Nitrophenols isolated from diesel exhaust particles regulate steroidogenic gene expression and steroid synthesis in the human H295R adrenocortical cell line.
Studies of nitrophenols isolated from diesel exhaust particles (DEPs), 3-methyl-4-nitrophenol (PNMC) and 4-nitro-3-phenylphenol (PNMPP) have revealed that these chemicals possess estrogenic and anti-androgenic activity in vitro and in vivo and that PNMC accumulate in adrenal glands in vivo. However, the impacts of exposure to these compounds on adrenal endocrine disruption and steroidogenesis have not been investigated. To elucidate the non-receptor mediated effects of PNMC and PNMPP, we investigated the production of the steroid hormones progesterone, cortisol, testosterone, and estradiol-17beta and modulation of nine major enzyme genes involved in the synthesis of steroid hormones (CYP11A, CYP11B1, CYP17, CYP19, 17betaHSD1, 17betaHSD4, CYP21, 3betaHSD2, StAR) in human adrenal H295R cells supplied with cAMP. Exposure to 10(-7) to 10(-5) M PNMC and 1 mM 8-Br-cAMP for 48 h decreased testosterone, cortisol, and estradiol-17beta levels and increased progesterone secretion. At 10(-5) M, PNMC with 1 mM 8-Br-cAMP significantly stimulated expression of the 17betaHSD4 and significantly suppressed expression of 3betaHSD2. In comparison, 10(-7) to 2 x 10(-5) M PNMPP with 1 mM 8-Br-cAMP for 48 h decreased concentrations of estradiol-17beta, increased progesterone levels, but did not affect testosterone and cortisol secretion due to the significant suppression of CYP17 and the non-significant but obvious suppression of CYP19. Our results clarified steroidogenic enzymes as candidates responsible for the inhibition or stimulation for the production of steroid hormones in the steroidogenic pathway, thus providing the first experimental evidence for multiple mechanisms of disruption of endocrine pathways by these nitrophenols.
Furuta
Chie
C
Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.
Noda
Shiho
S
Li
ChunMei
C
Suzuki
Akira K
AK
Taneda
Shinji
S
Watanabe
Gen
G
Taya
Kazuyoshi
K
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000302:isolation & purification / Q000633:toxicity*; D045744:Cell Line, Tumor; D003408:Cresols / Q000008:administration & dosage / Q000302:isolation & purification / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D006913:Hydroxysteroid Dehydrogenases / Q000187:drug effects / Q000378:metabolism; D009596:Nitrophenols / Q000008:administration & dosage / Q000302:isolation & purification / Q000633:toxicity*; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D011374:Progesterone / Q000096:biosynthesis; D013739:Testosterone / Q000096:biosynthesis; D001335:Vehicle Emissions / Q000633:toxicity*; D000098682:Steroidogenic Acute Regulatory Protein
C494060:4-nitro-3-phenylphenol; D001713:Biphenyl Compounds; D003408:Cresols; D009596:Nitrophenols; D010750:Phosphoproteins; D001335:Vehicle Emissions; D000098682:Steroidogenic Acute Regulatory Protein; D015124:8-Bromo Cyclic Adenosine Monophosphate; C008636:4-nitro-3-cresol; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D006913:Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone