ENVIRONMENTAL TOXINS AND ENDOMETRIOSIS

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ENVIRONMENTAL TOXINS AND ENDOMETRIOSIS Hulusi B. Zeyneloglu, MD, Aydin Arici, MD, and David L. Olive, MD

The pathogenesis of endometriosis is believed to be a complex series of events linking genetic predisposition, immunologic abnormalities, anatomic factors, and even environmental inputs. As the rate of diagnosis increases for this disease, attention has turned to the role of environmental factors as a stimulant for endometriosis growth and maintenance. This article considers the evidence supporting a role for such factors in the genesis of this disease. ESTROGENIC TOXICANTS

Many natural, environmental or manufactured substances exhibit estrogenic activity. The level of activity of these substances can be highly variable, ranging from 0.001 x to 1 x 17P-estradiol (EZ). Because estrogens share a common flat ring (a phenol or the functional equivalent of a phenol) and are mostly lipophilic, they can escape from metabolism and undergo bioconcentration in adipose tissues (Fig. 1). Estrogens of natural origins include not only the ovarian estrogenic steroids but also many natural products produced by plants and microorganisms. Some of these latter compounds are derived from components of normal dietary foodstuffs and have their activity enhanced by gut flora of animals and humans; others enter the diet of humans or livestock by means of contamination. Synthetic estrogens include nonsteroidal hormonal agonist and phenolic impurities found in pH From the Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut ~

OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA VOLUME 24 * NUMBER 2 JUNE 1997

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indicator dyes and phenolic components used in the fabrication of polycarbonate plastics. Many industrial chemicals, agricultural pesticides, and their metabolites also have estrogenic activity when chlorinated (Table 1). Other molecules such as methoxychlor may undergo bioactivation by metaboTable 1. ESTIMATED MASS BALANCE OF HUMAN EXPOSURES TO ENVIRONMENTAL AND DIETARY ESTROGENS AND ANTIESTROGENS

Source Estrogens Morning-after pill Oral contraceptive PostmenopausalHRT Flavanoids in foods (1.020 mg/day X 0.0001) Environmental organochlorine estrogens (2.5 x 0.000001) Antlestrogens TCDD and organochlorines (80-120 pg/day) Indolo[3,2-b]carbazole in 100 g brussel sprouts

Estrogen Equivalents (Idday) 333,500 16,675 3350 102 0.0000025

0.000080-0.00012 0.000250-0.00128

HRT = hormone replacement therapy. From Safe SH:Environmental and dietary estrogens and human health: Is there a problem? Environ Health Perspec 103:346, 1995; with permission.

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lism to phenols. Some molecules such as 0.p’-DDT (l,l,l-trichloro-2,2-

bis(p-chlorophenyl)ethane,which has low estrogenic activity, may not require such bioactivation. There are also some examples of estrogenic activity of nonaromatic compounds; these are usually of low potency (e.g., endosulfan, kepone, toxaphene). As the structural similarity of an estrogenic compound deviates from that of estradiol, estrogenic activity of the compound is frequently determined by its hydrophobic features. Chlorine substituents elevate the lipophilicity two to nine fold. Hydrophobic compounds, which are particularly resistant to metabolic degradation, persist in the environment and may undergo bioconcentration. Because of their lipophilicity, these compounds can accumulate to high levels in lipids and membranes, from which they can be released slowly to provide low, persistent levels of the compound in blood. The polychlorinated dibenzo-p-dioxins (dioxins) and polychlorinated dibenzofurans are a series of 210 individual congeners. They are tricyclic aromatic hydrocarbons with a planar configuration. None have ever been used commercially but are formed as contaminants in the production of various chlorinated compounds (eg., 2,4,5-trichlorophenoxyacetic acid and chlorinated phenols) and in different combustion pr0cesses.l The prototype of these chemicals is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), which serves as the reference compound for halogenated aromatic hydrocarbons.84Other polyhalogenated congeners with bromine or chlorine in the four lateral positions also possess dioxin-like activity (binding to the same intracellular receptor as dioxin) as do structurally related members of the polyhalogenated dibenzofurans, polychlorinated biphenyls (PCBs), naphthalenes, and azobenzenes and azoxybenzenes.92 Dioxins cause a wide variety of responses, ranging from obvious adverse effects, that is, lethality, to biochemical changes, for example, induction of drug-metabolizing enzymes. These molecules are biologically and ecologically persistent, with an estimated half-life of 7 years in humans. They possess numerous acute effects in rodents and other small animal models and have been shown to be carcinogens, teratogens, and immunotoxins in animals. There are suggestions of sex and age differences in the susceptibility to the lethal effects of dioxin, but these effects have not been clearly examined in rodents? Considerable controversy and uncertainty remains, however, concerning the toxic and carcinogenic potency of dioxin in humans and the reliability of using animal data to predict human risks. The toxicity of the environmental pollutants and their effects in general are not in the scope of this article and for this the reader is referred to other reviews.96,Io7 Environmental Exposure to TCDD and Dioxin-like Substances In the absence of potential occupational or accidental contact, the major route of human exposure to TCDD and dioxin-like substances is

