Click for next page ( 436


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 435
7 Reproductive Effects and Impacts on Future Generations This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2006, hereafter referred to as Update 2006 (IOM, 2007), on the association between exposure to herbicides and adverse reproduc- tive or developmental effects. (Analogous shortened names are used to refer to the updates for 1996, 1998, 2000, 2002, and 2004 [IOM, 1996, 1999, 2001, 2003, 2005].) The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. The literature considered in this chapter includes studies of a broad spectrum of reproductive effects in Vietnam veterans or other populations occupationally or environmentally exposed to the herbicides sprayed in Vietnam or to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Because some polychlorinated biphenyls (PCBs) and polychlorodibenzofurans (PCDFs) have dioxin-like biologic activity, studies of populations exposed to PCBs or PCDFs were reviewed if their results were presented in terms of toxicity equivalence quotients (TEQs). As in previous updates, the adverse outcomes evaluated include impaired fertility (in which endometriosis or declines in sperm quality may be involved), increased fetal loss (spontaneous abortion and stillbirth) or neonatal and infant mortality, and other adverse birth outcomes (including low birth weight, preterm birth, and birth defects). In addition to the more delayed problem of childhood cancer in their offspring, this update also addresses the concern of Vietnam vet- erans that their military exposures may contribute to other problems that their children experience later in life or are manifested in later generations. To reduce repetition throughout the report, Chapter 5 presented design in- formation on new studies that report findings on multiple health outcomes. To provide context for publications that present new results on study populations 4

OCR for page 435
46 VETERANS AND AGENT ORANGE: UPDATE 2008 that were addressed in publications reviewed in earlier updates, Chapter 5 also discussed the overall characteristics of those populations with details about de- sign and analysis relevant to individual papers. For new studies that report only reproductive health outcomes and that are not revisiting previously studied popu- lations, design information is summarized in this chapter with results. This chapter’s primary emphasis is on the potential adverse reproductive effects of herbicide exposure of men because the vast majority of Vietnam vet- erans are men. However, about 8,000 women served in Vietnam (H. Kang, US Department of Veterans Affairs, personal communication, December 14, 2000), so findings relevant to female reproductive health are also included. Whenever the information was available, an attempt was made to evaluate the effects of maternal and paternal exposure separately. Exposure scenarios in human popula- tions and experimental animals studied differ in their applicability to our popula- tion of concern according to whether the exposed parent was a male or female veteran. In addition, for published epidemiologic or experimental results to be fully relevant to evaluation of the plausibility of reproductive effects in Vietnam veterans, female as well as male, the timing of exposure needs to correspond to the veterans’ experience (that is, occur only prior to conception). With the possible exception of female veterans who became pregnant while serving in Vietnam, pregnancies that might have been affected occurred after deployment, when primary exposure had ceased. BIOLOGIC PLAUSIBILITY OF REPRODUCTIVE EFFECTS This chapter opens with a general discussion of factors that influence the plausibility that TCDD and the four herbicides used in Vietnam could produce adverse reproductive effects. There have been very few reproductive studies of the four herbicides in question, particularly picloram and cacodylic acid, and those studies generally have shown toxicity only at very high doses, so the pre- ponderance of the following discussion concerns TCDD. Because dioxin is stored in fat tissue and has a very long biologic half-life, internal exposure at generally constant concentrations may continue after epi- sodic, high-level exposure to external sources has ceased. If a person had high ex- posure, there may still be high amounts of dioxin stored in fat tissue, which may be mobilized, particularly at times of weight loss. That would not be expected to be the case for nonlipophilic chemicals, such as cacodylic acid. The paternal contribution to a pregnancy is limited to the contents of the sperm that fertilizes an egg, any damage would be conveyed as DNA mutations or epigenetic effects (that is, heritable changes in genome function that occur without a change in primary DNA sequences). Dioxins have not been shown to alter DNA sequences (they do not produce mutations), so the potential effects in offspring are limited to epigenetic effects. Two possible mechanisms could theoretically produce affected children: if sperm stem cells are altered by expo-

OCR for page 435
