TY - JOUR
T1 - Redox regulation of hormone sensitive lipase
T2 - Potential role in the mechanism of MEHP-induced stimulation of basal steroid synthesis in MA-10 Leydig cells
AU - Zhou, Christine
AU - Zaman, Ninad
AU - Li, Yunbo
AU - Martinez-Arguelles, Daniel B.
AU - Papadopoulos, Vassilios
AU - Zirkin, Barry
AU - Traore, Kassim
N1 - Publisher Copyright:
© 2018
PY - 2019/4
Y1 - 2019/4
N2 - Mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of di-(2-ethylhexyl) phthalate (DEHP), is a plasticizer with endocrine disruptor activity that has been shown to stimulate basal steroid biosynthesis in Leydig cells. The mechanism by which it does so is unknown. Using MA-10 mouse tumor Leydig cells, we assessed the effects of MEHP on reactive oxygen species (ROS) levels, and on the signal transduction pathways that mobilize cholesterol. Exposure to 0–300 μM MEHP stimulated basal progesterone production in a dose-dependent manner. Progesterone stimulation was correlated with increases in the phosphorylation of hormone-sensitive lipase (HSL; aka cholesteryl ester hydrolase), which is involved in the production of free cholesterol, and of steroidogenic acute regulatory (STAR) protein expression. Co-treating MA-10 cells with MEHP and the ROS scavenger N-acetyl cysteine (NAC) blocked the activation of HSL, blunted MEHP-induced STAR, and reduced basal progesterone formation. These observations suggest that ROS generation by MEHP leads to activation of HSL and increase in STAR which, together, result in increased free-cholesterol bioavailability and progesterone formation.
AB - Mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of di-(2-ethylhexyl) phthalate (DEHP), is a plasticizer with endocrine disruptor activity that has been shown to stimulate basal steroid biosynthesis in Leydig cells. The mechanism by which it does so is unknown. Using MA-10 mouse tumor Leydig cells, we assessed the effects of MEHP on reactive oxygen species (ROS) levels, and on the signal transduction pathways that mobilize cholesterol. Exposure to 0–300 μM MEHP stimulated basal progesterone production in a dose-dependent manner. Progesterone stimulation was correlated with increases in the phosphorylation of hormone-sensitive lipase (HSL; aka cholesteryl ester hydrolase), which is involved in the production of free cholesterol, and of steroidogenic acute regulatory (STAR) protein expression. Co-treating MA-10 cells with MEHP and the ROS scavenger N-acetyl cysteine (NAC) blocked the activation of HSL, blunted MEHP-induced STAR, and reduced basal progesterone formation. These observations suggest that ROS generation by MEHP leads to activation of HSL and increase in STAR which, together, result in increased free-cholesterol bioavailability and progesterone formation.
KW - Antioxidants
KW - Phthalates
KW - ROS
UR - http://www.scopus.com/inward/record.url?scp=85060516045&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060516045&partnerID=8YFLogxK
U2 - 10.1016/j.reprotox.2018.12.010
DO - 10.1016/j.reprotox.2018.12.010
M3 - Article
C2 - 30648648
AN - SCOPUS:85060516045
SN - 0890-6238
VL - 85
SP - 19
EP - 25
JO - Reproductive Toxicology
JF - Reproductive Toxicology
ER -