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through the diet. The World Health Organization (WHO) currently recommends limiting dietary intake to 10 pg of TCDD or dioxin-like substances per kg body weight per day.”* The United States Environmental Protection Agency (EPA) suggests smaller dioxin daily uptake to be even more protective of human health. Dioxin and dioxin-like substances are released into the aquatic, atmospheric, or terrestrial environment by primary resources, which include chemical side reactions associated with the manufacture of a variety of chloroaromatic substances (e.g., the bleaching of brown pulp for white paper production) and combustion-related sources (e.g., all forms of waste incineration; many forms of metal production; fossil fuel and petroleum refinement; wood products industry and chloralkali industry; natural combustion such as volcanic eruption, forest fires, and domestic wood combustion). These substances may be distributed worldwide through the atmosphere, usually following air movement trajectories originating from industrial-urban centers where the concentrations are higher than in the rural areas or inhabited places. Because these substances are nonpolar, they exhibit low solubility in water and tend to associate with materials sharing similar properties, such as lipid droplets. Thus, municipal water supplies have demonstrated very low concentrations of TCDD, which has been attributed to the filtration that removes lipid and particulate matter.85 The fish-eating water birds of the Great Lakes have been exposed to polychlorinated hydrocarbons. These exposures have resulted in a number of adverse effects on their reproductive potential, including lethal deformities and embryo-toxicity.40The cessation of the manufacture, use, and disposal of chemicals has resulted in an increase in populations of some fish-eating water birds39;however, other adverse effects such as localized impairment of reproductive performance and anatomic defects have persisted. Large-scale industrial production of dioxin-like polychlorinated naphthalenes began during World War I. Production of these substances followed in the late 1920s (Table 2). The thermal and chemical stability of polycarbonated substances led to their widespread use in transformers, capacitors, carbonless copy paper, plasticizers, and numerous other applications. Inadvertent exposure of people to large amounts of dioxinlike compounds began at the turn of the century. Chloracne was observed during World War I following exposure to polychlorinated naphthalenes. Several of the best-known occupational exposures to dioxin occurred in the 1940s and 1950s in facilities manufacturing TCDDcontaminated herbicides. In the Yusho and Yu-Cheng incidents, people consumed rice oil contaminated with these compounds. Large populations were exposed to dioxin by the use of the herbicide Agent Orange in Southeast Asia (also including Vietnam veterans), the spreading of dioxin-contaminated wastes in Missouri (Times Beach), and the accidental explosion in a chemical plant at Seveso, Italy.

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Table 2. CHRONOLOGY OF INCIDENTS RELATED TO DIOXIN AND DIOXIN-LIKE COMPOUNDS Date

Incident

1899 1918 1920-1 940

Chloracne characterized Outbreaks of chloracne following exposure to chlorinated naphthalenes Dramatic increase of PCDD and PCDF levels in North American lake sediments (reported 1984) US commercial production of PCBs begins “X’ disease described in cattle in the United States Monsatto incident (Nitro, West Virginia) Boehringer incident BASF incident TCDD identified as unwanted contaminant in the manufacture of trichlorophenols; “Chick edema disease” outbreak in poultry in southeastern United States Agent Orange used in Southeast Asia Holmesburg prison experiments Outbreaks of reproductive and development effects noted in Great Lakes fish-eating birds Yusho “oil disease” (Japan) TCDD found to cause birth defects in mice Contamination of Times Beach and other Missouri sites Ah receptor hypothesis developed Polybrominated biphenyls accidentally added to cattle feed in Michigan TCDD detected in human breast milk from south Vietnam Accident in Seveso, Italy US commercial production of PCBs halted TCDD found to cause cancer in rats Discovery of dioxin emissions from trash incinerators USEPA emergency suspension of some 2.4.5-Tuses Yu-Cheng “oil disease” (Taiwan) Association of soft tissue sarcoma with TCDD and phenoxyacetic acid herbicides TCDD found to modulate hormones and their receptors Evaluation of Love Canal Capacitor fire in Binghamton, NY, contaminates state office building with PCBs and PCDFs General public found to be contaminated with PCDD and PCDF USEPA health assessment of TCDD Production of dioxin by chlorine-bleached paper mills discovered although proposed earlier First USEPA reassessment of dioxins Second Babury conference on dioxins NlOSH cancer mortality study of US chemical workers US-Canadian International Joint Commission Sixth Biennial Report

1929 1947 1949 1952- 954 1953 1957 1962- 970 1965- 966 Mid-1960s 1968 1971 1972-1 976 1973 1974 1976 1977 1978 1979

1980 1981 1983-1 985 1985 1986 1988 1990 1991 1992

From Webster T, Commoner B: Overview: The Dioxin Debate. In Schecter A (ed): Dioxins and Health. New York, Plenum Press, 1994, p 3;with permission.

