* Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku, Finland; Department of Physiology, University of Turku, 20520 Turku, Finland;
Department of Environmental Health, Laboratory of Toxicology, National Public Health Institute, Box 95, 70701 Kuopio, Finland;
Department of Pediatrics, University of Turku, 20520 Turku, Finland; ¶ Department of Anatomy, University of Turku, 20520 Turku, Finland
1 To whom correspondence should be addressed at Department of Anatomy, University of Turku, 20520 Turku, Finland. Fax: +358-(0)23337352. E-mail: paranko{at}utu.fi.
Received June 17, 2005; accepted August 30, 2005
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: TCDD; steroidogenesis; follicle-stimulating hormone; FSH; luteinizing hormone; LH; mRNA; infant; ovary; testis; rat.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Maternal exposure to TCDD may, in adult male and female progeny, result in genital dysmorphogenesis and impaired fertility (e.g., Flaws et al., 1997; Heimler et al., 1998
; Salisbury and Marcinkiewicz, 2002
). Because the elimination half-life of TCDD in female rats is 26 days (Li et al., 1995b
), developing organs in animals exposed to TCDD in utero and via lactation are continuously exposed to TCDD. The developing reproductive tract is sensitive to TCDD, and the notion that the placental transfer of TCDD to offspring is much less effective compared to lactational transfer (Chen et al., 2001
; Li et al., 1995b
; Salisbury and Marcinkiewicz, 2002
) emphasizes the exceptionally high dioxin sensitivity of the reproductive tract during fetal development.
Even though developmental exposure studies have confirmed adverse effects of TCDD on androgen-dependent growth of male accessory sex organs and epididymal sperm numbers (Gray et al., 1995, 1997a
, 1997b
; Mably et al., 1992a
, 1992b
; Simanainen et al., 2004
), effects on testicular androgen synthesis have remained ambiguous (Cooke et al., 1998
; Haavisto et al., 2001
, in press; Roman et al., 1995
). In female progeny, developmental reproductive toxicity of TCDD has been associated with deformed external genitalia and incomplete or delayed vaginal opening (Gray and Ostby, 1995
), as well as with decreased ovulatory success (Li et al., 1995a
; Petroff et al., 2003
).
A number of cytochrome enzymes regulate steroid hormone production. These enzymes are potential targets of TCDD-induced toxicity. In vitro, TCDD has been shown to reduce the mRNA expression of cytochrome P-450 cholesterol side-chain cleavage (P450scc) and cytochrome P-450 aromatase (P450arom) enzymes in rat granulosa cells (Dasmahapatra et al., 2000), and the protein expression levels of cytochrome P-450 17
-hydroxylase/17,20-lyase (P45017
) in human luteinized granulosa cells (Morán et al., 2003
). Less, however, is known about in vivo effects of TCDD on the expression levels of steroidogenic enzymes.
In the present study, gonadal mRNA expression levels of steroid acute regulatory protein (StAR) and the selected key steroidogenic enzymes were analyzed in 10- to 16-day-old male and female rat infant pups. During this time period, prepubertal peak in serum FSH and estradiol (E2) levels occurs in female pups (Döhler et al., 1977). In developing male rats, the perinatal activity peak in steroidogenesis occurs prenatally (Habert and Picon, 1984
), and the postnatal serum FSH, LH, and testosterone remain at relative low levels until puberty (El Gehani et al., 1998
). However, because of observed stimulatory effects of TCDD in the prenatal rat testis (Haavisto et al., 2001
), it is important to analyze whether the hormonal effect is visible in infant testis where fetal-type Leydig cells remain the prevailing steroidogenic cell population. In the present study, the exposure to non-fetolethal doses of TCDD was carried out on GD 13 when the first signs of sex-dependent morphological differentiation are detectable in the gonadal primordia but the gonads still are steroidogenically quiescent. As a result of different end-point effects of TCDD reported in male and female reproductive organs and reproductive physiology, the aim of the present study was to analyze whether sex-dependent differences can be recognized in infancy of in utero and lactationally exposed rat offspring.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Treatments.
