7,12-Dimethylbenz[a]anthracene Inhibition of Steroid Production in MA-10 Mouse Leydig Tumor Cells Is Not Directly Linked to Induction of CYP1B1

Mandal, Prabir K.; McDaniel, Lisa R.; Prough, Russell A.; Clark, Barbara J.

doi:10.1006/taap.2001.9241

Cited by 27 publications

(23 citation statements)

References 39 publications

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“…The TCDD-mediated reduction of progesterone and testosterone production, however, can be completely abolished at a higher dose (50 ng/ml) of hCG treatment. This observation is in agreement with other reports using animal models, whereas high doses of hCG could alleviate TCDD-mediated inhibition of Leydig cell functions (Wilker et al 1995, Mandal et al 2001 and prevented the TCDD-elicited reduction of cytochrome P450 enzymes (Ruangwises et al 1991). To delineate the underlying mechanism of TCDD-mediated inhibition of testosterone synthesis, we measured the changes in the expression of some key steroidogenic enzymes.…”

Section: Discussionsupporting

confidence: 91%

Inhibition of CYP450scc expression in dioxin-exposed rat Leydig cells

Lai¹,

Wong²,

Wong³

2005

Journal of Endocrinology

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Polychlorinated dibenzo-p-dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been recognized as highly potent developmental and reproductive toxins. We have previously demonstrated effects of TCDD in modulating the expression of rat Sertoli cell secretory products and markers for cell-cell interaction. In this study, we examined the direct biological effects of TCDD in rat Leydig cell primary cultures. Mature rat Leydig cells were purified by Percoll gradient centrifugation and the cell purity was determined by 3 -hydroxysteroid dehydrogenase (3 -HSD) staining and a testosterone induction assay. To examine TCDD-induced biological consequences, we measured the changes in the secretion of progesterone and testosterone, as well as transcript levels of some selected steroidogenic enzymes (i.e. StAR, P450scc, 3 -HSD and CYP17 ), in TCDD/human chorionic gonadotropin (hCG) co-treated cells. Our results indicated that TCDD (0·2 or 2 ng/ml) treatment significantly suppressed hCG (5 or 10 ng/ml)-induced testosterone secretion. The suppressive effect aligned with a reduction of progesterone secretion (P<0·05), as well as a decrease of P450scc mRNA and protein expression (P<0·05). The mechanistic action of TCDD was found to be via the reduction of cellular cAMP levels in the hCG-treated cells. This observation was further confirmed, as the TCDD-mediated suppressive effect could be reversed by dibutyryl cAMP co-treatment. The data indicate that TCDD can modulate cAMP signaling in rat Leydig cells to affect the process of steroidogenesis.

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Section: Discussionsupporting

confidence: 91%

Inhibition of CYP450scc expression in dioxin-exposed rat Leydig cells

Lai¹,

Wong²,

Wong³

2005

Journal of Endocrinology

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“…On the contrary, circulating testosterone in BaP-exposed rats decreased significantly throughout the above-mentioned time periods and may have resulted from the exposure of Leydig cells to sequestered BaP in high-density lipoproteins that are essential for steroid hormone biosynthesis (Polyakov et al, 1996). Mandal et al (2001) have demonstrated that DMBA inhibits the ability of Leydig cells to synthesize and release testosterone.…”

Section: Discussionmentioning

confidence: 99%

“…In this context it is worth mentioning that the tissues in the male reproductive organs and the Leydig cells in particular extensively metabolize PAHs including BaP Lee and Nagayama, 1980;Williams et al, 2000). The metabolites of inhaled BaP may have significantly reduced the ability of the Leydig cell to synthesize and release testosterone due to ROS-induced aging (Senft et al, 2002;Mandal et al, 2001). Peltola et al (1996) have shown that ROS can damage critical components of the steroidogenetic pathway in Leydig cells, including steroidogenic acute regulatory (StAR) protein (Diemer et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene

