NURR1 Alterations in Perinatal Stress: A First Step towards Late-Onset Diseases? A Narrative Review

Abstract

Perinatal life represents a delicate phase of development where stimuli of all sorts, coming to or from the mother, can influence the programming of the future baby’s health. These stimuli may have consequences that persist throughout adulthood. Nuclear receptor related 1 protein (NURR1), a transcription factor with a critical role in the development of the dopaminergic neurons in the midbrain, mediates the response to stressful environmental stimuli in the perinatal period. During pregnancy, low-grade inflammation triggered by maternal obesity, hyperinsulinemia or vaginal infections alters NURR1 expression in human gestational tissues. A similar scenario is triggered by exposure to neurotoxic compounds, which are associated with NURR1 epigenetic deregulation in the offspring, with potential intergenerational effects. Since these alterations have been associated with an increased risk of developing late-onset diseases in children, NURR1, alone, or in combination with other molecular markers, has been proposed as a new prognostic tool and a potential therapeutic target for several pathological conditions. This narrative review describes perinatal stress associated with NURR1 gene deregulation, which is proposed here as a mediator of late-onset consequences of early life events.

A Scoping Review of Life-Course Psychosocial Stress and Kidney Function

“…At the same time, reduced functional capacity can limit the ability of the organ to adapt to an increased functional load imposed postnatally, and increase the risk for later life kidney disease, heart failure, and diabetes [ 61 ]. Specifically, current evidence shows that the developmental programming of chronic conditions, such as diabetes, cardiovascular disease, obesity, and depression, has a transgenerational effect [ 11 , 62 ] through the excessive expression of the glucocorticoid-responsive transcription factor called nuclear-receptor related 1 protein (NURR1) with environmental stress interactions during early life [ 63 ].…”

NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast

“…We found that NR4A2 expression was higher at term compared to preterm gestation. Upregulation in placental NR4A2 has been hypothesised to be associated with inflammatory processes 21 , 44 . To further understand these changes across gestation, it would be beneficial to examine NR4A2 in first trimester placental tissue, where, if NR4A2 is involved in inflammation as hypothesised, there may be increased NR4A2 expression given many inflammatory pathways are integral in driving successful extravllous cytotrophoblast invasion and critical arteriole remodelling 20 .…”

Melatonin promotes cell cycle progression of neural stem cells subjected to manganese via Nurr1

“…15 Nurr1 can mediate perinatal responses to stressful environmental stimuli, so epigenetic disorders involving Nurr1 in developing animals are often related to neurotoxic compounds, and they have potential intergenerational effects. 16 Many of the direct target genes of Nurr1 have been identified as essential for the cell cycle and for DNA replication during brain development. 17 There are thus reasons to suspect that Nurr1 may be a key molecule in Mel alleviating Mn-induced cell cycle arrest in NSCs.…”

“…A potential target of Mel in this regard is nuclear receptor‐related protein 1 (Nurr1), which is widely distributed in the CNS during development 15 . Nurr1 can mediate perinatal responses to stressful environmental stimuli, so epigenetic disorders involving Nurr1 in developing animals are often related to neurotoxic compounds, and they have potential intergenerational effects 16 . Many of the direct target genes of Nurr1 have been identified as essential for the cell cycle and for DNA replication during brain development 17 .…”