Timed pregnant rats were randomly assigned to control and experimental groups (n 10 per group). The day when sperm was found in the vagina was considered as gestational day (GD) 0. TCDD (Ufa-Oil Institute, Russia), >99% pure as assessed by gas chromatographymass spectrometry, was dissolved in diethyl ether, and adjusted volumes of the solution were mixed with corn oil after which the ether was allowed to evaporate. Diethyl ether and corn oil were of analytical grade and purchased from Merck (Darmstadt, Germany) and from BDH Laboratory Supplies (Poole, England), respectively. Before maternal dosing, the solution was carefully mixed in a magnetic stirrer and sonicated for 20 min. A single dose of TCDD (0, 0.04, 0.2, or 1.0 g/kg) in corn oil (4 ml/kg) was given by gavage on GD 13. Presumed exposure continued via lactation until the sample collection.
Sampling.
The day of birth was considered PND 0. One day after birth the litter size was adjusted to 4 male and 4 female pups to allow uniform lactational exposure. From controls and pups exposed to 1 µg/kg TCDD, samples were collected on PND 10, 12, 14, and 16. For doseresponse analysis, samples from pups exposed to doses of 0.04 and 0.2 µg TCDD/kg were taken on PND 14. Dams and pups were anesthetized using a mixture of carbon dioxide and oxygen; they were then weighed and blood samples were collected in heparinized syringes. Blood kept on ice was centrifuged for 5 min at 1000 x g at +4°C. Plasma was stored at 20°C for the measurement of progesterone (P4), testosterone (T), E2, LH, and FSH levels. Ovaries and testes were excised, snap frozen in liquid nitrogen, and stored at 70°C.
For histology, 14-day-old testes and ovaries were fixed in 5% glutaraldehyde buffered in 0.16 mol/l S-collidine-HCl (pH 7.4) and postfixed with potassium ferrocyanide-osmium fixative. Dehydrated tissue pieces were embedded in Epon, and 1-µm-thick sections were stained with a 0.5% toluidine blue solution. Testis and ovarian histology and the number of developing ovarian follicles were evaluated under a light microscope from control and exposed (TCDD 1 µg/kg) pups. Gonads from five animals in each group were analyzed.
Hormone measurements.
T, P4, and E2 were measured from diethyl ether extracts of heparin plasma by time-resolved fluoroimmunoassay (DELFIA, PerkinElmer Life and Analytical Sciences, Wallac Oy, Turku, Finland) as described elsewhere (Haavisto et al., 2001). Serum LH and FSH concentrations were determined by two-site time-resolved immunofluorometric assays (DELFIA) for rat LH and FSH. The assay detection limit was 0.100 ng/ml for T, 0.250 ng/ml for P4, 0.014 ng/ml for E2, 0.040 ng/ml for LH, and 0.100 ng/ml for FSH. The intra- and inter-assay variations were under 6% and 12%, respectively. For testosterone, the enhancement of assay sensitivity from 0.100 ng/ml to 0.040 ng/ml was obtained by an additional dilution of the commercial tracer and antisera to 5/8 from their original concentrations.
Ex vivo aromatase assay.
Doseresponse analysis of TCDD-induced changes in ovarian P450arom enzyme activity was determined ex vivo in the isolated PND 14 ovarian follicles by measuring the incorporation of tritium from 1ß, 2ß-3H-androstenedione (NEN, Zaventem, Belgium) into water phase as described elsewhere (Lephart and Simpson, 1991). Ovarian follicles were isolated and cultured for 5 days in the presence of 1.1 IU of hFSH as described (Myllymäki et al., 2005
). After 4 days in culture, 10 pM of 1ß,2ß-3H-labeled androstenedione was added to culture medium. Radioactivity of ether-extracted water phase was measured using a Microbeta scintillation counter (Perkin Elmer Wallac).
Two-step real-time RT-PCR.
Total RNA was extracted from snap-frozen testes and ovaries with RNeasy Kit (Qiagen, Germantown, MD) according to the manufacturer's instructions. The tissue was homogenized with motor-driven plastic Eppendorf pestles, and DNA was subsequently sheared using Qia-shredder columns (Qiagen). Two micrograms of total RNA was reverse transcribed using Avian Myeloblastosis Virus (AMV, 30 U), Reverse Transcriptase Reaction Buffer (Promega), 1 µg Oligo(dT)15 Primer (Promega), and 40 units of RNase inhibitor (RNasin, Promega) in a final volume of 25 µl. For quantification of P450scc, P45017, P450arom, 3ß-hydroxy-steroid-dehydrogenase/
5-
4 isomerase type I (3ß-HSD1), StAR, and S26 cDNA transcripts, real-time PCR was performed with specific primer pairs (Table 1). The annealing temperature was 57°C, and the reactions were performed using the QuantiTect SYRB-Green RT-PCR Kit (Qiagen) according to the manufacturer's instructions, which included use of the DNA Engine Opticon system (MJ Research, Inc., Waltham, MA) with the use of continuous fluorescence detection. Ribosomal S26 was included as the endogenous normalization control for the amount of loaded RNA.