4 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS sure, they could continue to produce altered sperm; and mobilization of dioxin from storage in adipose tissue (for example, due to weight loss) could continue to damage a man’s developing sperm, and thus interfere with conception and conceptuses. In any case, any exposure of the father that could affect his children must occur before their conception. Although ova, the maternal contribution to a conceptus, do not undergo the repeated 90-day cycles of spermatogenesis, they might be damaged by modes of exposure analogous to those affecting male gametes. In addition, at critical peri- ods of gestation and even postnatally through breast milk, the female can mediate exposure to the offspring as it develops. Such exposure can interfere with cell replication, differentiation, and migration; with formation of tissues, organs, and systems; and with structure. Dioxin in her bloodstream, whether from external sources or released from fat stores, can cross the placenta and expose the develop- ing embryo and fetus. Mobilization of dioxin during pregnancy or lactation may be increased because the body is drawing on fat stores to supply nutrients to the developing fetus or nursing infant. Breast milk has a high fat content, and the concentration of dioxin in breast milk is about 100 times that in a mother’s blood. In animal studies, TCDD crosses the placenta and is transferred via breast milk. In humans, TCDD has been measured in circulating maternal blood, cord blood, placenta, and breast milk (Suzuki et al., 2005), and it is estimated that an infant breastfed for 1 year accumulates a dose of TCDD that is 6 times as high as that in an infant not breastfed (Lorber and Phillips, 2002). Thus, the exposure of human infants to TCDD in utero and via lactation has been demonstrated. Toxicologists often distinguish between reproductive effects, which concern the reproductive process itself, and developmental effects, which involve differ- entiation of fetal tissues and maturation of the offspring. A connection between TCDD exposure and human reproductive and developmental effects is, in general, biologically plausible. However, more definitive conclusions about the potential for such TCDD toxicity in humans are complicated by differences in sensitivity and susceptibility among individual animals, strains, and species; by the lack of strong evidence of organ-specific effects among species; by differences in route, dose, duration, and timing of exposure; and by substantial differences in the toxicokinetics of TCDD between laboratory animals and humans. Experiments with 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) indicate that they have subcellular effects that could constitute a biologically plausible mechanism for reproductive and developmental effects. Evidence from animals, however, indicates that they do not have reproductive effects and that they have developmental effects only at very high doses. There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of those compounds’ reproductive or developmental effects. The biologic plausibility portions of sections on the specific outcomes con- sidered in this chapter present more detailed toxicologic findings that are of particular relevance to the outcomes discussed.

OCR for page 435
48 VETERANS AND AGENT ORANGE: UPDATE 2008 ENDOMETRIOSIS Endometriosis (International Classification of Diseases, 9th reision [ICD-9], code 617) affects 5.5 million women in the United States and Canada at any given time (NICHD, 2007). The endometrium is the tissue that lines the inside of the uterus and is built up and shed each month during menstruation. In endometrio- sis, endometrial cells are found outside the uterus—usually in other parts of the reproductive system, in the abdomen, or on surfaces near the reproductive organs. That misplaced tissue develops into growths or lesions that continue to respond to hormonal changes in the body and break down and bleed each month in concert with the menstrual cycle. Unlike blood released during normal shedding of the endometrium lining the uterus, blood released in endometriosis has no way to leave the body, and the results are inflammation, internal bleeding, and degenera- tion of blood and tissue that can cause scarring, pain, infertility, adhesions, and intestinal problems. There are several theories of the etiology of endometriosis, including a ge- netic contribution, but the cause remains unknown. Estrogen dependence and im- mune modulation are established features of endometriosis but do not adequately explain the cause of this disorder. It has been proposed that endometrium is distributed through the body via blood or the lymphatic system; that menstrual tissue backs up into the fallopian tubes, implants in the abdomen, and grows; and that all women experience some form of tissue backup during menstruation but only those with immune-system or hormonal problems experience the tissue growth associated with endometriosis. Despite numerous symptoms that can indicate endometriosis, diagnosis is possible only through laparoscopy or a more invasive surgical technique. Several treatments for endometriosis are available, but there is no cure. Conclusions from VAO and Updates Endometriosis was first reviewed in this series of reports in Update 2002, which identified two relevant environmental studies, and Update 2004 examined three environmental studies. Two additional environmental studies considered in Update 2006 did not change the conclusion that the evidence was inadequate or insufficient to support an association with herbicide exposure. Table 7-1 provides a summary of relevant studies that have been reviewed. Update of the Epidemiologic Literature No new Vietnam-veteran or occupational studies addressing endometriosis have been published since Update 2006.