Ramesh

Inyang

Lunstra

et al. 2008

Experimental and Toxicologic Pathology

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The objective of this study was to evaluate the reproductive risk associated with exposure of adult male Fisher-344 rats to inhaled benzo(a)pyrene (BaP). Rats were assigned randomly to a treatment or control group. Treatment consisted of sub-chronic exposure of rats via inhalation to 75μg BaP/ m 3 , 4 hours daily for 60 days, while control animals were unexposed (UNC). Blood samples were collected immediately after the cessation of exposures (time 0) and subsequently at 24, 48, and 72 hrs, to assess the effect of bioavailable BaP on plasma testosterone and luteinizing hormone (LH) concentrations. Rats were sacrificed after the last blood collection. Testes were harvested, weighed and prepared for histology and morphometric analysis, and cauda epididymides were isolated for the determination of progressive motility and density of stored spermatozoa. BaP exposure reduced testis weight compared with UNC (Mean ± SE; 2.01 ± 0.11 vs. 3.04 ± 0.16 g; P< 0.025), and caused significant reductions in the components of the steroidogenic and spermatogenic compartments of the testis. Progressive motility and mean density of stored spermatozoa were reduced (P< 0.05). Plasma testosterone concentrations were decreased by two-thirds in BaPexposed rats throughout the time periods studied compared with those of their UNC counterparts (P< 0.05), concomitant with increased concentrations of LH in BaP-exposed rats (P< 0.05). These data suggest that sub-chronic exposure to inhaled BaP contribute to reduced testicular and epididymal function in exposed rats.

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“…Similarly to other CYP1A/B inducers, coplanar PCB congeners bind to the cytosolic aryl hydrocarbon receptor (AhR) and elicit AhR-mediated toxic and biochemical responses (Safe 1994). Unlike CYP1A1, CYP1B1 is constitutively expressed in the rat adrenal cortex (Bhattacharyya et al 1995;Brake and Jefcoate 1995;Walker et al 1995;Brake et al 1999;Mandal et al 2001). Otto and coworkers reported that essentially all DMBA metabolism in the rat adrenal is catalysed by CYP RAP, later identified as CYP1B1 (orthologous to the enzyme from the mouse which was assigned to a new CYP1 family, CYP1B, in 1994) (Otto et al 1992;Savas et al 1994;Bhattacharyya et al 1995).…”

Section: Discussionmentioning

confidence: 99%

Target cells for cytochrome P450-catalysed irreversible binding of 7,12-dimethylbenz[a]anthracene (DMBA) in rodent adrenal glands

Lindhe

Granberg

Brandt

2002

Archives of Toxicology

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7,12-Dimethylbenz[a]anthracene (DMBA) is an adrenocorticolytic agent that causes apoplexy (haemorrhage) and massive necrosis in the adrenal cortex in rat. Several explanations regarding the origin of toxicity have been proposed. Huggins and Morii (J Exp Med 114:741-60, 1961) suggested that the cells of the inner adrenal cortex are the primary target, whereas Horváth and Kovács (Pathol Eur 8:43-59, 1973) suggested the vascular endothelium as being the origin of toxicity. In the present study, cultured precision-cut tissue slices were used to localize target cells for irreversible [(3)H]DMBA binding in rat and mouse adrenal cortex. The sites of binding were confirmed by autoradiography in vivo. Irreversible [(3)H]DMBA binding was confined to zona fasciculata/reticularis cells in rat (but not in mouse) adrenal cortex. Pronounced binding was observed in clusters of cells (focal binding), localized predominantly in zona reticularis of rat. [(3)H]DMBA binding in zona fasciculata/reticularis cells was inhibited by the cytochrome p450 1A/B (CYP1A/B) inhibitors ellipticine, alpha-naphthoflavone, and 1-ethynylpyrene. The CYP11B1-inhibitor metyrapone did not reduce [(3)H]DMBA binding. In CYP1-induced (PCB 126-treated) rats and mice, intense irreversible [(3)H]DMBA binding was found also in endothelial cells of the adrenal cortex. The endothelial binding was abolished by the CYP1 inhibitors but remained unaffected by metyrapone. We conclude that the metabolic activation in adrenal parenchymal cells is presumably catalysed by CYP1B1, whereas CYP1A1 presumably catalyses the activation in endothelial cells. We suggest that the adrenocorticolytic effect of DMBA is the result of a dual mode of action, targeting both endothelial and parenchymal cells in the rat adrenal cortex.

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7,12-Dimethylbenz[a]anthracene Inhibition of Steroid Production in MA-10 Mouse Leydig Tumor Cells Is Not Directly Linked to Induction of CYP1B1

Cited by 27 publications

References 39 publications

Inhibition of CYP450scc expression in dioxin-exposed rat Leydig cells

Inhibition of CYP450scc expression in dioxin-exposed rat Leydig cells

Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene

Target cells for cytochrome P450-catalysed irreversible binding of 7,12-dimethylbenz[a]anthracene (DMBA) in rodent adrenal glands

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