TY - JOUR
T1 - Isothiazolinone Disrupts Reproductive Endocrinology by Targeting the G-Protein-Coupled Receptor Signaling
AU - Tang, Lizhu
AU - Liu, Mengyuan
AU - Li, Jing
AU - Zhou, Bingsheng
AU - Lam, Paul K.S.
AU - Hu, Chenyan
AU - Chen, Lianguo
N1 - Publisher Copyright:
© 2024 American Chemical Society
PY - 2024/1/16
Y1 - 2024/1/16
N2 - The unintended exposure of humans and animals to isothiazolinones has led to an increasing concern regarding their health hazards. Isothiazolinones were previously found to disrupt reproductive endocrine homeostasis. However, the long-term reproductive toxicity and underlying mechanism remain unclear. In this study, life-cycle exposure of medaka to dichlorocthylisothiazolinone (DCOIT), a representative isothiazolinone, significantly stimulated the gonadotropin releasing hormone receptor (GnRHR)-mediated synthesis of follicle stimulating hormone and luteinizing hormone in the brain. Chem-Seq and proteome analyses revealed disturbances in the G-protein-coupled receptor, MAPK, and Ca2+ signaling cascades by DCOIT. The G protein αi subunit was identified as the binding target of DCOIT. Gαi bound by DCOIT had an enhanced affinity for the mitochondrial calcium uniporter, consequently changing Ca2+ subcellular compartmentalization. Stimulation of Ca2+ release from the endoplasmic reticulum and blockage of Ca2+ uptake into the mitochondria resulted in a considerably higher cytoplasmic Ca2+ concentration, which then activated the phosphorylation of MEK and ERK to dysregulate hormone synthesis. Overall, by comprehensively integrating in vivo, ex vivo, in silico, and in vitro evidence, this study proposes a new mode of endocrine disrupting toxicity based on isothiazolinones, which is expected to aid the risk assessment of the chemical library and favor the mechanism-driven design of safer alternatives.
AB - The unintended exposure of humans and animals to isothiazolinones has led to an increasing concern regarding their health hazards. Isothiazolinones were previously found to disrupt reproductive endocrine homeostasis. However, the long-term reproductive toxicity and underlying mechanism remain unclear. In this study, life-cycle exposure of medaka to dichlorocthylisothiazolinone (DCOIT), a representative isothiazolinone, significantly stimulated the gonadotropin releasing hormone receptor (GnRHR)-mediated synthesis of follicle stimulating hormone and luteinizing hormone in the brain. Chem-Seq and proteome analyses revealed disturbances in the G-protein-coupled receptor, MAPK, and Ca2+ signaling cascades by DCOIT. The G protein αi subunit was identified as the binding target of DCOIT. Gαi bound by DCOIT had an enhanced affinity for the mitochondrial calcium uniporter, consequently changing Ca2+ subcellular compartmentalization. Stimulation of Ca2+ release from the endoplasmic reticulum and blockage of Ca2+ uptake into the mitochondria resulted in a considerably higher cytoplasmic Ca2+ concentration, which then activated the phosphorylation of MEK and ERK to dysregulate hormone synthesis. Overall, by comprehensively integrating in vivo, ex vivo, in silico, and in vitro evidence, this study proposes a new mode of endocrine disrupting toxicity based on isothiazolinones, which is expected to aid the risk assessment of the chemical library and favor the mechanism-driven design of safer alternatives.
KW - G protein-coupled receptor
KW - MAPK phosphorylation
KW - calcium signaling
KW - endocrine disruption
KW - isothiazolinone
KW - reproduction
UR - http://www.scopus.com/inward/record.url?scp=85182002811&partnerID=8YFLogxK
U2 - 10.1021/acs.est.3c08577
DO - 10.1021/acs.est.3c08577
M3 - Article
C2 - 38166396
AN - SCOPUS:85182002811
SN - 0013-936X
VL - 58
SP - 1076
EP - 1087
JO - Environmental Science and Technology
JF - Environmental Science and Technology
IS - 2
ER -