Estradiol-mediated suppression of CYP1B1 expression in mouse MA-10 Leydig cells is independent of protein kinase A and estrogen receptor

Abstract

Estrogens have multifaceted roles in mammalian testis. In the present study, we focused on estradiol as a potential regulator of testicular cytochrome P450 1B1 (CYP1B1) expression and investigated the possible mechanisms involved in the estradiol-mediated suppression. CYP1B1 protein levels were measured in the testes of rats that were treated with 17β-estradiol benzoate (1.5 mg/kg) at different stages of development. In addition, CYP1B1 mRNA levels were measured in mouse MA-10 Leydig tumor cells treated with (a) various concentrations of 17β-estradiol benzoate, (b) 17β-estradiol benzoate in the presence of exogenous luteinizing hormone (LH), or (c) 17β-estradiol benzoate in the presence of ICI 182,780, a competitive steroidal antagonist of estrogen receptors (ERs). Treatment of neonatal, pubertal, or adult rats with 17β-estradiol benzoate was associated with a reduction of approximately 90% in testicular CYP1B1 protein content compared to age-matched controls. Treatment of MA-10 cells with 17β-estradiol benzoate (10-500 nM) produced a concentration- and time-dependent decrease in CYP1B1 mRNA levels, but had no effect on LH receptor mRNA levels or on protein kinase A (PKA) activity. However, 17β-estradiol benzoate (10-500 nM), regardless of the concentration tested, failed to attenuate the LH-elicited increase in CYP1B1 mRNA or PKA activity in MA-10 cells that were co-treated with LH and estradiol. Similarly, ICI 182,780 (10-1000 µM) did not reverse the suppressive effect of estradiol on CYP1B1 mRNA expression in MA-10 cells co-treated with estradiol and ICI 182,780. The results indicate that downregulation of testicular CYP1B1 by estradiol was independent of PKA activity and was not mediated by ERs in MA-10 cells.

Expression Profiling of CYP1B1 in Oral Squamous Cell Carcinoma: Counterintuitive Downregulation in Tumors

“…For example, the male patient 110 and the female patient 101 show downregulation of CYP1B1 at both the mRNA and the protein levels (see Figure 1B and Table S1 ). Thus unlike the previous reports in mouse Leydig cells and endometrial cancer [16] , [17] , the downregulation of CYP1B1 does not seem to be governed by estrogen. However, similar to our study, the absence of gender differences in the pattern of CYP1B1 expression has also been observed recently in OSCC [18] , [19] .…”

Systemic Compensatory Response to Neonatal Estradiol Exposure Does Not Prevent Depletion of the Oocyte Pool in the Rat

“…By contrast, E2 treatment had no effect on physiological neonatal Cyp1b1 down-regulation and Gsta2 up-regulation of expression in the liver. Cyp1b1 response to E2 exposure seems to be organ-specific since its expression is either inducible by E2 and deoxymiroestrol (a strong phyto-estrogen in mouse hepatocyte primary culture [69]) or down-regulated by estrogenic compounds in peripheral organs such as rat and mouse testis and the reproductive tract of developing female rats [38], [70], [71]. This may also be the case for Gst enzymes as genistein increases Gsta2 mRNA levels and decreases Gstp1 mRNA levels without affecting general GST activity in adult males, and deoxymiroestrol increases Gsta2 expression in adult mice hepatocyte primary culture [69], [72].…”

Correction: Systemic Compensatory Response to Neonatal Estradiol Exposure Does Not Prevent Depletion of the Oocyte Pool in the Rat

“…By contrast, E2 treatment had no effect on physiological neonatal Cyp1b1 down-regulation and Gsta2 upregulation of expression in the liver. Cyp1b1 response to E2 exposure seems to be organ-specific since its expression is either inducible by E2 and deoxymiroestrol (a strong phyto-estrogen in mouse hepatocyte primary culture [69]) or down-regulated by estrogenic compounds in peripheral organs such as rat and mouse testis and the reproductive tract of developing female rats [38,70,71]. This may also be the case for Gst enzymes as genistein increases Gsta2 mRNA levels and decreases Gstp1 mRNA levels without affecting general GST activity in adult males, and deoxymiroestrol increases Gsta2 expression in adult mice hepatocyte primary culture [69,72].…”