* Environmental and Occupational Toxicology Division, Health Protection Branch, Department of Health, Ottawa, Ontario, Canada; and
Department of Obstetrics and Gynecology and
Center for Women's Health, Cedars-Sinai Medical Center, Los Angeles, California 90048
Received February 4, 2000; accepted April 11, 2000
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ABSTRACT |
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Key Words: endometriosis; cynomolgus monkey; toxicology; laparoscopy; 2,3,7,8-tetrachlorodibenzo-p-dioxin; interleukin-6; interleukin-6sR..
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INTRODUCTION |
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Chemical contaminants have been inculpated in the pathobiology of endometriosis as a result of a series of animal and epidemiology studies. The notion that environmental contaminants are involved in the pathophysiology of endometriosis gained momentum with the demonstration (Rier et al., 1993) that the incidence and severity of spontaneous endometriosis was increased in rhesus monkeys following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD is a ubiquitous contaminant produced during the manufacture of chlorophenols and phenoxy herbicides (Firestone et al., 1972
; Lilienfield and Gallo., 1989
), waste incineration (Alexandrou and Pawliszyn, 1989
; Rappe et al., 1979
) and the bleaching of pulp for paper (EPA, 1987
). The mean adipose tissue level for the American population has been reported (Orban et al., 1994
; Schecter et al., 1994a
,b
) to be between 5.2 and 5.4 ng/kg. Adipose tissue levels in individuals exposed, either through the workplace or as a result of accidental exposure, range between 10 and 141 ng/kg (Schecter et al., 1994b
). In women with both endometriosis and measurable levels of TCDD in whole blood, the non-lipid-adjusted concentration of TCDD was between 0.7 and 1.2 ng/kg (Mayani et al., 1997
). Two epidemiology studies (Gerhard and Runnebaum, 1992
; Mayani et al., 1997
) suggest a potential positive association between endometriosis and exposure to environmental contaminants while others have been unable to find a positive association (Boyd et al., 1995
; Lebel et al., 1998
). Hence, the human data neither confirm nor refute the hypothesis that environmental contaminants play a role in the pathobiology of endometriosis. Consequently, the role of TCDD in the pathophysiology of endometriosis remains highly controversial.
The objective of this study was to test the hypothesis that subchronic exposure to TCDD facilitates the survival and growth of surgically induced endometriosis in monkeys. The dose levels used in the current study (1, 5, and 25 ng/kg, 5 days/week) were selected so as to be comparable with those of a previous study in rhesus monkeys (Rier et al., 1993). Finally, surgical induction of endometriosis was employed in the present study since prior studies (Fanton and Golden, 1991
; Rier et al., 1993
) have shown that the development of spontaneous endometriosis in the monkey, induced by either TCDD or radiation exposure, involves a substantial time delay of between 6 and 7 years.
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MATERIALS AND METHODS |
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Monkeys were randomly assigned to 1 of 4 treatment groups, control (n = 5), 1, 5, and 25-ng/kg TCDD (n = 6, each). Doses were prepared for each animal by emulsifying TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, Lot number 129404, AccuStandard, New Haven, CT., purity > 99%) in saline and a 20 % Tween solution (Bio-Rad Laboratories, Mississauga, ON.) at a concentration of 1000 µg/ml TCDD, thus forming a stock emulsion. Serial dilutions were prepared and TCDD was added to glucose-filled capsules to yield appropriate doses for each animal, based on their monthly body weight. Animals assigned to the control group received gelatin capsules containing glucose only. The monkeys received 1 capsule 5 days per week, and hence, the actual delivered doses were 0.71, 3.57, and 17.86 ng/kg/day, respectively.
All monkeys were housed in individual cages in light- and temperature-controlled rooms with lights on 6:00 A.M. to 6:00 P.M., with a temperature of 2022°C. Access to food (Purina monkey chow; Ralston-Purina, St. Louis, MO) and water was on an ad libitum basis. The diets were supplemented with fruits and vegetables. All animal husbandry practices and experimental procedures were reviewed and approved by the Institutional Animal Care and Use Committee of the Health Protection Branch and followed the guidelines of the Canadian Council of Animal Care.