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Mechanism of Action of Dioxin-like Compounds Many of the biochemical and toxic effects of dioxin appear to be mediated by means of the aryl hydrocarbon receptor (Ah receptor), which has a high affinity for dioxin.84Other compounds that bind to the intracellular Ah receptor are considered dioxin-like compounds; most of these have coplanar structures. Most PCB congeners that are noncoplanar are reported to have low affinity for the Ah receptor. Receptor activation follows stereospecific ligand binding and translocation to the nucleus (Fig. 2). This is a complex event in which heat shock proteins dissociate from the receptor, and the Ah receptor nuclear translocator (ARNT) protein associates with the receptor. The ligand-AhR-ARNT complex acts as a transcriptional enhancer: it binds to regulatory regions on DNA, upstream of the CYPlAl gene and other dioxin-responsive genes such as CYPlA2, aldehyde-3-dehydrogenase,NAD(P)H quinone oxidoreductase, and glutathione S transferase Ya, and increases the transcription of these genes.48, Interestingly, TCDD and other Ah receptor agonists also inhibit estrogen (E2)-induced genes, including uterine epidermal growth factor, c-fos proto-oncogene, progesterone receptor, estrogen receptor (ER), and cathepsin D genes in human breast cancer cell lines.91In MCF-7 human breast cancer cells, E2 induces cathepsin D gene expression. This is associated with the formation of an ER/Spl complex in the promoter region of this gene. Within 30 minutes, TCDD disrupts the E2-mediated ER/Spl complex and inhibits E2-induced gene expression?l This altered transcription of genes in the ligand Ar-responsive gene battery is believed to be the mechanism by which dioxin-like compounds produce their biologic effects.lo2AhR appears to activate tyrosine phosphorylation, which is one of the regulators of second messengers within the cytoplasm.12,35, 65 TCDD causes downregulation of binding activity of estrogen and epidermal growth factor (EGF) receptors52and also causes changes in cytokine pathways. These effects suggest that the Ah receptor plays an important role in regulating the cell cycle. Several structural analogues of TCDD, such as the polychlorinated dibenzofurans, also interact with the Ah receptor, and they produce the same spectrum of responses in animal and cell models as TCDD, depending on their binding affinity to the Ah receptor.16 Selective Effects of Dioxin and Dioxin-like Compounds Developmental Effects

Ectodermal abnormalities and cognitive and motor deficits were discovered among children who had accidental perinatal exposure to dioxins and nondioxins in cooking oil in 1968.15,89 Since then, research has accumulated on the developmental effects of dioxins. Perinatal exposures to dioxins in animal studies have provided information on effects

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in several developing systems, including reproductive, endocrine, neurobehavioral, and immune systems. Brain levels of thyroxine and dopamine were reduced in rats by perinatal exposures to PCBS.~~, 97 Because thyroxine crosses the placenta and blood-brain barrier, changes in hormone levels in the fetus may affect normal development in the brain. Adverse reproductive or developmental effects after perinatal exposure include reduced fertility in altered sexual differentiation in and growth male and female rats,lo,*l reduced sperm counts in 78 In addition, thymic hypoplasia, retardation in primates and hematologic alterations, decreased fetal growth, and perinatal mortality have been observed in laboratory animals. Some effects seen in animal studies appear to have corresponding outcomes in humans:51for example, reductions in infant height and in primary immune response are seen in Inuit infants whose mothers had breast milk with high PCB levels30 and reduced cognitive or motor functions in infants whose mothers ingested PCB-contaminated cooking 53, 89 In humans, perinatal oil or fish during pregnancy or 1a~tation.l~~ exposure of 200 Dutch children caused elevated neonatal thyroid-stimulating hormone (TSH) levels for up to 3 months.95The increased TSH levels were related to increased breast milk dioxin and coplanar PCB values; however, these are not correlated with thyroid hormone levels. On the other hand, in another study, neonatal T, levels were found to be elevated.83 In animal experiments, perinatal exposure to dioxins caused endocrine abnormalities in the offspring, although maternal toxicity was not observed. The recognized effects of maternal dioxin exposure involve deficits in androgen-dependent differentiation and neurologic development, as well as alterations in thyroid metabolism in rodent offspring.

