title: Low concentrations of o,p'-DDT inhibit gene expression and prostaglandin synthesis by estrogen receptor-independent mechanism in rat ovarian cells.
abstract: o,p'-DDT is an infamous xenoestrogen as well as a ubiquitous and persistent pollutant. Biomonitoring studies show that women have been internally exposed to o,p'-DDT at range of 0.3-500 ng/g (8.46×10(-10) M-1.41×10(-6) M) in blood and other tissues. However, very limited studies have investigated the biological effects and mechanism(s) of o,p'-DDT at levels equal to or lower than current exposure levels in human. In this study, using primary cultures of rat ovarian granulosa cells, we determined that very low doses of o,p'-DDT (10(-12)-10(-8) M) suppressed the expression of ovarian genes and production of prostaglandin E2 (PGE2). In vivo experiments consistently demonstrated that o,p'-DDT at 0.5-1 mg/kg inhibited the gene expression and PGE2 levels in rat ovary. The surprising results from the receptor inhibitors studies showed that these inhibitory effects were exerted independently of either classical estrogen receptors (ERs) or G protein-coupled receptor 30 (GPR30). Instead, o,p'-DDT altered gene expression or hormone action via inhibiting the activation of protein kinase A (PKA), rather than protein kinase C (PKC). We further revealed that o,p'-DDT directly interfered with the PKA catalytic subunit. Our novel findings support the hypothesis that exposure to low concentrations of o,p'-DDT alters gene expression and hormone synthesis through signaling mediators beyond receptor binding, and imply that the current exposure levels of o,p'-DDT observed in the population likely poses a health risk to female reproduction.
authors.affiliation: MOE Key Lab of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Meirong
authors.initials: M
authors.lastname: Zhao
authors.forename: Shulin
authors.initials: S
authors.lastname: Zhuang
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Ye
authors.initials: Y
authors.lastname: Yang
authors.forename: Weiping
authors.initials: W
authors.lastname: Liu
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D003634:DDT / Q000737:chemistry / Q000494:pharmacology*; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006107:Granulosa Cells / Q000187:drug effects* / Q000378:metabolism*; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004968:Estrogens, Non-Steroidal; C109584:GPER1 protein, human; D011453:Prostaglandins; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D003634:DDT; C016340:o,p'-DDT; D017868:Cyclic AMP-Dependent Protein Kinases