The experimental design is summarized in Figure 1. Briefly, menstrual cycle characteristics were monitored daily to insure that all animals were cycling normally before and throughout the study. Time zero was assigned to the month in which endometriosis was induced by auto-transplantation of endometrial strips, and TCDD treatment was initiated the morning after surgical induction of endometriosis. Laparoscopies were performed in all groups at 1, 3, and 6 months to monitor the survival of endometrial implants and to obtain peritoneal fluid for determination of interleukin-6 (IL-6) and interleukin-6 soluble receptor (IL-6sR) concentrations and immunotyping. However, the amount of peritoneal fluid present in our monkeys was insufficient for assay purposes. Therefore, the peritoneal cavity was flushed with 150 ml of body temperature isotonic saline; 10 min later, the fluid was collected for flow cytometric analyses (data not shown). Blood was collected at the time of laparoscopies for routine hematology and at 6 and 12 months for assessment of circulating levels of the endometrial growth regulatory cytokine IL-6 and IL-6sR. Serum gonadal steroid levels were determined at the time of necropsy. All monkeys were euthanized at 12 months of treatment in the early to mid luteal phase to minimize the influence of menstrual cycle on circulating gonadal steroid levels.
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Induction of Endometriosis
Endometriosis was induced on days 1214 of the menstrual cycle by auto-transplantation of endometrial strips to multiple abdominal sites. This time interval was selected because the endometrium in these animals has achieved maximal thickness by this stage of the menstrual cycle. Briefly, a mid-line abdominal incision was made, the uterus was exposed, and an anterior-vertical fundal hysterotomy made. The endometrium was dissected from the myometrium on both sides of the hysterotomy incision site only. Endometrial strips were removed and placed in warm sterile saline and the uterus was closed.
The endometrial strips were cut into 6 small pieces of equal size (4 x 1 mm2). Five of the 6 endometrial explants were auto-transplanted with a single 80 nylon micro-suture stitch (Ethicon Inc., Johnson and Johnson Co., Somerville, NJ) to 5 sites: the uterine fundus (UF), left and right ovary (LO and RO), and the posterior surface of the left and right broad ligament (LBL and RBL). These sites were chosen on the basis that in the human, the most frequent locations of endometriosis are the ovary and Douglas's pouch. During surgical induction of endometriosis, one uterine strip from each monkey was immediately preserved in 10% buffered formalin and processed for histology to verify the presence of endometrial tissues. The abdomen was closed and the animals were allowed to recover.
Laparoscopy
A pneumoperitoneum was created in the anesthetized monkey and a pediatric laparoscope (Wolf, Germany) was inserted through the trocar sheath (Wolf, Germany) which was connected to a video camera (OTV-S2 Olympus Camera, AR-TF2, Japan). A laparoscopy was performed at 1, 3, and 6 months to evaluate the survival of endometrial implants. Blood was collected for hematology at each laparoscopy. No measurements of implant size were made at this time.
Necropsy
Monkeys were euthanized in the early to mid luteal phase of the cycle in all cases, with the exception of 4 acyclic monkeys (one each from control and the low-dose group and 2 from the moderate-dose group). Euthanasia was achieved by a 2.0-ml intravenous injection of pentobarbitol (240 mg/ml Euthanyl, M.T.C. Pharmaceuticals, Cambridge, Ont.), exsanguination and perfusion fixation with 10% buffered formalin. Endometrial implants were examined in situ and photographed, before being dissected free of surrounding tissue. Vernier calipers were used to obtain both a maximum and minimum diameter (recorded to the nearest 0.5 mm) for each implant. All surviving endometrial implants were placed in fresh fixative and processed for routine histology. Tissues collected for histology were processed through a graded series of alcohol and xylene solutions and embedded in paraffin. Four- to 5-ml thick representative sections were collected and stained with hematoxylin and eosin for histological analysis.
Concentration of Interleukin-6 (IL-6) and Interleukin-6 Soluble Receptor (IL-6 sR) in the Sera
Since IL-6 is a growth regulatory cytokine for the endometrium, and dysregulation of this system has been demonstrated in women with endometriosis (Rier et al., 1995a), we elected to explore the effect of TCDD treatment on circulating levels of IL-6 and IL-6sR. The concentrations of IL-6 and IL-6sR were quantified in the sera obtained at 6 and 12 months after starting exposure to TCDD, using commercially available sandwich enzyme immunoassays for the human (Quantikine IL-6 and IL-6sR ELISAs, R&D Systems, Minneapolis, MN). The detection limits of these assays were 0.7 pg/mL for IL-6, and 7 pg/mL for IL-6sR, and all samples were assayed on the same day. The intra-assay coefficients of variation were less than 9% and 11%, respectively.
