Species-specific dibutyl phthalate fetal testis endocrine disruption correlates with inhibition of SREBP2-dependent gene expression pathways.
Fetal rat phthalate exposure produces a spectrum of male reproductive tract malformations downstream of reduced Leydig cell testosterone production, but the molecular mechanism of phthalate perturbation of Leydig cell function is not well understood. By bioinformatically examining fetal testis expression microarray data sets from susceptible (rat) and resistant (mouse) species after dibutyl phthalate (DBP) exposure, we identified decreased expression of several metabolic pathways in both species. However, lipid metabolism pathways transcriptionally regulated by sterol regulatory element-binding protein (SREBP) were inhibited in the rat but induced in the mouse, and this differential species response corresponded with repression of the steroidogenic pathway. In rats exposed to 100 or 500 mg/kg DBP from gestational days (GD) 16 to 20, a correlation was observed between GD20 testis steroidogenic inhibition and reductions of testis cholesterol synthesis endpoints including testis total cholesterol levels, Srebf2 gene expression, and cholesterol synthesis pathway gene expression. SREBP2 expression was detected in all fetal rat testis cells but was highest in Leydig cells. Quantification of SREBP2 immunostaining showed that 500 mg/kg DBP exposure significantly reduced SREBP2 expression in rat fetal Leydig cells but not in seminiferous cords. By Western analysis, total rat testis SREBP2 levels were not altered by DBP exposure. Together, these data suggest that phthalate-induced inhibition of fetal testis steroidogenesis is closely associated with reduced activity of several lipid metabolism pathways and SREBP2-dependent cholesterologenesis in Leydig cells.
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA. johnson@medsci.udel.edu
Kamin J
KJ
Johnson
Erin N
EN
McDowell
Megan P
MP
Viereck
Jessie Q
JQ
Xia
D000818:Animals; D015153:Blotting, Western; D003993:Dibutyl Phthalate / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005865:Gestational Age; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D051379:Mice; D038081:Organogenesis / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics*; D013737:Testis / Q000187:drug effects* / Q000196:embryology; D013739:Testosterone / Q000096:biosynthesis
D052244:Endocrine Disruptors; D051782:Sterol Regulatory Element Binding Protein 2; D003993:Dibutyl Phthalate; D013739:Testosterone
Birth Defects Res B Dev Reprod Toxicol. 2005 Jun;74(3):277-85
15954088
Endocrinology. 2001 Apr;142(4):1525-33
11250933
Philos Trans R Soc Lond B Biol Sci. 2009 Jul 27;364(1526):2063-78
19528056
Mol Nutr Food Res. 2011 Jan;55(1):7-31
20564479
J Lipid Res. 2009 Apr;50 Suppl:S15-27
18974038
Nucleic Acids Res. 2003 Feb 15;31(4):e15
12582260
Toxicol Sci. 2008 Oct;105(2):360-7
18621746
J Biol Chem. 2009 Jan 16;284(3):1755-64
18996837
Toxicol Sci. 2004 Sep;81(1):60-8
15141095
Endocrinology. 2001 Jan;142(1):28-36
11145563
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
16199517
Biol Reprod. 2005 Jul;73(1):180-92
15728792
Int J Androl. 2006 Feb;29(1):140-7; discussion 181-5
16102138
Endocrinology. 2006 Mar;147(3):1427-37
16306078
Environ Health Perspect. 2006 Feb;114(2):270-6
16451866
Endocr Rev. 2009 Dec;30(7):883-925
19887492
Endocrinology. 2008 Oct;149(10):5280-7
18566125
Endocrinology. 2007 Dec;148(12):5851-64
17884934
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12027-32
14512514
Reprod Toxicol. 2002 Jan-Feb;16(1):19-28
11934529
Anat Histol Embryol. 2009 Nov;38(6):461-6
19793088
Endocrinology. 2004 Mar;145(3):1227-37
14617579
Clin Chim Acta. 2005 Nov;361(1-2):20-9
16004980
Cell. 2006 Jan 13;124(1):35-46
16413480
Hum Reprod. 2009 Sep;24(9):2244-54
19491204
Toxicol Sci. 2007 Jun;97(2):491-503
17361019
Toxicol Sci. 2003 Jun;73(2):431-41
12700402
Toxicol Appl Pharmacol. 2013 Sep 15;271(3):386-94
20850466
Toxicol Sci. 2006 Oct;93(2):369-81
16809437
Genomics. 1995 Feb 10;25(3):667-73
7759101
Cell Metab. 2008 Dec;8(6):512-21
19041766
Endocrinology. 2005 Feb;146(2):613-23
15539561
Toxicol Sci. 2001 Dec;64(2):233-42
11719706
Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6511-8
17428920
J Biochem Mol Toxicol. 2006;20(1):7-17
16498641
Endocr Rev. 2008 Aug;29(5):560-80
18436703
Genes Dev. 2009 Nov 15;23(22):2578-91
19933148
J Endocrinol. 1995 Nov;147(2):285-93
7490558
Environ Res. 2008 Oct;108(2):177-84
18949837
Toxicol Lett. 2004 Feb 2;146(3):207-15
14687758
Toxicol Sci. 2007 Jun;97(2):520-32
17379624
Mol Endocrinol. 2008 Mar;22(3):623-35
18032697
Mol Endocrinol. 2006 Oct;20(10):2265-77
16455816
J Androl. 2008 May-Jun;29(3):352-66
18222913
Biol Reprod. 2007 Dec;77(6):978-89
17881770