Endocrine Effects Toxic effects of TCDD, such as chloracne, hirsutism, and skin hyperpigmentation, suggest endocrine involvement; however, little is known about the effects of TCDD on endocrine organs. Prenatal dioxin in rats causes feminization and demasculinization of male offspring, as manifested by patterns of luteinizing hormone (LH) secretion and sexual behavior." The administration of TCDD to pregnant female rats (single oral dose of 0.064-1.00 pg/kg on gestational day 15) affected a variety of androgenic status indices (e.g., spermatogenesis, adult sexual behavior, LH hormone secretion pattern) in the male offspring in a dosedependent manner. Male offspring from TCDD-treated dams showed dose-dependent alterations in sexual behavior (e.g., demasculinization, feminization, feminized pattern of LH secretion)&,67 and reductions in daily sperm production and sperm counts in the caudal epididymis that continued into adulthood. It has been reported that TCDD may decrease serum testosterone in the rat by influencing the activity of the testicular microsomal cytochrome P-450-dependent enzymes 17-hydroxylase and 17,20-lya~e.~~ Sharpe and Skakkebaek reported that increased estrogen exposure

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may be responsible for falling sperm counts and disorders of the male reproductive tract.98They hypothesized that in utero exposure to environmental and dietary estrogens may also result in adverse effects in male offspring as they analyzed data showing that male sperm counts had decreased by over 40% during the past 50 years.14 The association of serum dioxin with total serum testosterone, LH, and follicle-stimulating hormone (FSH) was examined in 248 chemical production workers from New Jersey and Missouri plants and 231 controls in 1987,33and current serum dioxin was positively and significantly related to LH and FSH and inversely related to total testosterone after adjustment for potential confounders in linear regression analyses. Although in vitro exposure of spermatozoa to TCDD did not result in any there is no study regarding the sperm counts in humans exposed to TCDD. Reduction in libido has been a common symptom among men exposed to TCDD. Exposed men with chloracne reported this condition approximately 50% more often than did either the unexposed controls or individuals without ch10racne.~~ Dioxin-fed rats showed marked decreases in plasma levels of T4, insulin, and g l ~ c a g o nMean . ~ ~ T3% uptake was decreased significantly in Vietnam veterans who were exposed to Agent 0range.ll6 The authors concluded, however, that the differences in mean T3% uptake and mean TSH between high-exposure and low-exposure groups were not significant and that these changes were clinically unimportant. The serum levels of TCDD correlated significantly with the increased risk of diabetes or glucose.*o4 Logistic regression analysis showed that the diabetes risk was increased by approximately 12% for every 100 parts per trillion (ppt) TCDD. Age and body mass index played substantial roles in this study, however, which might have caused bias for the pure effect of dioxin. Dioxin is also known to modulate various hormone receptor systems that play a role in uterine function, including estrogen, progesterone, epidermal growth factor receptor, and prolactin receptors.” 90 Immune Effects

Dioxin-like compounds may act as immunosuppressors or enhancers in the lymphoid system depending on the cellular target. TCDD treatment in mice results in atrophy of lymphoid tissue and the thymus.108One study with severe cellular immune-deficient (SCID) mice engrafted with human fetal thymus and liver tissue fragments (SCID-hu mice) showed a dose-dependent decrease in thymus weight when exposed to 1 pg, 5 pg, or 25 pg TCDD/kg body weightz7Gas chromatography and mass spectrometry analysis showed similar TCDD tissue concentrations in the normal rat thymus and grafted human thymus, which may serve as evidence that the human thymus is a target for TCDD. The effects of dioxin-like compounds on macrophages suggest an enhancement of inflammatory activity and expression of cytokines, par-

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ticularly tumor necrosis factor (TNF) and IL-l.ls,57, Iol, Io5 In nonhuman primates, they cause changes in cell surface markers on T cells; dioxinexposed marmosets had changes in CD, helper cells/CD, cytotoxic cells ratio after an extremely low-dose (10 ng/kg) treatment of adults.79 There are species-specific differences in host sensitivity to dioxin effects that make extrapolation to the human difficult, however. Dewailly reported that infectious disease incidence is 20-fold higher in the first year of life among the Inuit, which may account for the decreased immunization take rate reported for Inuit children.30These children are found to have elevated levels of PCBs and dioxin. Bottle-fed and breastfed human infants were compared for lymphocyte subsets as well as for their response to stimulation by mi tog en^.^ Lower rates of lymphocyte stimulation by mitogens was observed in breastfed infants; however, colostrum may cause this inhibition because this effect disappeared by the fifth month of age. The T cell subsets of the cord blood showed similar changes to those observed in the dioxin-treated marmosets. Interestingly, adult humans are probably less susceptible to immunedepressive action of PCDDs/PCDFs than nonhuman primates. A study on modulation of surface receptors on lymphocyte subpopulations of workers with moderately increased body burdens of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDF) showed slight trends for the increase of some of the biomarkers (e.g., CD45RO +) in regression analysis.80None of the alterations observed are of medical relevance, however. This slight increase in the percentage of CD, + CD45RO cells remained significant even after covariant analysis took age-related changes into account. Nevertheless, these data do not provide any evidence to support an assumption that moderately increased body burdens of PCDDs/PCDFs in adults induce decrease in the cellular components of the human immune system. Most effects of dioxin on the immune system are assumed to occur by way of the Ah receptor, which in turn induces gene expression. TCDD has been shown to modulate the expression of a large array of genes, albeit often indirectly, by demonstration of protein or mRNA upregulation. By means of computer analysis of available promoter sequences, dioxin-responsive elements in the promoter regions of many putative AhR-regulated and therefore dioxin-inducible genes could be identified.62Target genes include cytochrome P450 and growth regulatory genes involved in both inflammation and differentiation, including plasminogen activator inhibitor-2, which is a factor that influences growth and differentiation by regulating proteolysis of the extracellular matrix; and IL-lp.42,lo3, Thus, dioxin alters the expression of growth regulatory genes and has effects similar to those of other tumor-promoting agents that affect both inflammation and differentiation. Hayashi demonstrated that AhR expression was increased through monocytic differentiation and that differentiated mononuclear cells were responsive to xenobioti~s.~~ Dioxin has also been shown to affect the humoral immunity by +