OCR for page 435
49 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS TABLE 7-1 Selected Epidemiologic Studies—Endometriosis Reference Study Population Study Results ENVIRONMENTAL New Studies Heilier Serum DLC and aromatase No association between TEQs of DLCs in serum et al., activity in endometriotic tissue and aromatase activity by regression analyses. 2006 from 47 patients in Belgium p-values = 0.37–0.90 for different endometriosis subgroups. Heilier 88 matched triads (264 total); Results for pelvic endometriosis vs controls et al., patients with deep endometriotic Dietary fat: OR = 1.0 (95% CI 1.0–1.0) 2007 nodules, pelvic endometriosis, BMI: OR = 1.0 (95% CI 0.9–1.0) controls matched for age, Occupation: OR = 0.5 (95% CI 0.2–1.1) gynecologic practice in Belgium; Traffic: OR = 1.0 (95% CI 0.3–2.8) routes of exposure to DLCs Incinerator: OR = 1.0 (95% CI 1.0–1.1) examined Tsuchiya 138 infertility patients in Japan; Results for advanced endometriosis et al., laproscopically confirmed case– Total TEQ: OR = 0.5 (95% CI 0.2–1.7) 2007 control status, serum dioxin, PCB Genotype-specific: ORs = 0.3–0.6 TEQ; P450 genetic polymorphism No significant interaction between genotype, dioxin TEQ Studies Reviewed in Update 2006 Heilier Endometriosis in Belgian women 50 exposed cases, risk of increase of 10 pg/p lipid et al., with overnight fasting serum of TEQ compounds: OR = 2.6 (95% CI 1.3–5.3) 2005 levels of PCDD, PCDF, PCB Porpora Case–control study of Italian Mean total PCBs (ng/g) et al., women with endometriosis, Cases, 410 ng/g 2006 measured serum PCBs Control, 250 ng/g All PCB congeners: OR = 4.0 (95% CI 1.3–13) Studies Review in Update 2004 De Felip Pilot study of Italian, Belgian Mean concentration of TCDD (ppt of lipid) et al., women of reproductive age; Italy: 2004 compared concentrations of Controls (10 pooled samples), 1.6 TCDD, total TEQ in pooled Cases (two sets of six pooled samples), 2.1, 1.3 blood samples from women who Belgium: had diagnosis endometriosis with Controls (seven pooled samples), 2.5 controls Cases (Set I, five pooled samples; Set II, six pooled samples), 2.3, 2.3 Mean concentration of TEQ (ppt of lipid) Italy: Controls (10 pooled samples), 8.9 ± 1.3 (99% CI 7.2–11) Cases (two sets of six pooled samples), 10.7 ± 1.6; 10.1 ± 1.5 Belgium: Controls (seven pooled samples), 24.7 ± 3.7 (99% CI 20–29) Cases (Set I, five pooled samples; Set II, six pooled samples), 18.1 ± 2.7; 27.1 ± 4 .0 continued

OCR for page 435
440 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 7-1 Continued Reference Study Population Study Results Fierens Belgian women with Mean concentration of TEQ a (ppt of lipid) et al., environmental exposure to Cases (n = 10), 26.2 (95% CI 18.2–37.7) 2003 PCDDs, PCDFs; compared Controls (n = 132), 25.6 (95% CI 24.3–28.9) analyte concentrations in cases vs No significant difference controls Eskenazi Residents of Seveso Zones A Serum TCDD (ppt) et al., and B up to 30 years old in 20.1–100 ppt (n = 8), OR = 1.2 2002 1976; compared incidence of (90% CI 0.3–4.5) endometriosis across serum > 100 ppt (n = 9), OR = 2.1 (90% CI 0.5–8.0) TCDD concentrations Studies Reviewed in Update 2002 Pauwels Patients undergoing infertility Six exposed cases: OR = 4.6 (95% CI 0.5–43.6) et al., treatment in Belgium; compared 2001 number of women with, without endometriosis who had serum dioxin levels up to 100 pg TEQ/g of serum lipid Mayani Residents of Jerusalem being Eight exposed cases: OR = 7.6 et al., evaluated for infertility; (95% CI 0.9–169.7) 1997 compared number of women with high TCDD who had (n = 44), did not have (n = 35) diagnosis of endometriosis ABBREVIATIONS: BMI, body mass index; CI, confidence interval; DLC, dioxin-like compound; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofuran; TCDD, 2,3,7,8-tetrachlorodibenzo- p-dioxin; TEQ, toxicity equivalent quotient. aTEQs calculated using the 1998 World Health Organization dioxin toxic equivalency factor (TEF) method (Van den Berg et al., 1998). Environmental Studies Three new studies concerning exposure to the compounds of interest and endometriosis have been conducted since the last update. The first two were conducted by the same research group that reported an increased risk of endo- metriosis with serum concentrations of dioxin-like compounds (DLCs) (Heilier et al., 2005). In the new studies, they sought to expand their findings by focusing on a possible biologic pathway (aromatase activity) and routes of exposure (such as diet and residential proximity to waste incinerators). However, neither study showed significant associations of endometriosis with the factors studied. The third new study (Tsuchiya et al., 2007), which looked at specific genes in addi- tion to dioxin exposure, did not find an association between dioxin exposure and early stage-endometriosis regardless of genotype. In contrast with some earlier

OCR for page 435