|
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Reductions in the offspring body weight, a feature of TCDD toxicity (Birnbaum, 1995; Pohjanvirta and Tuomisto, 1994
), confirmed the effectiveness of the present exposure regime. Maternally introduced TCDD (12 µg/kg) has also been shown to reduce absolute testis weight in adults (Gray et al., 1995
, 1997a
, 1997b
; Mably et al., 1992b
; Theobald et al., 2000
; Wilker et al., 1996
). Relative testis weights, however, may remain unaltered (Theobald et al., 2000
; Wilker et al., 1996
) or, as shown in the present study, may even be increased. This may suggest an initial compensatory response and/or reflect decreases in body weights. In the ovary, the absence of histological changes is in line with earlier reports showing unaltered numbers of primordial, primary, preantral, and small antral follicles in TCDD-exposed female pups (Salisbury and Marcinkiewicz, 2002
). As a result of specific growth-retarding effects on large preovulatory follicles (Gray and Ostby, 1995
; Salisbury and Marcinkiewicz, 2002
) TCDD may, however, reduce the size and structure of mature ovaries.
The present findings in the male infants corroborate the results of Cooke et al. (1998), showing that developmental exposure to TCDD does not alter testosterone production in 2-week-old Sprague-Dawley male rats. In this study, resistance of developing testis to non-fetolethal doses of TCDD was further confirmed by unaltered gonadotropin levels and mRNA levels of StAR, 3ß-HSD1, P450scc, and P450-17
. Studies in adult male rats have not found a significant impact of TCDD on the synthesis and secretion of gonadotropins (Bookstaff et al., 1990
). Unexpectedly, the present study indicates that in 10-day-old pups and in prenatal rats (Haavisto et al., 2001
), developmental exposure to TCDD may slightly increase testicular testosterone production. In adult male rats exposed to 50 µg TCDD/kg (Ruangwises et al., 1991
) and in juvenile male rats exposed in utero and via lactation to 1 µg/kg TCDD (Roman et al., 1995
), and in mouse Leydig tumor cells (Wilker et al., 1995
), human chorionic gonadotropin (hCG)-stimulation has been shown to normalize TCDD-induced depression of testosterone levels. Therefore, the present and earlier studies in male rats (Haavisto et al., 2001
; Simanainen et al., 2004
) suggest that adverse effects reported in adult male sex accessory organs and epididymal sperm numbers may more likely be associated with changes in androgen receptormediated signaling pathways than with altered testosterone production in the developing testis. Undoubtedly, acute high-dose toxic effects of TCDD comprise testicular atrophy and altered levels of steroid-metabolizing enzymes, like P450scc (Moore et al., 1991
).
The present results of the ovarian mRNA levels of StAR and steroidogenic enzymes correlate well with the reported postnatal steroidogenic profile characterized by high estradiol and FSH levels and relatively low LH levels in intact female offspring (Döhler and Wuttke, 1975; Herath et al., 2001
). A significant rise in FSH levels between PND 10 and PND 20 is considered crucial for the induction of the growth of the primary and secondary follicle pools and cyclicity of female reproductive functions (Arendsen de Wolff-Exalto, 1982
). A concomitant peak in plasma FSH and E2 levels in 14- to 15- day-old female rats (Herath et al., 2001
) possibly results from nonfunctional inhibin regulation of FSH (Rivier and Vale, 1987
) and a weakly developed estrogen-dependent negative feedback system (Kawagoe and Hiroi, 1983
). The observed TCDD-induced increase in infant female FSH levels has a potential link to the attenuated and developmentally premature gonadotropin release and ovulation failures described in TCDD-exposed female rats (Gray and Ostby, 1995
; Gao et al., 2001
; Li et al., 1995a
; Salisbury and Marcinkiewicz, 2002
). In immature female rats, TCDD has been shown to directly affect the hypothalamo-pituitary axis by causing too early, i.e., premature, release of FSH and LH (Li et al., 1995a
; Petroff et al., 2003
). The mechanisms of TCDD-induced stimulation of gonadotropin release, however, have remained unresolved.
