Role for Cystathionine γ Lyase (CSE) in an Ethanol (E)-Induced Lesion in Fetal Brain GSH Homeostasis

Abstract

Earlier, we reported that gestational ethanol (E) can dysregulate neuron glutathione (GSH) homeostasis partially via impairing the EAAC1-mediated inward transport of Cysteine (Cys) and this can affect fetal brain development. In this study, we investigated if there is a role for the transulfuration pathway (TSP), a critical bio-synthetic point to supply Cys in E-induced dysregulation of GSH homeostasis. These studies utilized an in utero E binge model where the pregnant Sprague–Dawley (SD) rat dams received five doses of E at 3.5 g/kg by gastric intubation beginning embryonic day (ED) 17 until ED19 separated by 12 h. The postnatal day 7 (PN7) alcohol model employed an oral dosing of 4 g/kg body weight split into 2 feedings at 2 h interval and an iso-caloric and iso-volumic equivalent maltose-dextrin milk solution served as controls. The in vitro model consisted of cerebral cortical neuron cultures from embryonic day (ED) 16–17 fetus from SD rats and differentiated neurons from ED18 rat cerebral cortical neuroblasts. E concentrations were 4 mg/mL. E induced an accumulation of cystathionine in primary cortical neurons (PCNs), 2nd trimester equivalent in utero binge, and 3rd trimester equivalent PN7 model suggesting that breakdown of cystathionine, a required process for Cys supply is impaired. This was associated with a significant reduction in cystathionine γ-lyase (CSE) protein expression in PCN (p < 0.05) and in fetal cerebral cortex in utero (53%, p < 0.05) without a change in the expression of cystathionine β-synthase (CBS). Concomitantly, E decreased Cse mRNA expression in PCNs (by 32% within 6 h of exposure, p < 0.05) and in fetal brain (33%, p < 0.05). In parallel, knock down of CSE in differentiated rat cortical neuroblasts exaggerated the E-induced ROS, GSH loss with a pronounced caspase-3 activation and cell death. These studies illustrate the importance of TSP in CSE-related maintenance of GSH and the downstream events via Cys synthesis in neurons and fetal brain.

Selenium at the Neural Barriers: AReview

“…The key enzyme of the trans-selenation pathway (cystathionine γ-lyase) is known to be expressed in the brain (Diwakar and Ravindranath, 2007;Patel et al, 2018;Seale et al, 2018b). Finally, a minor alternative pathway of Se entering the brain may be related to proteins leaking through the BBB (or BCB), first of all, under pathological conditions, impairing the barrier function, but this notion is rather speculative at the moment.…”

Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human Trophoblasts

“…Of note, alcohol exposure can provoke all the above cellular impacts. Relevant to the current studies, others and we have identified numerous E-related perturbations of cellular events/signaling pathways that underlie fetal brain and placental cell survival and function [12,13,20,21,22,23,24]. Thus, despite being an ephemeral organ, the placenta’s vital role in the adaptive signaling to program whole system development (fetal growth) renders it a multifunctional organ beyond a mere passive channel for bidirectional maternal/fetal exchange.…”

“…However, a myriad of exogenous causes of OS such as stress, inflammation, or xenobiotics, in the absence of genetic abnormalities have been shown to modify specific gene/molecular patterns or decrease the antioxidant capacity that can adversely amplify ROS levels and lead to placental dysfunction [9,12,13,16,27,28,29]. E-induced OS has been addressed as a compelling mechanism/target in the placenta and human placental villi [29], as previously demonstrated by us for liver and brain [20,21,30,31,32]. Notably, this is a setting where perturbations in the cell cycle, proliferation, migration and cell morphogenesis are impacted [4,13].…”

Ethanol inhibition of undifferentiated rat neural progenitor cell replication can be prevented by chlorogenic acid via the NFATc4/CSE signaling pathway

“…The current studies were enabled by earlier ones illustrating that EtOH can accelerate the normally occurring baseline apoptotic death of fetal cerebral cortical neurons and that an underlying mechanism is EtOH‐related oxidative stress/damage (Maffi et al, 2008; Patel et al, 2017, 2018; Watts et al, 2005). However, our prior studies with Tbr2‐expressing neuronal progenitor cells detected no evidence of an EtOH‐generated autophagy or apoptosis.…”

“…And, this is likely mediated, at least in part, at the transcriptional level (Figure 2B). The transsulfuration pathway mediates homocysteine conversion to cystathionine by cystathionine β‐synthase, which is converted to cysteine by CSE (Patel et al, 2018). Importantly, this pathway is one of the main sources of cysteine for synthesis of GSH in rodent and human brain (Hensley & Denton, 2015).…”