441 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS studies, it found dioxin exposure to be associated with a lower risk of advanced endometriosis. This lower risk was particularly strong in women who had a specific genotype. In the study of Heilier et al. (2006), 47 women admitted to a university hospital in Belgium for the treatment of endometriosis agreed to participate in a study aimed at determining whether aromatase activity was associated with the concentration of DLCs in the endometriotic tissue. Aromatase is an enzyme im- portant in the synthesis of estrogen, and drugs that block the synthesis of estrogen lead to a reduction in endometriotic tissue. The authors thought that DLCs might increase the aromatase, which would increase estrogen and lead to increased growth of endometrial tissue. Endometriotic tissue was surgically removed from the women, and DLCs and aromatase activity were measured in the laboratory. They found that the concentration of DLCs was not associated with higher aro- matase activity in endometriotic tissue. Heilier et al. (2007) studied a total of 264 women in the same gynecologic practice, divided equally into three groups matched on age; cases of pelvic endometriosis, cases of deep endometriotic nodules, and controls. Serum TEQ concentrations were available for 58 of these women who had participated in a previous study by the authors (Heilier et al., 2005), which found a risk of endo- metriosis associated with exposure to DLCs. Interviews conducted with patients and controls collected information on diet, occupation, and residential proximity to automobile traffic, waste incinerators, or other pollution sources. In the subset of women whose serum DLCs were measured, they found that those with higher concentrations were more likely to have consumed specific high-fat foods: pig meat, marine fish, and fresh cream. However, neither dietary fat consumption, body mass index (BMI), residential proximity to automobile traffic or waste incinerators, nor specific occupation was associated with pelvic endometriosis or with deep endometriotic nodules. The study used indirect measures of dioxin exposure that are expected to be less precise than measures of serum dioxin, so the results do not necessarily contradict those of their earlier study. The investi- gators were unable to identify any likely source of dioxin exposure that differed between cases and controls. The third new study was conducted by Tsuchiya et al. (2007) in Japan to ex- amine a possible association between genetic susceptibility to effects of exposure to DLCs and endometriosis. They studied a total of 138 women who sought treat- ment for infertility and had undergone laparoscopy. On the basis of laparoscopy, the women were classified as having early-stage endometriosis (stages I–II), ad- vanced endometriosis (stages III–IV), or no evidence of endometriosis (controls). They measured serum dioxin and DLCs (TEQ per gram of lipids) and extracted DNA from serum to determine polymorphisms (different genetic versions) of two genes (cytochromes P450 [CYP] 1A1 and 1B1), which regulate the synthesis and metabolism of endogenous and exogenous estrogens. They hypothesized that dif- ferences in genetic makeup might confer differences in susceptibility to effects of

OCR for page 435
442 VETERANS AND AGENT ORANGE: UPDATE 2008 DLCs and might explain why studies of endometriosis and dioxins show incon- sistent results. Overall, serum-dioxin concentrations did not differ significantly between cases with early or advanced endometriosis and controls (adjusted for age). Women who had advanced endometriosis were less likely to have high serum dioxins than controls (OR = 0.46, 95% CI 0.20–1.06), but the difference was of borderline statistical significance; the result was virtually unchanged by considering the total concentration of PCBs and dioxins. When genotype was considered, the authors found no significant interaction between genotype and serum dioxin in women who had early endometriosis. However, there was some evidence of interaction between CYP genes and dioxin exposure with respect to the risk of advanced endometriosis. There was a reduced risk of advanced endo- metriosis after high dioxin exposure in women who had the less common allele for CYP1A1, but the number of women in this group was very small. In summary, the study found some evidence of a gene–environment interaction related to the occurrence of endometriosis, but women who had higher concentrations of dioxin were found to be at lower risk for advanced endometriosis. Biologic Plausibility Laboratory studies that used animal models and examined gene-expression changes associated with human endometriosis and TCDD exposure provide evi- dence to support the biologic plausibility of a link between TCDD exposure and endometriosis. The first suggestion that TCDD exposure may be linked to endo- metriosis came as a secondary finding from a study that exposed female rhesus monkeys (Macaca mulatta) chronically to low concentrations of dietary TCDD for 4 years (Rier et al., 1993). Ten years