The observed decline in circulating estradiol levels in TCDD-exposed females is in line with the findings from other laboratories (Chaffin et al., 1996, 1997
; Salisbury and Marcinkiewicz, 2002
). The decrease in infant plasma estradiol levels in the presence of elevated FSH levels proposes ovarian-specific effects of TCDD. Stimulation of estradiol production in juvenile gonadotropin-primed female rats exposed to 1060 µg/kg TCDD (Gao et al., 2001
; Li et al., 1995a
; Mizuyachi et al., 2002
) suggests that the gonadotropin responsiveness of the developing ovary is relatively resistant to TCDD-induced changes.
The decrease in StAR mRNA, coding the protein needed to deliver cholesterol onto the inner mitochondrial membrane (Clark et al., 1994), was significant in 14-day-old females exposed to 0.2 µg TCDD/kg. The mechanism(s) of the putative downregulation of StAR transcripts by TCDD are not known. In the in vitro transfection assay, ligand-activated AhR has been shown to alter human StAR gene promoter activity (Sugawara et al., 2001
).
A significant decrease in mRNA coding for P450scc, an enzyme catalyzing cholesterol side chain cleavage, was observed in 16-day-old females at 1.0 µg/kg TCDD. Like StAR (Mizutani et al., 1997; Ronen-Fuhrmann et al., 1998
), P450scc is dominantly present in the infant rat theca cells and is upregulated in granulosa cells after gonadotropin stimulation (Ronen-Fuhrmann et al., 1998
). The reported interference with P450scc activity in rat granulosa cells (Dasmahapatra et al., 2000
) and in mouse (Fukuzawa et al., 2004
) and rat testis (Kleeman et al., 1990
) has raised cholesterol metabolism as a putative target of TCDD's steroidogenic action. However, in the present females the sporadic depression of P450scc mRNA levels apparently is not severe enough to interfere with pregnenolone formation. Progesterone levels remained at the control level, as did the mRNA levels of 3ß-HSD1. In cultured human lutenized granulosa cells, lyase activity has been considered one of the main targets of TCDD action (Morán et al., 2000
). However, because if considerable variation in physiological status, direct mechanistic cause-and-effect comparisons of TCDD-induced effects in prepubertal, preovulatory, ovulatory, and post-ovulatory follicles or isolated follicle cells may not be feasible. In adult rat ovarian thecal cell and granulosa cell cultures, for instance, TCDD stimulates steroid hormone synthesis in thecal cells, whereas in granulosa-thecal cell co-cultures the effect is inhibitory (Grochowalski et al., 2001
).
The cytochrome P-450 aromatase enzyme is the rate-limiting and FSH-dependent factor in estradiol synthesis. The results of the present study indicate that the levels of P450arom mRNA correlate well with low aromatase activity shown in the infant rat testes and with the relatively high peak enzyme activity values described also earlier in 10- to 16-day-old postnatal ovaries (George and Ojeda, 1987). In the TCDD-exposed 14-day-old female progeny, P450arom mRNA levels were significantly decreased at the 0.2 µg/kg dose, as was the enzyme activity at the 1.0 µg/kg dose of TCDD. Thus, aromatase gene expression seems to be a sensitive target of TCDD action. In cultured prepubertal and adult rat granulosa cells TCDD-induced elevation of CYP1A1 mRNA has been shown to parallel with a significant reduction in FSH-induced P450arom mRNA levels (Dasmahapatra et al., 2000
). Binding sites for AhR have also been indicated in P450arom (cyp19) genes of various species (Tong et al., 2003). In human luteinizing granulosa cells, however, reduced estradiol production apparently is not due to altered aromatase enzyme production or enzyme activity (Heimler et al., 1998
; Morán et al., 2000
, 2003
).
In summary, the present results propose that developmental exposure to TCDD exerts its most severe changes in infant female FSH secretion and ovarian estradiol synthesis, whereas testicular steroidogenesis and male gonadotropin secretion are relatively resistant to reproductive toxicity of TCDD. Further studies are needed to resolve the pituitary-gonadal effects of TCDD in developing female offspring. Among female steroidogenic enzymes, P450arom apparently is one of the most sensitive targets of TCDD-induced toxicity.