Circulating Levels of Estradiol (E2) and Progesterone (P4)
Circulating levels of E2 and P4 were determined using commercial double antibody radioimmunoassay kits (DPC Los Angeles, CA.). The detection limit was 1.4 pg/mL for E2 and 1.2 ng/mL for P4. All samples were assayed on the same day and the intra-assay coefficients of variation were less than 7% and 9%, respectively.
Data Analysis
All surgical and analytical procedures were conducted with the treatment group of each animal or tissue unknown to the evaluator and technician. Effect of TCDD on survival of endometrial implants over time was evaluated by repeated measures ANOVA. Treatment effects on implant diameter, serum hormones, IL-6 and IL-6sR were examined for using 1-way analysis of variance (ANOVA). Within-group comparisons were tested for by the Student-Newman-Keuls method for multiple comparisons. All calculations were done with Sigma Stat software (Jandel Scientific, San Rafael, CA). Differences were considered significant at the p < 0.05 level.
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RESULTS |
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Follow-up laparoscopies revealed that there was a continuous loss of endometrial implant over time in each dose group. At 1, 3, and 6 months of study, the decrease in the number of surviving endometrial implants was not significantly different among the various dose groups, until 12 months of study, when a significantly higher rate of survival of endometrial implants was observed in the 3.57 and 17.86-ng/kg/day dose groups compared to that of controls (Fig. 2). No significant difference was found between the 0.71 ng/kg/day dose group and animals of the control group. At 12 months after surgical induction of endometriosis, regardless of dose level, the highest survival rate of endometrial implants was found on the ovaries. All lesions disappeared from the left broad ligament, whereas 2 on the right broad ligament and one on the uterine fundus survived.
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DISCUSSION |
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Surgical induction of endometriosis was employed as a model in this study. The laparoscopic and histological examination of the lesions revealed that the endometriotic implants were similar in appearance to endometriosis found in humans (Ueki et al., 1995) and that the success rate of endometriosis induction is in agreement with previous reports (Canis et al., 1995
; Mann et al., 1986
). Histologic examination of implants demonstrated the presence of endometrial glands and stroma in all of the sections from all animals.
Laparoscopies revealed a continuous trend of endometrial implant resorption over the course of study, in each dose group. The ovaries, in contrast to other anatomical implant sites, favored endometrial implant survival at all time points during the study. The site variation of survival rates of endometriotic implants may be due to various factors such as access to blood supply, the hormonal milieu, as well as the local action of growth factors and cytokines. Spontaneous disappearance of surgically induced endometriosis has previously been documented, even in the presence of endogenous steroids (Canis et al., 1995; Mann et al., 1986
). Our data suggest that TCDD, at a dose level of 3.57 and 17.86 ng/kg/day, acts to facilitate the survival and growth of endometrial implants. We were surprised to discover that the low dose of TCDD (0.17 ng/kg/day) was inhibitory, as shown by a decrease in both the maximum and minimum implant diameters when compared to controls, whereas, a dose of TCDD representative of occupational or accidental exposure induced an increase in lesion diameters when compared to the control group. The inhibitory effect of the low dose of TCDD on implant growth is supported by the histological appearance of these implants, which were cystic, with a limited amount of surviving stroma, no surviving glands, and fibrotic changes. Our results appear to both confirm and extend, as well as to contradict an earlier report in which TCDD was shown to induce a dose-dependent increase in the incidence and severity of endometriosis in rhesus monkeys, using exposures of 5 and 25 ng/kg/day (Rier et al., 1993
). Divergence of our findings from those of Rier and colleagues (1993) may reflect differences in the doses of TCDD used. Specifically, inhibitory effects of TCDD were found only in the 0.71-ng/kg/day-dose group of the present study, a dose not used in the prior study (Rier et al, 1993
). Both the 3.57 and 17.86 ng/kg/day of the TCDD dose groups facilitated the survival of the implants, whereas only the 17.86-ng/kg/day-TCDD dose induced an increase in the maximum and minimum diameters of endometriotic implants, which extends the findings in the rhesus monkey (Rier et al., 1993
).