after the exposure ended, the investiga- tors documented an increased incidence of endometriosis in the monkeys that correlated with the dioxin exposure concentration. The small sample prevented a definitive conclusion that TCDD was a causal agent in the development of the endometriosis, but it led to numerous studies of the ability of TCDD to promote the growth of pre-existing endometriotic lesions. When fragments of uterine tissue were implanted in the peritoneal cavity to mimic eutopic endometrial lesions, TCDD exposure was shown to promote the survival and growth of the lesions in monkeys and in rodents (Cummings et al., 1996; Johnson et al., 1997; Yang et al., 2000). In mice, direct treatment of endo- metrial tissue with TCDD before placement into the peritoneal cavity resulted in increased size and number of endometrial lesions (Bruner-Tran et al., 1999). A number of proposed mechanisms by which TCDD may promote endome- trial lesions provide additional biologic plausibility of the link between TCDD and endometriosis. Human endometrial tissue expresses the aryl hydrocarbon receptor (AHR) and its dimerization partner, the aryl hydrocarbon nuclear trans- locator (ARNT) (Khorram et al., 2002), and three AHR target genes: CYP1A1,

OCR for page 435
44 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS 1A2, and 1B1 (Bulun et al., 2000). That suggests that endometrial tissue is respon- sive to TCDD. Furthermore, TCDD significantly decreases the ratio of progester- one receptor B to progesterone receptor A in normal human endometrial stromal cells and blocks the ability of progesterone to suppress matrix metalloproteinase (MMP) expression; these actions may promote endometrial-tissue invasion. Both the reduced ratio and the resistance to progesterone-mediated MMP suppression are observed in endometrial tissue from women who have endometriosis (Igarashi et al., 2005). Progesterone prevents endometrial breakdown before menstruation by down-regulating expression of endometrial matrix metalloproteins during the secretory phase of the menstrual cycle. Bruner-Tran et al. (2008) have proposed that environmental toxicants, such as TCDD, that disrupt progesterone action may predispose the endometrium to an inflammatory microenvironment that would promote a process of tissue loss at menstruation. Their hypothesis is supported by their evidence that TCDD inhibits expression of progesterone receptor and transforming growth factor β2 in the endometrium and possibly expression of other immune modulators regulated by progesterone. TCDD induces changes in gene expression that mirror those observed in endometrial lesions. For example, TCDD can induce expression of histamine- releasing factor, which is increased in endometrial lesions and accelerates their growth (Oikawa et al., 2002, 2003). Similarly, TCDD stimulates expression of RANTES (regulated on activation, normal T cell–expressed, and secreted) in endometrial stromal cells, and RANTES concentration and bioactivity are in- creased in women who have endometriosis (Zhao et al., 2002). The two CC-motif chemokines (chemotactic cytokines), RANTES and macrophage-inflammatory protein (MIP)-1α, have been identified as potential contributors to the pathogen- esis and progression of endometriosis. To probe the effect of dioxin exposure and estrogen on expression of those chemokines in endometriosis-associated cells and to explore the pathogenesis of endometriosis, endometrial stromal cells were exposed to a combination of 17β-estradiol and TCDD. The combined treatment increased the secretion of RANTES and MIP-1α, promoted the invasiveness of endometrial stromal cells, and increased the expression of matrix metallopro- teins MMP-2 and MMP-9 in endometrial stromal cells, indicating that combined TCDD and estradiol may facilitate the onset of endometriosis and contribute to its development by increasing the invasion of endometrial stromal cells medi- ated by CC-motif chemokines (Yu et al., 2008). Those data are consistent with the evidence of an interaction between the AHR and the estrogen receptor that induces estrogen-mediated proliferative effects in the mouse uterus (Ohtake et al., 2008). Differences between the mouse uterus and the human endometrium pre- vent absolute extrapolation, but the data suggest that dioxins may induce changes in endometrial physiology. In summary, it may be expected that TCDD exposure would create an inflammatory endometrial microenvironment that could disrupt endometrial function and cause disease.

OCR for page 435