![]() |
NOTES |
---|
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Beatty, P. W., Vaughn, W. K., and Neal, R. A. (1978). Effect of alteration of rat hepatic mixed-function oxidase (MFO) activity on the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol. Appl. Pharmacol. 45, 513519.[CrossRef][ISI][Medline]
Birnbaum, L. S. (1995). Developmental effects of dioxins and related endocrine disrupting chemicals. Toxicol. Lett. 8283, 743750.[CrossRef]
Bjerke, D. L., and Peterson, R. E. (1994). Reproductive toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male rats: Different effects of in utero versus lactational exposure. Toxicol. Appl. Pharmacol. 127, 241249.[CrossRef][ISI][Medline]
Bookstaff, R. C., Moore, R. W., Peterson, R. E. (1990). 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases the potency of androgens and estrogens as feedback inhibitors of luteinizing hormone secretion in male rats. Toxicol. Appl. Pharmacol. 104, 212224.[CrossRef][ISI][Medline]
Chaffin, C. L., Peterson, R. E., and Hutz, R. J. (1996). In utero and lactational exposure of female Holtzman rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin: modulation of the estrogen signal. Biol. Reprod. 55, 6267.[Abstract]
Chaffin, C. L., Trewin, A. L., Watanabe, G., Taya, K., and Hutz, R. J. (1997). Alterations to the pituitary-gonadal axis in the peripubertal female rat exposed in utero and through lactation to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biol. Reprod. 56, 14981502.[Abstract]
Chen, C. Y., Hamm, J. T., Hass, J. R., and Birnbaum, L. S. (2001). Disposition of polychlorinated dibenzo-p-dioxins, dibenzofurans, and non-ortho polychlorinated biphenyls in pregnant Long-Evans rats and the transfer to offspring. Toxicol. Appl. Pharmacol. 173, 6588.[CrossRef][ISI][Medline]
Clark, B. J., Wells, J., King, S. R., and Stocco, D. M. (1994). The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J. Biol. Chem. 269, 2831428322.
Cooke, G. M., Price, C. A., and Oko, R. J. (1998). Effects of in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on serum androgens and steroidogenic enzyme activities in the male rat reproductive tract. J. Steroid Biochem. Mol. Biol. 67, 347354.[CrossRef][ISI][Medline]
Dasmahapatra, A. K., Wimpee, B. A., Trewin, A. L., Wimpee, C. F., Ghorai, J. K., and Hutz, R. J. (2000). Demonstration of 2,3,7,8-tetrachlorodibenzo-p-dioxin attenuation of P450 steroidogenic enzyme mRNAs in rat granulosa cell in vitro by competitive reverse transcriptase-polymerase chain reaction assay. Mol. Cell. Endocrinol. 164, 518.[CrossRef][ISI][Medline]
Döhler, K. D., Gartner, K., von zur, Muhler, A., and Dohler, U. (1977). Pituitary luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin from birth to puberty in female and male rats. Acta Endocrinol. (Copenh.) 85, 718728.[Medline]
Döhler, K. D., and Wuttke, W. (1975). Changes with age in levels of serum gonadotropins, prolactin and gonadal steroids in prepubertal male and female rats. Endocrinology 97, 898907.[Abstract]
El Gehani, F., Zhang, F. P., Pakarinen, P., Rannikko, A., and Huhtaniemi, I. (1998). Gonadotropin-independent regulation of steroidogenesis in the fetal rat testis. Biol. Reprod. 58, 116123.[Abstract]
Flaws, J. A., Sommer, R. J., Silbergeld, E. K., Peterson, R. E., and Hirshfield, A. N. (1997). In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces genital dysmorphogenesis in the female rat. Toxicol. Appl. Pharmacol. 147, 351362.[CrossRef][ISI][Medline]
Fukuzawa, N. H., Ohsako, S., Wu, Q., Sakaue, M., Fujii-Kuriyama, Y., Baba, T., and Tohyama, C. (2004). Testicular cytochrome P450scc and LHR as possible targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the mouse. Mol. Cell Endocrinol. 221, 8796.[CrossRef][ISI][Medline]
Gao, X., Mizuyachi, K., Terranova, P. F., and Rozman, K. K. (2001). 2,3,7,8-Tetrachlorodibenzo-p-dioxin decreases responsiveness of the hypothalamus to estradiol as a feedback inducer of preovulatory gonadotropin secretion in the immature gonadotropin-primed rat. Toxicol. Appl. Pharmacol. 170, 181190.[CrossRef][ISI][Medline]
George, F. W., and Ojeda, S. R. (1987). Vasoactive intestinal peptide enhances aromatase activity in the neonatal rat ovary before development of primary follicles or responsiveness to follicle-stimulating hormone. Proc. Natl. Acad. Sci. U. S. A. 84, 58035807.
