Mediating Roles of PPARs in the Effects of Environmental Chemicals on Sex Steroids

Table 1

Various kinds of environmental activators of PPARs and their impact on sex steroids.

Chemicals	PPARs subtype	Methods	Effects on sex steroids	Experimental model	References
DEHP	α, γ	Docking, transcript profiles, antagonism	Enhanced expression of aromatase, altered levels of estradiol	Rat, endometrial cells, fish	[22–25]
MEHP	α, β/δ, γ	Antagonism, transcript profiles	Decreased expression of aromatase and estradiol production	Rat ovarian granulosa cells, rat model, human liposarcoma cells, 3T3-L1 cells	[25–29]
DEHT	α	Docking	No significant impact	Rat model	[30]
PFNA	α, β/δ, γ	Transcript profiles, PPRE reporter	Elevated expression of CYP4A	Zebrafish, monkey kidney CV-1 cell line	[31, 32]
PFOA	α, γ	PPRE reporter, transcript profiles, antagonism, gene silencing	/	Monkey kidney CV-1 cell line, mice	[31, 33–36]
PFOS	α, γ	PPRE reporter; transcript profiles, antagonism, gene silencing	/	Monkey kidney CV-1 cell line, O. melastigma, mice	[31, 33, 35–39]
PFDA	α	PPRE reporter	/	Monkey kidney CV-1 cell line	[31]
PFUnDA	α	PPRE reporter	/	monkey kidney CV-1 cell line	[31]
TBBPA	γ	PPRE reporter	Increased apelin expression and secretion	Epithelial ovarian cancer cell line (OVCAR-3)	[40, 41]
TCBPA	γ	PPRE reporter	Increased apelin expression and secretion	OVCAR-3	[40, 41]
BPA	a, β/δ, γ	Transcript profiles, PPRE reporter, docking	Decreased expression of aromatase and estradiol production	Human ovarian granulosa cell, mouse embryo fibroblasts, OVCAR-3	[41–46]
PCB77	a, β/δ, γ	Docking, antagonism	/	/	[47]
PCB118	a, β/δ, γ	Docking, antagonism	/	Cell model, mice model	[7, 47]
PCB126	α	Transcript profiles	Altered the secretion of estradiol	Rat model, mice model	[48]
DDT	γ	Transcript profiles	Enhanced expression of CYP4A	Human mesenchymal stem cells	[49]
2,4-D	γ	Transcript profiles, gene silencing	Decreased cholesterol levels	Mice leydig cells, mice model	[6]
TBT	a, β/δ, γ	PPRE reporter	Inhibition of gonad development	Juvenile salmon, cell model	[50, 51]
EE2	γ	Transcript profiles		Brown trout	[11]

“/” indicated data is not available as we known; The experimental methods to support the interaction between chemicals and PPARs are depicted as follows, Antagonism: PPARs was antagonized by specific antagonist. Then, the effects elicited by chemicals were re-assessed. If the effects were diminished or enhanced, the mediating roles of PPARs could be confirmed; Transcript profiles: Transcript profiles of PPARs were modulated by chemicals treatment; Docking: Computing methods to predict the structural binding between chemicals and PPARs; PPRE reporter: Reporter system was constructed by transfecting the luciferase reporting plasmid containing PPRE sequence into the cells. Then, the cells were treated with chemicals to determine whether chemicals functioned through activating PPARs; Gene silencing: The expression of PPARs was inhibited by RNAi or gene knockout. Then, the effects elicited by chemicals were re-assessed. If the effects were diminished or enhanced, the mediating roles of PPARs could be confirmed; Abbreviation: di-(2-ethylhexyl) phthalate, DEHP; mono-(2-ethylhexyl) phthalate, MEHP; di(2-ethylhexyl) terephthalate, DEHT; perfluorododecanoic acid, PFDoA; perfluorononanoic acid, PFNA; perfluorooctanoic acid, PFOA; perfluorodecanoic acid, PFDA; perfluoroundecanoic acid, PFUnDA; perfluorooctane sulfonate, PFOS; BPA diglycidyl ether, BADGE; tetrabromobisphenol A, TBBPA; tetrachlorobisphenol A, TCBPA; bisphenol A, BPA; polychlorinated biphenyls, PCB; dichlorodiphenyltrichloroethane, DDT; 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD; 2,4-dichlorophenoxyacetic acid, 2,4-D; organotin, TBT; ethinylestradiol, EE2.