444 VETERANS AND AGENT ORANGE: UPDATE 2008 Although those studies do not establish the degree to which TCDD may cause or promote endometriosis, they do provide evidence that supports the bio- logic plausibility of a link between TCDD exposure and endometriosis. Synthesis The three new studies described above were designed to follow on previous studies showing an association between DLCs and endometriosis. Two of the studies (Heilier et al., 2006, 2007) were conducted by the same research group that had found a significant association between blood concentrations of DLCs and risk of endometriosis. They sought to shed light on possible biologic path- ways and routes of exposure that might expand on the previous findings. How- ever, neither the evaluation of an enzyme important in the synthesis of estrogen nor examination of routes of exposure to dioxin yielded evidence of association with endometriosis. The third new study (Tsuchiya et al., 2007) found a decreased risk of endometriosis in women with higher dioxin concentrations. Overall, the studies linking dioxin exposure with endometriosis are few in number and inconsistent. The association in animal studies is biologically plau- sible, but it is possible that human exposures are too low to show an association consistently. Conclusion On the basis of the evidence reviewed here and in the previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to sup- port an association between exposure to the chemicals of interest and human endometriosis. FERTILITY Male reproductive function is under the control of several components whose proper coordination is important for normal fertility. Several of the components and some health outcomes related to male fertility, including reproductive hor- mones and sperm characteristics, can be studied as indicators of fertility. The reproductive neuroendocrine axis involves the central nervous system, the an- terior pituitary gland, and the testis. The hypothalamus integrates neural inputs from the central and peripheral nervous systems and regulates the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both are se- creted into the circulation in episodic bursts by the anterior pituitary gland and are necessary for normal spermatogenesis. In the testis, LH interacts with receptors on Leydig cells, where it stimulates increased testosterone synthesis. FSH and the testosterone from the Leydig cells interact with the Sertoli cells in the semi- niferous tubule epithelium to regulate spermatogenesis. More detailed reviews

OCR for page 435
44 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS of the male reproductive hormones can be found elsewhere (Knobil et al., 1994; Yen and Jaffe, 1991). Several agents, such as lead and dibromochloropropane, affect the neuroendocrine system and spermatogenesis (for reviews, see Bonde and Giwercman, 1995; Tas et al., 1996). Studies of the relationship between chemicals and fertility are less common in women than in men. Some chemicals may disrupt the female hormonal bal- ance necessary for proper functioning. Normal menstrual-cycle functioning is also important in the risk of hormonally related diseases, such as osteopenia, breast cancer, and cardiovascular disease. Chemicals can have multiple effects on the female system, including modulation of hormone concentrations result- ing in menstrual-cycle or ovarian-cycle irregularities, changes in menarche and menopause, and impairment of fertility (Bretveld et al., 2006a,b). In this section, we also discuss studies that have focused on menstrual-cycle characteristics and age at menarche or menopause. An affect on age at menarche would be of concern among the daughters of Vietnam veterans rather than among female veterans themselves, but the occurrence of this effect in other populations would demonstrate the ability of the chemicals in question to perturb functioning of the female reproductive system. Conclusions from VAO and Updates The committee responsible for the original VAO report (IOM, 1994) con- cluded that there was inadequate or insufficient evidence of an association be- tween exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered sperm characteristics or infertility. Overall, additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that finding. Reviews of the relevant studies are presented in the earlier reports. Tables 7-2 and 7-3 summarize the studies related to male and female fertility, respectively. Update of the Epidemiologic Literature Male Fertility Vietnam-Veteran Studies One new Vietnam-veteran study has been published since Update 2006. Gupta et al. (2006) compared serum testosterone concentra- tions measured in 1987 with TCDD concentrations measured at the same time in veterans in the Air Force Health Study. A total of 971 Ranch Hand veterans and 1,266 comparison veterans with serum TCDD and serum testosterone measure- ments were included in the analyses. After adjustment for age and BMI in 1987 and for a percentage change in BMI from the end of their Southeast Asia tour to 1987, higher serum TCDD was significantly associated with lower testoster- one concentrations in both Ranch Hands (slope for ln[TCDD] = -0.02, 95% CI

OCR for page 435