Gray, L. E., Kelce, W. R., Monosson, E., Ostby, J. S., and Birnbaum, L. S. (1995). Exposure to TCDD during development permanently alters reproductive function in male Long-Evans rats and hamsters: Reduced ejaculated and epididymal sperm numbers and sex accessory gland weights in offspring with normal androgenic status. Toxicol. Appl. Pharmacol. 131, 108118.[CrossRef][ISI][Medline]
Gray, L. E., and Ostby, J. S. (1995). In utero 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters reproductive morphology and function in female rat offspring. Toxicol. Appl. Pharmacol. 133, 285294.[CrossRef][ISI][Medline]
Gray, L. E., Ostby, J. S., and Kelce, W. R. (1997a). A doseresponse analysis of the reproductive effects of a single gestational dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male Long-Evans hooded rat offspring. Toxicol. Appl. Pharmacol. 146, 1120.[CrossRef][ISI][Medline]
Gray, L. E., Wolf, C., Mann, P., and Ostby, J. S. (1997b). In utero exposure to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin alters reproductive development of female Long Evans hooded rat offspring. Toxicol. Appl. Pharmacol. 146, 237244.[CrossRef][ISI][Medline]
Grochowalski, A., Chrzaszcz, R., Pieklo, R., and Gregoraszczuk, E. L. (2001). Estrogenic and antiestrogenic effect of in vitro treatment of follicular cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Chemosphere 43, 823827.[CrossRef][ISI][Medline]
Haavisto, T. E., Myllymäki, S. A., Adamsson, N. A., Brokken, L. J. S., Viluksela, M., Toppari, J., and Paranko, J. (2005). The Effects of Maternal Exposure to 2,3,7,8-Tetrachlorodibenzo/-p-/dioxin (TCDD) on Testicular Steroidogenesis in Infantile Male Rats. Int. J. Androl., in press.
Haavisto, T., Nurmela, K., Pohjanvirta, R., Huuskonen, H., El Gehani, F., and Paranko, J. (2001). Prenatal testosterone and luteinizing hormone levels in male rats exposed during pregnancy to 2,3,7,8-tetrachlorodibenzo-p-dioxin and diethylstilbestrol. Mol. Cell. Endocrinol. 178, 169179.[CrossRef][ISI][Medline]
Habert, R., and Picon, R. (1984). Testosterone, dihydrotestosterone and estradiol-17 beta levels in maternal and fetal plasma and in fetal testes in the rat. J. Steroid Biochem. 21, 193198.[CrossRef][ISI][Medline]
Heimler, I., Trewin, A. L., Chaffin, C. L., Rawlins, R. G., and Hutz, R. J. (1998). Modulation of ovarian follicle maturation and effects on apoptotic cell death in holtzman rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) in utero and lactationally. Reprod. Toxicol. 12, 6973.[CrossRef][ISI][Medline]
Herath, C. B., Watanabe, G., Katsuda, S., Yoshida, M., Suzuki, A. K., and Taya, K. (2001). Exposure of neonatal female rats to p-tert-octylphenol disrupts afternoon surges of luteinizing hormone, follicle-stimulating hormone and prolactin secretion, and interferes with sexual receptive behavior in adulthood. Biol. Reprod. 64, 12161224.
Huang, P., Rannug, A., Ahlbom, E., Håkansson, H., and Ceccatelli, S. (2000). Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the expression of cytochrome P450 1A1, the aryl hydrocarbon receptor, and the aryl hydrocarbon receptor nuclear translocator in rat brain and pituitary. Toxicol. Appl. Pharmacol. 169, 159167.[CrossRef][ISI][Medline]
Kawagoe, S., and Hiroi, M. (1983). Maturation of negative and positive estrogen feedback in the prepubertal female rat. Endocrinol. Jpn. 30, 435441.[Medline]
Khorram, O., Garthwaite, M., and Golos, T. (2002). Uterine and ovarian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) mRNA expression in benign and malignant gynaecological conditions. Mol. Hum. Reprod. 8, 7580.