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suppressing antibody production in B cells.17, 99 Similarities in the independent actions of the pleiotropic cytokine IL-4 and TCDD on murine B lymphocytes suggests immunosuppression mediated by direct exposure to TCDD in vitro may be due to an IL-4like biologic activity. TCDD preincubation results in decreased secretion of IgGl and IgE in murine B-cell cultures stimulated to undergo immunoglobulin class switching by incubation with bacterial lipopolysaccharide (LPS) and IL4?6 These observations indicate that TCDD is able to suppress secretion of several classes of murine immunoglobulin. In humans, however, there were no significant differences in the levels of immunoglobulins or the number of T and B lymphocytes, in the responsiveness to phytohemagglutinin A, and in the number of helper and suppressor T cell counts in peripheral blood between exposed workers and unexposed controls matched for age, race, sex, smoking habit, and alcohol consumption.54 Immunoglobulin levels measured in Seveso residents were similar to unexposed controls.86 Recent animal studies have demonstrated that dioxin exposure results in an enhanced inflammatory response. The mechanisms whereby TCDD increases cellular influx are unknown. Moos et a175examined the role of the proinflammatory cytokines IL-1 and tumor necrosis factor (TNF) in TCDD-induced hyperinflammation in mice. Intraperitoneal administration of recombinant IL-1 j3 (0.4 U) or TNF a (10 ng) resulted in an enhanced peritoneal inflammatory response compared to phosphatebuffered saline-injected control animals measured 20 hours following injection of sheep red blood cells (SRBC). The effect of exogenous cytokines mimicked the effects of exposure to 5 pg/kg TCDD. When endogenous IL-1 activity was blocked using an IL-1 receptor antagonist (IL-lra, 1 mg every 3 hours), the polymorphonuclear neutrophil leukocyte (PMN) influx was significantly decreased in control animals but not in animals exposed to 20 pg/kg TCDD. When endogenous TNF activity was blocked using a TNF-soluble receptor (rhuTNFR:Fc, 100 pg), the numbers of total PEC and macrophages (MAC) harvested from control mice were reduced, whereas in mice exposed to 20 pg/kg TCDD, inhibition of TNF activity dramatically reduced the numbers of PEC, MAC, and PMN. Following rhTNFRFc treatment, there was no difference between TCDD-treated and control mice in inflammatory cell influx. Besides, a dose-dependent increase in plasma TNF (Y was measured by ELISA in TCDD-treated mice following SRBC injection. These results demonstrate that TNF plays a major role in mediating TCDD-induced hyperinflammation. 647

Dioxin and Endometriosis

The first study to suggest a relationship between dioxins and endometriosis was by Gerhard et al, who found higher levels of PCB congeners in 28 patients with endometriosis compared with 441 women without endometriosis in a population of female subjects with infertility.38 Within this population, patients with elevated antithyroid antibodies