499 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS Dimich-Ward H, Hertzman C, Teschke K, Hershler R, Marion SA, Ostry A, Kelly S. 1996. Reproduc- tive effects of paternal exposure to chlorophenate wood preservatives in the sawmill industry. Scandinaian Journal of Work, Enironment and Health 22(4):267–273. Donovan JW, MacLennan R, Adena M. 1984. Vietnam service and the risk of cogenital anomalies: A case–control study. Medical Journal of Australia 140(7):394–397. Driscoll R, Donovan B, Esswein E, Mattorano D. 1998. Health hazard evaluation report. US Depart- ment of Agriculture 1–72. Edwards TM, Myers JP. 2007. Environmental exposures and gene regulation in disease etiology. Enironmental Health Perspecties 115(9):1264–1270. Egeland GM, Sweeney MH, Fingerhut MA, Wille KK, Schnorr TM, Halperin WE. 1994. Total serum testosterone and gonadotropins in workers exposed to dioxin. American Journal of Epidemiol- ogy 139:272–281. Ehrlich M. 2003. Expression of various genes is controlled by DNA methylation during mammalian development. Journal of Cellular Biochemistry 88:899–910. Ergaz Z, Avgil M, Ornoy A. 2005. Intrauterine growth restriction—etiology and consequences: What do we know about the human situation and experimental animal models? Reproductie Toxicol- ogy 20(3):301–322. Erickson J, Mulinare J, Mcclain P, Fitch T, James L, McClearn A, Adams M. 1984a. Vietnam Veter- ans’ Risks for Fathering Babies with Birth Defects. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control. Erickson JD, Mulinare J, McClain PW, Fitch TG, James LM, McClearn AB, Adams MJ. 1984b. Vietnam veterans’ risks for fathering babies with birth defects. Journal of the American Medical Association 252(7):903–912. Eskenazi B, Mocarelli P, Warner M, Samuels S, Vercellini P, Olive D, Needham LL, Patterson DG Jr, Brambilla P, Gavoni N, Casalini S, Panazza S, Turner W, Gerthoux PM. 2002. Serum dioxin concentrations and endometriosis: A cohort study in Seveso, Italy. Enironmental Health Per- specties 110(7):629–634. Eskenazi B, Mocarelli P, Warner M, Chee WY, Gerthoux PM, Samuels S, Needham LL, Patterson DG Jr. 2003. Maternal serum dioxin levels and birth outcomes in women of Seveso, Italy. En- ironmental Health Perspecties 111(7):947–953. Eskenazi B, Warner M, Marks AR, Samuels S, Gerthoux PM, Vercellini P, Olive DL, Needham L, Patterson D Jr, Mocarelli P. 2005. Serum dioxin concentrations and age at menopause. Eniron- mental Health Perspecties 113(7):858–862. Eskenazi B, Warner M, Samuels S, Young J, Gerthoux PM, Needham L, Patterson D, Olive D, Gavoni N, Vercellini P, Mocarelli P. 2007. Serum dioxin concentrations and risk of uterine leiomyoma in the Seveso Women’s Health Study. American Journal of Epidemiology 166(1):79–87. Farr SL, Cooper GS, Cai J, Savitz DA, Sandler DP. 2004. Pesticide use and menstrual cycle charac- teristics among premenopausal women in the Agricultural Health Study. American Journal of Epidemiology 160(12):1194–1204. Farr SL, Cai J, Savitz DA, Sandler DP, Hoppin JA, Cooper GS. 2006. Pesticide exposure and tim- ing of menopause: The Agricultural Health Study. American Journal of Epidemiology 163(8): 731–742. Felix JF, Van Dooren MF, Klaassens M, Hop WCJ, Torfs CP, Tibboel D. 2008. Environmental factors in the etiology of esophageal atresia and congenital diaphragmatic hernia: Results of a case–control study. Birth Defects Research Part A—Clinical and Molecular Teratology 82(2):98–105. Fenton SE, Hamm JT, Birnbaum LS, Youngblood GL. 2000. Adverse effects of TCDD on mammary gland development in long evans rats: A two generational study. Organohalogen Compounds 48:157–160.

OCR for page 435
00 VETERANS AND AGENT ORANGE: UPDATE 2008 Fenton SE, Hamm JT, Birnbaum LS, Youngblood GL. 2002. Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). Toxicological Sciences 67(1):63–74. Field B, Kerr C. 1988. Reproductive behaviour and consistent patterns of abnormality in offspring of Vietnam veterans. Journal of Medical Genetics 25:819–826. Fierens S, Mairesse H, Heilier JF, de Burbure C, Focant JF, Eppe G, de Pauw E, Bernard A. 2003. Dioxin/polychlorinated biphenyl body burden, diabetes and endometriosis: Findings in a population-based study in Belgium. Biomarkers 8(6):529–534. Fitzgerald EF, Weinstein AL, Youngblood LG, Standfast SJ, Melius JM. 1989. Health effects three years after potential exposure to the toxic contaminants of an electrical transformer fire. Archies of Enironmental Health 44:214–221. Flower KB, Hoppin JA, Lynch CF, Blair A, Knott C, Shore DL, Sandler DP. 2004. Cancer risk and parental pesticide application in children of Agricultural Health Study participants. Enironmen- tal Health Perspecties 112(5):631–635. Fujita H, Samejima H, Kitagawa N, Mitsuhashi T, Washio T, Yonemoto J, Tomita M, Takahashi T, Kosaki K. 2006. Genome-wide screening of dioxin-responsive genes in fetal brain: Bioinfor- matic and experimental approaches. Congenital Anomalies 46(3):135–143. Fujiwara K, Yamada T, Mishima K, Imura H, Sugahara T. 2008. Morphological and immunohis- tochemical studies on cleft palates induced by 2,3,7,8-tetrachlorodibenzo- p-dioxin in mice. Congenital Anomalies 48(2):68–73. Gao Y, Sahlberg C, Kiukkonen A, Alaluusua S, Pohjanvirta R, Tuomisto J, Lukinmaa