The mechanism(s) of TCDD action on endometrial implants are unknown. TCDD is widely recognized as an anti-estrogen, as shown by decreased circulating levels of gonadal steroids in monkeys (Barsotti et al., 1979) and decreased concentrations of the estrogen (DeVito et al., 1994
) and epidermal growth factor receptors in rodents (Madhukar et al., 1984
). However, no effect of TCDD on the expression of hepatic and uterine estrogen receptors has also been reported in mice (DeVito et al., 1992
). Furthermore, the dose level required to induce suppression of gonadal steroids (500 ppt for 6 months, Barsotti et al, 1979) was far in excess of the dose used in the present study. Since there was no effect of treatments in the present study on the circulating levels of either E2 or P4 we propose that in all dose groups the ectopic endometrial implants received a similar exposure to these steroids. However, since a TCDD-induced decrease in estrogen-receptor expression or post-receptor signaling in ectopic endometrium was not studied, such an effect of TCDD cannot be excluded.
TCDD is an immunosuppressive compound in mice, as demonstrated by decreased T-lymphocyte activity (Hill, 1992; House et al., 1990
; Mann et al, 1986
; Rier et al., 1995b
). Although TCDD is without effect on macrophage and NK-cell activity (House et al., 1990
), it does adversely affect leukocyte production of cytokines known to participate in the regulation of uterine physiology (Taylor et al., 1990
; Hoglen et al., 1992
). Furthermore, peritoneal leukocytes are reported to be in an activated state in women with endometriosis compared to women without endometriosis (Hill, 1988). Therefore, we speculate that TCDD treatment (3.57 and 17.86 ng/kg/day) in the current study enhanced the survival of endometriotic implants through effects upon peritoneal leukocytes and endometrial stromal cells. Increased peritoneal fluid levels of tumor necrosis factor-alpha (TNF-
) and interleukin-1 (IL-1) have been demonstrated in women with endometriosis relative to women without endometriosis (Eisermann et al., 1988
; Taketani et al., 1992
). IL-1ß is a target gene for TCDD (Sutter et al., 1991
) whereas TNF-
sensitizes and activates phagocytic cells (Tabibzadeh, 1991
; Tabibzadeh et al., 1989
) as well as inducing the production of IL-6 by endometrial stromal cells (Alsarif et al., 1994
). IL-6 is a growth factor derived from multiple cell types including leukocytes, fibroblasts, keratinocytes, endothelial cells (Van Snick, 1990
) and endometrial stromal cells (Rier et al., 1995a
). IL-6 is involved in the mediation of inflammatory responses and remodeling of the endometrium where it is growth inhibitory for normal uterine endometrial stromal cells (Rier et al., 1995a
; Tabibzadeh et al., 1989
). In the present study, increased levels of IL-6 and suppressed levels for IL-6sR in the sera of the animals that received 17.86 ng/kg/day of TCDD suggest a possible role of this cytokine in the pathophysiology of endometriosis. The peritoneal fluid levels of the endometrial growth regulatory cytokine IL-6 and production of interleukin-6-soluble receptor (IL-6sR) by endometrial stromal cells were shown to be elevated and suppressed, respectively, in women with endometriosis compared to a control group of women without endometriosis (Rier et al., 1995a
). Peritoneal fluid levels in cynomolgus monkeys were found to be insufficient for our assay requirements. Hence peripheral blood, although remote to the site of the endometrial implants, was collected for these determinations. Our results demonstrate that the mechanisms regulating the production and interaction of IL-6 and its receptor IL-6sR are affected by TCDD treatment; this would obviate the endometrial growth inhibitory effect of IL-6.
The role of man-made chemicals in the pathophysiology of endometriosis remains a controversial topic. A positive association has been described previously (Gerhard and Runnebaum, 1992; Mayani et al., 1997
) while no-association has also been described by others (Boyd et al., 1995
; Lebel et al., 1998
). Investigations in non-human primates suggest that exposure to environmental hazards such as radiation (Fanton and Golden, 1991
) or TCDD (Rier et al., 1993
) may be etiologic factors in the development of endometriosis. This study was not designed to examine the effects of TCDD as a causative factor in endometriosis but our results do support the hypothesis that TCDD facilitates the survival and, depending on exposure level, the growth of endometrial implants, and thus it may play a role in the pathobiology of this disease. The bimodal effect of TCDD on the diameter of endometrial implants may in part account for the discrepant findings in the human literature regarding a link between exposure and endometriosis.
In summary, TCDD exerts a bimodal effect on both the maximal and minimal diameter of endometriotic implants. At dose levels representative of occupational or accidental exposure, survival and growth of endometrial implants was facilitated, whereas the low dose of TCDD inhibited the growth of endometrial implants. Therefore, we conclude that TCDD, at dose levels representative of human adipose tissue levels, affects endometrial implant survival and growth.
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ACKNOWLEDGMENTS |
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NOTES |
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