Kleeman, J. M., Moore, R. W., and Peterson, R. E. (1990). Inhibition of testicular steroidogenesis in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats: Evidence that the key lesion occurs prior to or during pregnenolone formation. Toxicol. Appl. Pharmacol. 106, 112125.[CrossRef][ISI][Medline]
Lephart, E. D., and Simpson, E. R. (1991). Assay of aromatase activity, Methods Enzymol. 206, 477483.[ISI][Medline]
Li, X. L., Johnson, D. C., and Rozman, K. K. (1995a). Reproductive Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in female rats: Ovulation, hormonal regulation, and possible mechanism(s). Toxicol. Appl. Pharmacol. 133, 321327.[CrossRef][ISI][Medline]
Li, X., Weber, L. W. D., and Rozman, K. K. (1995b). Toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats including placental and lactational transfer to fetuses and neonates. Fundam. Appl. Toxicol. 27, 7076.[CrossRef][ISI][Medline]
Mably, T. A., Moore, R. W., and Peterson, R. E. (1992a). In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1. Effects on androgenic status. Toxicol. Appl. Pharmacol. 114, 97107.[CrossRef][ISI][Medline]
Mably, T. A., Bjerke, D. L., Moore, R. W., Gendron-Fitzpatrick, A., and Peterson, R. E. (1992b). In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 3. Effects on spermatogenesis and reproductive capability. Toxicol. Appl. Pharmacol. 114, 118126.[CrossRef][ISI][Medline]
Mebus, C. A., Reddy, V. R., and Piper, W. N. (1987). Depression of rat testicular 17-hydroxylase and 17,20-lyase after administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Biochem. Pharmacol. 36, 727731.[CrossRef][ISI][Medline]
Mizutani, T., Sonoda, Y., Minegishi, T., Wakabayashi, K., and Miyamoto, K. (1997). Molecular cloning, characterization and cellular distribution of rat steroidogenic acute regulatory protein (StAR) in the ovary. Life Sci. 61, 14971506.[CrossRef][ISI][Medline]
Mizuyachi, K., Son, D. S., Rozman, K. K., and Terranova, P. F. (2002). Alteration in ovarian gene expression in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin: Reduction of cyclooxygenase-2 in the blockage of ovulation. Reprod. Toxicol. 16, 299307.[CrossRef][ISI][Medline]
Moore, R. W., Jefcoate, C. R., and Peterson, R. E. (1991). 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits steroidogenesis in the rat testis by inhibiting the mobilization of cholesterol to cytochrome P450scc. Toxicol. Appl. Pharmacol. 109, 8597.[CrossRef][ISI][Medline]
Morán, F. M., Conley, A. J., Corbin, C. J., Enan, E., VandeVoort, C., Overstreet, J. W., and Lasley, B. L. (2000). 2,3,7,8-Tetrachlorodibenzo-p-dioxin decreases estradiol production without altering the enzyme activity of cytochrome P450 aromatase of human luteinized granulosa cells in vitro. Biol. Reprod. 62, 11021108.
Morán, F. M., VandeVoort, C. A., Overstreet, J. W., Lasley, B. L., and Conley, A. J. (2003). Molecular target of endocrine disruption in human luteinizing granulosa cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin: Inhibition of estradiol secretion due to decreased 17-hydroxylase/17,20-lyase cytochrome P450 expression. Endocrinology 144, 467473.
Myllymäki, S., Haavisto, T., Vainio, M., Toppari, J., and Paranko, J. (2005). In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles. Toxicol. Appl. Pharmacol. 204, 6980.[CrossRef][ISI][Medline]
Petroff, B. K., Croutch, C. R., Hunter, D. M., Wierman, M. E., and Gao, X. (2003). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) stimulates gonadotropin secretion in the immature female Sprague-Dawley rat through a pentobarbital- and estradiol-sensitive mechanism but does not alter gonadotropin-releasing hormone (GnRH) secretion by immortalized GnRH neurons in vitro. Biol. Reprod. 68, 21002106.