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had also higher levels of PCB. Koninckx et a159indicated that the incidence of endometriosis in Belgium is 60% to 80% in women with infertility and pain,6O which has been thought to be one of the highest reported incidences in the world. The WHO report in 1989Il3 showed that dioxin concentrations in breast milk in Belgium have been among the highest in the world, and the authors concluded that the breast milk concentrations may reflect the high dioxin accumulation in women, which theoretically may explain the high incidence of endometriosis. In 1993, Rier et a1 published the first paper on the direct relationship between dioxin and endometriosis.88Twenty-four rhesus monkeys (MUCUM rnulata) were randomly assigned to three groups: control, low-dose (5 ppt), and high-dose dioxin (25 ppt) in diet; treatment was administered for 5 years. In 1989, 7 years following the termination of dioxin exposure, one monkey in the 25 ppt group died. At autopsy, the animal was found to exhibit widespread peritoneal endometriosis and obstruction of the colon. In 1991, a second monkey in the same group died and was also found at autopsy to have extensive peritoneal endometriosis with blockage of the jejunum. In 1992, a third monkey in the same group died, again showing severe peritoneal endometriosis at autopsy. The other deaths (n = 4)in varying groups were of different causes irrelevant to endometriosis. The remaining 17 monkeys then underwent laparoscopies in which any endometriosis was identified and classified. Endometriosis was present in 71% and 86% of animals in the 5 ppt and 25 ppt groups, respectively, whereas among controls endometriosis was absent in 4 and minimal endometriosis was detected in 2 (33%). Another control group was formed retrospectively from 304 normal, noncastrated animals who had undergone autopsy. Among those animals over age 13 years at the time of autopsy, endometriosis was detected in 51 of 169 animals (30%),a rate similar to the 26% prevalence reported by Fanton and Golden37but considerably lower than that of the dioxin-exposed groups. Both the rat and mouse model have also been used to evaluate the effects of dioxin in experimental endometriosis.22, 23 Cummings et al" recently published a study that involved dioxin-related endometriosis in both species. Female rats and mice were pretreated with TCDD at 0 pg, 3 Fg, or 10 kg TCDD/kg for 3 weeks before induction surgery, which produces endometriosis, and were treated again at the time of surgery and at 3, 6, and 9 weeks following surgery. TCDD produced a dose-dependent increase in endometriotic site diameter when all time points were pooled within each dose in rats and a dramatic increase in site diameter in mice at 9 and 12 weeks. In rats but not mice, ovarian weight was decreased at 9 and 12 weeks, the occurrence of persistent vaginal estrus was increased at these times, and histologic evaluation of the ovaries revealed ovulatory arrest at 12 weeks. In both species, thymic atrophy, indicating potential immune dysfunction, and hepatomegaly were observed as consequences of TCDD exposure. Body weight was reduced in rats but not in mice. Histologic evaluations of endometriotic sites revealed fibrosis in control rats, necrotic and inflammatory changes

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in the sites from TCDD-treated rats, and predominantly fibrotic changes in sites from TCDD-treated mice. These results suggest that mechanisms mediating TCDDs action to promote endometriosis are complex and may be different in rats and mice. Recently, Yang et all'* induced endometriosis in mice after oophorectomy and subcutaneous estrogen implant replacement with surgical autotransplantation of the left uterine horn. Beginning 1 week later, subcutaneous injections of TCDD at doses of 0 (vehicle), 10, 50, or 100 ppt were administered for 4 weeks. Two days after terminating TCDD injection, animals were biopsied to measure the diameters of endometrial implants and to score adhesions. Survival of endometrial implant cysts, the formation and scores of adhesion, and the serum levels of estrogen were not significantly different among the TCDD dose and the vehicle groups; however, histology of implants showed a significant regression of endometrial tissues in the animals receiving 50 and 100 ppt TCDD daily compared with controls and 10 ppt TCDD-treated groups. The results of this study suggested that TCDD acts as an antiestrogenic agent, which causes regression of surgically induced endometriosis in the mouse model. A recent study by Osteen et alS1used human endometrial tissues treated in vitro with steroids and injected intraperitoneally into ovariectomized nude mice as a model of endometriosis. The in vitro treatment groups were E2 alone, E2 plus progesterone, sex steroids plus TCDD, and TCDD alone. The authors also analyzed the steroid-sensitive metalloproteinase (MMP) expression in vitro in cell culture. Animals were sacrificed at 5- to 20-day intervals. MMP secretion was observed in cultures treated with E2, whereas progesterone treatment suppressed MMP secretion in vitro. TCDD treatment alone or in combination with steroids had an acute, stimulatory effect on the secretion of stromal and epithelial-specific MMPs. Progesterone-mediated suppression of MMPs prevented the establishment of lesions in all recipient animals, whereas co-treatment with TCDD and progesterone resulted in development of lesions in more than 75% of recipient animals. Recipient animals receiving TCDD-treated tissue exhibited more extensive lesion development (size and number) compared with the positive control group and the stromal component of TCDD-associated lesions was considerably more prominent. The authors suggested that TCDD may affect endometriosis by stimulating MMP expression or blocking the cellular mechanisms associated with progesterone suppression of these enzymes. Clearly, the heterogeneity of the above results make definitive conclusions difficult. It appears that the effect of TCDD on endometriosis may vary considerably depending on the species and model used. What makes this relationship of compelling interest, however, is the fact that TCDD appears to function as an antiestrogen in reproductive organs.5,90 The mechanism differs from that of the weak agonists such as clomiphene and tamoxifen; TCDD appears to act by directly decreasing the amount of estrogen recept0r.4~The mechanism for this action is by means of binding to a response element in the estrogen-controlled genes

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upstream from the estrogen receptor binding site."O If TCDD should prove to promote endometriosis in the human, it would be the first substance found to do so in the absence of estrogen-mediated stimulation, thus providing an important lead in the investigation of pathogenic mechanism of the disease. Human studies, such as the epidemiologic investigation of dioxin-exposed women in Seveso, will help clarify the importance of such findings. OTHER TOXICANTS

