TY - JOUR
T1 - N-acetyl cysteine mediated inhibition of glucose regulated protein-78 abrogates activating transcription factor-4 dependent endoplasmic reticulum stress and neurodegeneration following exposure to di-2-ethylhexyl phthalate in zebrafish brain
AU - Sarangi, Prerana
AU - Pradhan, Lilesh Kumar
AU - Bhoi, Suvam
AU - Sahoo, Bhabani Sankar
AU - Chauhan, Nishant Ranjan
AU - Raut, Sangeeta
AU - Das, Saroj Kumar
N1 - Publisher Copyright:
© 2025 Elsevier B.V.
PY - 2025/9/15
Y1 - 2025/9/15
N2 - Recent findings have highlighted the neurological consequences of exposure to the plasticizer di-2-ethylhexyl phthalate (DEHP), including neurobehavioral transformation, cognitive dysfunction, and neurodegeneration. Endoplasmic reticulum (ER) stress plays a distinct role in altering cellular responses by inducing cell death. Based on existing literature, we were primarily interested in understanding whether the gross biochemical and neuromorphological outcomes of DEHP are associated with augmented ER stress in the neuronal microenvironment. Furthermore, we aimed to establish the neuroprotective efficacy of N-acetyl cysteine (NAC) against DEHP-induced ER stress in the zebrafish brain. Our core findings strongly support the argument that DEHP, being a global neurotoxicant, induces heightened oxidative stress and dysregulated calcium homeostasis, which contribute to ER stress mediated neurodegeneration via ATF4-dependent upregulation of GRP78 in the zebrafish brain. However, NAC reversed DEHP-induced calcium dysregulation (F4,20 = 11.97, p < 0.05; n = 6/group) and ATF4-mediated (F4,8 = 11.05; p < 0.05; n = 6/group) ER stress by inhibiting GRP78 (F4,8 = 31.83; p < 0.05; n = 6/group) in the zebrafish brain. NAC also promoted neuroprotection through upregulation of endogenous BDNF (F₄,₈ = 13.93, p < 0.05; n = 6/group) and NeuN (F₄,₈ = 56.95, p < 0.05; n = 6/group) expression and inhibition of CC3-mediated (F₄,₈ = 22.03, p < 0.05; n = 6/group) neurodegeneration in the periventricular grey zone (PGZ) of the zebrafish brain. To summarize these observations, our study establishes a strong correlation between NAC co-supplementation and restoration of DEHP-induced ER stress and neuropathology in zebrafish, but the study needs further validation to warrant the NAC-mediated potential therapeutic development against DEHP.
AB - Recent findings have highlighted the neurological consequences of exposure to the plasticizer di-2-ethylhexyl phthalate (DEHP), including neurobehavioral transformation, cognitive dysfunction, and neurodegeneration. Endoplasmic reticulum (ER) stress plays a distinct role in altering cellular responses by inducing cell death. Based on existing literature, we were primarily interested in understanding whether the gross biochemical and neuromorphological outcomes of DEHP are associated with augmented ER stress in the neuronal microenvironment. Furthermore, we aimed to establish the neuroprotective efficacy of N-acetyl cysteine (NAC) against DEHP-induced ER stress in the zebrafish brain. Our core findings strongly support the argument that DEHP, being a global neurotoxicant, induces heightened oxidative stress and dysregulated calcium homeostasis, which contribute to ER stress mediated neurodegeneration via ATF4-dependent upregulation of GRP78 in the zebrafish brain. However, NAC reversed DEHP-induced calcium dysregulation (F4,20 = 11.97, p < 0.05; n = 6/group) and ATF4-mediated (F4,8 = 11.05; p < 0.05; n = 6/group) ER stress by inhibiting GRP78 (F4,8 = 31.83; p < 0.05; n = 6/group) in the zebrafish brain. NAC also promoted neuroprotection through upregulation of endogenous BDNF (F₄,₈ = 13.93, p < 0.05; n = 6/group) and NeuN (F₄,₈ = 56.95, p < 0.05; n = 6/group) expression and inhibition of CC3-mediated (F₄,₈ = 22.03, p < 0.05; n = 6/group) neurodegeneration in the periventricular grey zone (PGZ) of the zebrafish brain. To summarize these observations, our study establishes a strong correlation between NAC co-supplementation and restoration of DEHP-induced ER stress and neuropathology in zebrafish, but the study needs further validation to warrant the NAC-mediated potential therapeutic development against DEHP.
KW - BDNF
KW - Calcium homeostasis
KW - Di-2-ethylhexyl phthalate
KW - N-acetyl cysteine
KW - Neurodegeneration
KW - Oxidative stress
UR - https://www.scopus.com/pages/publications/105010847232
UR - https://www.scopus.com/pages/publications/105010847232#tab=citedBy
U2 - 10.1016/j.scitotenv.2025.180068
DO - 10.1016/j.scitotenv.2025.180068
M3 - Article
C2 - 40683237
AN - SCOPUS:105010847232
SN - 0048-9697
VL - 995
JO - Science of the Total Environment
JF - Science of the Total Environment
M1 - 180068
ER -