Pohjanvirta, R., and Tuomisto, J. (1994). Short-term toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals: Effects, mechanisms, and animal models. Pharmacol. Rev. 46, 483549.
Rivier, C., and Vale, W. (1987). Inhibin: Measurement and role in the immature female rat. Endocrinology 120, 16881690.[Abstract]
Roman, B. L., Sommer, R. J., Shinomiya, K., and Peterson, R. E. (1995). In utero and lactational exposure of the male rat to 2,3,7,8-tetrachlorodibenzo-p-dioxin: Impaired prostate growth and development without inhibited androgen production. Toxicol. Appl. Pharmacol. 134, 241250.[CrossRef][ISI][Medline]
Ronen-Fuhrmann, T., Timberg, R., King, S. R., Hales, K. H., Hales, D. B., Stocco, D. M., and Orly, J. (1998). Spatio-temporal expression patterns of steroidogenic acute regulatory protein (StAR) during follicular development in the rat ovary. Endocrinology 139, 303315.
Ruangwises, S., Bestervelt, L. L., Piper, D. W., Nolan, C. J., and Piper, W. N. (1991). Human chorionic gonadotropin treatment prevents depressed 17 alpha-hydroxylase/C17-20 lyase activities and serum testosterone concentrations in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats. Biol. Reprod. 45, 143150.
Rune, G. M., de Souza, P., Krowke, R., Merker, H. J., and Neubert, D. (1991). Morphological and histochemical pattern of response in rat testes after administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Histol. Histopathol. 6, 459467.[ISI][Medline]
Salisbury, T. B., and Marcinkiewicz, J. L. (2002). In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,4,7,8-pentachlorodibenzofuran reduces growth and disrupts reproductive parameters in female rats. Biol. Reprod. 66, 16211626.
Schultz, R., Suominen, J., Varre, T., Hakovirta, H., Parvinen, M., Toppari, J., and Pelto-Huikko, M. (2003). Expression of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator messenger ribonucleic acids and proteins in rat and human testis. Endocrinology 144, 767776.
Simanainen, U., Haavisto, T., Tuomisto, J. T., Paranko, J., Toppari, J., Tuomisto, J., Peterson, R. E., and Viluksela, M. (2004). Pattern of male reproductive system effects after in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in three differentially TCDD-sensitive rat lines. Toxicol. Sci. 80, 101108.
Sotnichenko, A. I., Severin, S. E., Posypanova, G. A., Feldman, N. B., Grigor'ev, M. I., Severin, E. S., and Petrov, R. V. (1999). Water-soluble 2,3,7,8-tetrachlorodibenzo-p-dioxin complex with human alpha-fetoprotein: Properties, toxicity in vivo and antitumor activity in vitro. FEBS Lett. 450, 4950.[CrossRef][ISI][Medline]
Sugawara, T., Nomura, E., Sakuragi, N., and Fujimoto, S. (2001). The effect of the arylhydrocarbon receptor on the human steroidogenic acute regulatory gene promoter activity. J. Steroid Biochem. Mol. Biol. 78, 253260.[CrossRef][ISI][Medline]
Theobald, H. M., Roman, B. L., Lin, T. M., Ohtani, S., Chen, S. W., and Peterson, R. E. (2000). 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits luminal cell differentiation and androgen responsiveness of the ventral prostate without inhibiting prostatic 5alpha-dihydrotestosterone formation or testicular androgen production in rat offspring. Toxicol. Sci. 58, 324338.
Tong, S. K., and Chung, B. C. (2003). Analysis of zebrafish cyp19 promoters. J. Steroid Biochem. Mol. Biol. 86, 381386.[CrossRef][ISI][Medline]
Wilker, C., Johnson, L., and Safe, S. (1996). Effects of developmental exposure to indole-3-carbinol or 2,3,7,8-tetrachlorodibenzo-p-dioxin on reproductive potential of male rat offspring. Toxicol. Appl. Pharmacol. 141, 6875.[CrossRef][ISI][Medline]
Wilker, C. E., Welsh, J., Safe, S. H., Narasimhan, T. R., and Johnson, L. (1995). Human chorionic gonadotropin protects Leydig cell function against 2,3,7,8-tetrachlorodibenzo-p-dioxin in adult rats: Role of Leydig cell cytoplasmic volume. Toxicology 95, 93102.[CrossRef][ISI][Medline]
|