Alcohol Several of the gynecologic symptoms in women with endometriosis are also often part of the clinical picture of women who abuse alcohol or are dependent on alcohol; these include anovulation, ovarian dysfunction, heavy menstrual flow and dysmenorrhea pathology, and luteal phase dysfunction.6,114 The parallelism between the symptoms of endometriosis and alcoholism led to research to investigate an association between these two, and the results confirm a relationship. Endometriosis patients have higher scores than the control patients in Michigan Alcoholism Screening Test (MAST) self-administered questionnaires.82Endometriosis patients with high MAST scores (25) tended to consume more alcohol on a yearly basis than did normal control subjects with high MAST scores ( P = 0.07). Endometriosis patients reported increasing their alcohol consumption when experiencing gynecologic symptoms more frequently than did control patients and patients experiencing other gynecologic disorders. G r ~ d s t e i ninvestigated ~~ the link between social and behavioral factors, alcohol, and infertility by analyzing the data obtained from 1880 case subjects and 4023 control subjects. After adjustment of risk factors such as number of sexual partners, smoking, caffeine intake, age, and infertility center, the odds ratio for endometriosis was 1.7 (95% confidence interval [C.I.] 1.2-2.5) for moderate drinkers and 1.8 (95% CI 1.0-3.2) for heavy drinkers compared with the infertile women who did not drink. Numerous mechanisms for such a relationship have been proposed. Perper et als2 hypothesized that excessive alcohol consumption may exacerbate the symptoms of endometriosis and the progression of the disease. Alcohol consumption in both premenopausal and postmenopausal women increases plasma E2 levels", 87 by increasing androstenedione levels19,31 or decreasing the E2 clearance, which in turn may increase the E2 levels at target sites in endometriosis patients.41Early female puberty has an association with onset of consumption of alcohol2,115 which also is a risk factor for endometriosis. Furthermore, alcohol ingestion may impair immunity. IL-2-induced lymphokine-activated killer activity was significantly reduced in blood samples obtained after alcohol ingestion when compared with prealcohol samples ( P < 0.01). Ingestion of a small amount of alcohol also impairs the cytotoxic capacity of peripheral blood mononuclear cells.I3

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Recently, Ben-Eliyahu demonstrated that acute alcohol intoxication caused a marked suppression of natural killer activity in vivo and a tenfold increase in the number of MADB106 tumor metastases in rats.7

Caffeine Grodstein et a145examined caffeine use in 1050 women with primary infertility and 3833 women who had recently given birth and found a significant increase in the risk of infertility because of tuba1 disease or endometriosis for the upper levels of caffeine intake, suggesting a threshold effect. For endometriosis, the relative risk was 1.9 (950/, CI 1.2-2.9) in women who consumed 5.1 to 7 g per month and 1.6 (95% CI 1.1-2.4) in those with an intake of more than 7 g per month. Although the effect of caffeine on E2 levels is inconclusive, this effect seems more likely to be a result of lifestyle of patients with endometriosis. Further epidemiologic studies are required to evaluate these results, however.

Smoking Epidemiologic studies have investigated the effects of smoking on reproductive function.21,26, 63, 69, 74 One study showed that smoking one pack of cigarettes per day (odds ratio = 1.36) and starting to smoke before 18 years of age (odds ratio = 1.30) were significantly associated with increased risk of infertility.63Life-table and proportional hazards analysis indicated that smoking did not significantly increase the time required to conceive among infertile women. Epidemiologic results indicate that women who smoke cigarettes are relatively estrogen deficient. Smokers have an early natural menopause, a lowered risk of cancer of the endometrium? and an increased risk of some osteoporotic fractures. Smoking does not appear to be clearly related to E2 levels, although levels of adrenal androgens are increased.=, 58 Furthermore, smoking appears to alter the metabolism of E2, leading to enhanced formation of the inactive catechol estrogens.73Women who smoke may have a reduced risk of uterine fibroids, endometriosis,2*,26, 69 hyperemesis gravidarum,26 and benign breast suggesting a protective effect on these disorders. The well-known adverse effects of smoking clearly outweigh the potential protective benefits on endometriosis, however. Conversely, smoking may account for a significant fraction of dioxin exposure in some women. Dioxin has been reported to be present in cigarette smoke. Muto and Takizawa have estimated that a pack-aday smoker has a daily intake of about of 4.3 pg of polychlorinated dibezodiozins per kg of body weight per day, whereas Lofroth and Zebuhr’s measurements of mainstream smoke imply an intake of 18 pg Toxicity Equivalence Factor (TEF) per day per person for a 1-pack-per

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day smoker, about 13% of the daily median intake estimated from other sources in EPA exposure assessment.

