsia [ 60 ] and in neurodevelopmental deficits [ 61 , 62 ], to name a few of prenatal pathologies. Given that there are some indications that Nrf2 can possibly co-operate with Atf4 signaling in order to induce an antioxidant-cytoprotective response [ 63 ], it would be plausible that such an interaction may also be present in life in utero and consist one of the mechanisms of embryonic protection.…”

Protein Carbonylation as a Biomarker of Oxidative Stress and a Therapeutic Target in Neonatal Brain Damage

“…Despite this vulnerability, the immature brain during the fetal period is exposed to multiple agents that can increase OS, such as environmental pollutants, infections or exposure to alcohol or other drugs [9,[14][15][16]. Heavy metals, xeno-hormones, fertilizers, pesticides and herbicides are increasingly present in modern life and can reach the fetus through the mother, directly or indirectly generating an increase in OS [14].…”

“…These agents disrupt mitochondrial energy generation and perturb the redox state irreversibly, precipitating towards an imbalance termed OS [5][6][7]. Finally, OS can lead to endoplasmic reticulum (ER) stress [9]. Since the normal functioning of the ER requires strict control of the redox environment, the surge in OS leads to functional alteration of the ER, with the consequent impairment of normal protein synthesis and activation of a variety of signaling pathways that lead to brain damage [9].…”

Evaluation of plasma GRP78 levels in patients with autism spectrum disorder

“…Literature findings regarding the role of ER stress in neurodevelopmental diseases other than ASD are limited. However, oxidative stress and ER stress were i d e n t i f i e d a s i m p o r t a n t m e c h a n i s m s i n neurodevelopmental impairments of the fetal brain caused by prenatal exposure to drugs such as cocaine, methamphetamines and nicotine (19).…”