Tamoxifen, commonly used as adjuvant therapy in breast cancer, is an estrogen antagonist/agonist often associated with antiestrogenic effects such as hot flashes and vaginal dryness in premenopausal women. Estrogenic side effects, such as thromboembolic phenomena and endometrial proliferation, have been reported in postmenopausal women. Paradoxically, tamoxifen also has been shown to be capable of increasing estrogen levels in premenopausal women. The development of endometriosis, endometriomas, and endometrioid cancer within the endometriosis has been reported in pre- and postmenopausal women receiving tamoxifen for breast cancer?,46, 76 In addition, the rate of adenomyosis described among those postmenopausal breast cancer patients treated with tamoxifen is three to four times higher than the rate reported in the literature for pre- and postmenopausal women.” It is suggested that the prolonged and unopposed estrogen-like stimulation by tamoxifen may play a causal role in the development of this pathologic entity. Interestingly, when CD-1 female mice were treated with various combinations of corn oil, E2, tamoxifen, and/or TCDD in corn oil, E2 had little effect on acute TCDD lethality but increased severity of TCDDinduced ascites and antagonized TCDD-induced uterine suppression.106 Tamoxifen antagonized the estrogenic effects of E2 and E2 and TCDD. Although the dose of tamoxifen used was otherwise nontoxic, tamoxifen greatly increased liver toxicity of TCDD in a dose-response fashion, suggesting that a portion of the toxicity of TCDD is manifest through activity of the estrogen receptor complex. It is also claimed that TCDD toxicity by tamoxifen is associated with decreased excretion of TCDD, leading to elevated liver retention and enhanced severity of liver pathology..68One of the metabolites of tamoxifen is 4-hydroxytamoxifen, which exhibits a more potent estrogen agonist/antagonist activity than tamoxifen. Tamoxifen 4-hydroxylation was increased by treatment of chick embryos with TCDD and phenobarbitaL6I Phenobarbital-treated livers had increased expression of a P450 fraction containing CYP2H1/H2, the major PB-induced P450s which had the highest tamoxifen 4-hydroxylase and N-demethylase, suggesting that exposure of women undergoing tamoxifen therapy to agents that induce human CYPlA2 or CYPB1/2 analogues may produce increased levels of 4-hydroxytamoxifen, and that this may affect the therapeutic potency of tamoxifen. RADIATION

A positive correlation between endometriosis and radiation exposure has been suggested.%* 70,loo A theorized mechanism for this effect is

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by means of alteration of the immunologic response of the host, promoting implantation and proliferation of the ectopic er~dometrium.~~, 117 The first such notation was in 1971 when Eisenfeld and Wagenen noted that 8 of 13 monkeys receiving 600 to 900 roentgen units of x-ray developed endometriosis. A more comprehensive study was performed by the United States Air Forces School of Aerospace Medicine looking at the acute and delayed effects of proton radiation in 1964.’17 A colony of rhesus monkeys were acutely exposed to protons of discrete energies within the spectrum of space radiation and 151 female monkeys were retained within the colony for lifetime observation (128 exposed; 23 controls). The monkeys were examined triannually. Rectal digital examinations were performed as a screening test for endometriosis starting in 1977. If a mass was detected, exploratory laparotomy was performed. The shortest elapsed time between exposure and discovery of endometriosis was 6 years, and 55 of 151 female monkeys developed endometriosis; 52 were irradiated (41%) and 3 were controls (13%).These data were later updated by Fanton and Golden.37In total, 80 endometriosis cases were detected. The incidence of endometriosis was 73% in the 11 animals receiving mixed-proton radiation simulating solar flare radiation (Fig. 3). None of the monkeys younger than 8 years of age developed endome-

.___......

Controls

Endo Total

g

n 0.4-

Controls All exposed

3 52

23 128

All exposec

Breslow, P< ,013

0.2-

48

60

72

84

96

108 120 132 144 156 168 180 192 204

Months Post Exposure Figure 3. The proportion of the total subjects without endometriosis (Kaplan-Meier survival curves). “Endo” and “Total” indicate occurrence of endometriosis among the 151 subjects. (From Wood DH, Yochmowitz MG, Salmon YL, et al: Proton irradiation and endometriosis. Aviat Space Environ Med 54:718,1983;with permission.)

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triosis. There is no comparable human evidence of a link between radiation and endometriosis.

CONCLUSION Dioxin is the prototype and the reference compound for halogenated aromatic hydrocarbons. TCDD and related chemicals cause a wide variety of responses, ranging from frankly adverse effects such as lethality, to biochemical changes such as induction of drug-metabolizing enzymes. They are biologically and ecologically persistent. These compounds cause cancer and have detrimental effects on skin, endocrine organs, the immune system, reproductive function, and fetal development in both laboratory animals and wildlife. Data concerning human health is still controversial, however. TCDD has been reported to cause endometriosis in rhesus monkeys; however, research to date has produced conflicting results because the TCDD effect on endometriosis has proven to be species specific. Other toxicants such as radiation, alcohol, and drugs such as tamoxifen also may enhance endometriosis. To clarify the role of such substances on the genesis of endometriosis will require both basic research into the pathogenetic mechanisms of the disease as well as higher quality epidemiologic studies of endometriosis-associated toxicants.

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