PL. 2004. Lacta- tional exposure of Han/Wistar rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin interferes with enamel maturation and retards dentin mineralization. Journal of Dental Research 83(2):139–144. García AM, Benavides FG, Fletcher T, Orts E. 1998. Paternal exposure to pesticides and congenital malformations. Scandinaian Journal of Work, Enironment and Health 24(6):473–480. Garry VF, Schreinemachers D, Harkins ME, Griffith J. 1996. Pesticide appliers, biocides, and birth defects in rural Minnesota. Enironmental Health Perspecties 104(4):394–399. Gray L, Ostby J, Kelce WR. 1997a. A dose response analysis of reproductive effects of a single ges- tational dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male Long Evans Hooded rat offspring. Toxicology and Applied Pharmacology 146:11–20. Gray L, Wolf C, Mann P, Ostby J. 1997b. In utero exposure to low doses of 2,3,7,8-tetrachlorodibenzo- p-dioxin alters reproductive development of female Long Evans hooded rat offsprings. Toxicol- ogy and Applied Pharmacology 146:237–244. Greenlee AR, Arbuckle TE, Chyou PH. 2003. Risk factors for female infertility in an agricultural region. Epidemiology 14(4):429–436. Gupta VK, Ali I, Suhas, Saini VK. 2006. Adsorption of 2,4-D and carbofuran pesticides using fertil- izer and steel industry wastes. Journal of Colloid and Interface Science 299(2):556–563. Hanify JA, Metcalf P, Nobbs CL, Worsley KJ. 1981. Aerial spraying of 2,4,5-T and human birth malformations: An epidemiological investigation. Science 212:349–351. Heacock H, Hogg R, Marion SA, Hershler R, Teschke K, Dimich-Ward H, Demers P, Kelly S, Ostry A, Hertzman C. 1998. Fertility among a cohort of male sawmill workers exposed to chloro- phenate fungicides. Epidemiology 9(1):56–60. Heacock H, Hertzman C, Demers PA, Gallagher R, Hogg RS, Teschke K, Hershler R, Bajdik CD, Dimich-Ward H, Marion SA, Ostry A, Kelly S. 2000. Childhood cancer in the offspring of male sawmill workers occupationally exposed to chlorophenate fungicides. Enironmental Health Perspecties 108(6):499–503. Heiden TCK, Struble CA, Rise ML, Hessner MJ, Hutz RJ, Carvan IMJ. 2008. Molecular targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) within the zebrafish ovary: Insights into TCDD- induced endocrine disruption and reproductive toxicity. Reproductie Toxicology 25(1):47–57. Heilier JF, Nackers F, Verougstraete V, Tonglet R, Lison D, Donnez J. 2005. Increased dioxin-like compounds in the serum of women with peritoneal endometriosis and deep endometriotic (ad- enomyotic) nodules. Fertility and Sterility 84(2):305–312.

OCR for page 435
01 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS Heilier JF, Donnez J, Defrere S, Van Kerckhove V, Donnez O, Lison D. 2006. Serum dioxin-like compounds and aromatase (CYP19) expression in endometriotic tissues. Toxicology Letters 167(3):238–244. Heilier JF, Donnez J, Nackers F, Rousseau R, Verougstraete V, Rosenkranz K, Donnez O, Grandjean F, Lison D, Tonglet R. 2007. Environmental and host-associated risk factors in endometrio- sis and deep endometriotic nodules: A matched case–control study. Enironmental Research 103(1):121–129. Henriksen GL, Michalek JE, Swaby JA, Rahe AJ. 1996. Serum dioxin, testosterone, and gonadotro- pins in veterans of Operation Ranch Hand. Epidemiology 7(4):352–357. Hertz-Picciotto I, Samuels SJ. 1988. Incidence of early loss of pregnancy. New England Journal of Medicine 319(22):483–484. Hertz-Picciotto I, Jusko TA, Willman EJ, Baker RJ, Keller JA, Teplin SW, Charles MJ. 2008. A cohort study of in utero polychlorinated biphenyl (PCB) exposures in relation to secondary sex ratio. Enironmental Health: A Global Access Science Source 7:37. Ho HM, Ohshima K, Watanabe G, Taya K, Strawn EY, Hutz RJ. 2006. TCDD increases inhibin a production by human luteinized granulosa cells in vitro. Journal of Reproduction and Deelop- ment 52(4):523–528. Hojo R, Zareba G, Kai JW, Baggs RB, Weiss B. 2006. Sex-specific alterations of cerebral cortical cell size in rats exposed prenatally to dioxin. Journal of Applied Toxicology 26(1):25–34. Hutt KJ, Shi Z, Albertini DF, Petroff BK. 2008. The environmental toxicant 2,3,7,8-tetrachlorodibenzo- p-dioxin disrupts morphogenesis of the rat pre-implantation embryo. BMC Deelopmental Biology 8(1). Igarashi TM, Bruner-Tran KL, Yeaman GR, Lessey BA, Edwards DP, Eisenberg E, Osteen KG. 2005. Reduced expression of progesterone receptor-B in the endometrium of women with endome- triosis and in cocultures of endometrial cells exposed to 2,3,7,8-tetrachlorodibenzo- p-dioxin. Fertility and Sterility 84(1):67–74. Ikeda M, Tamura M, Yamashita J, Suzuki C, Tomita T. 2005b. Repeated in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure affects male gonads in offspring, leading to sex ratio changes in F2 progeny. Toxicology and Applied Pharmacology 206(3):351–355. Ilvesaro J, Pohjanvirta R, Tuomisto J, Viluksela M, Tuukkanen J. 2005. Bone resorption by aryl hydrocarbon receptor-expressing osteoclasts is not disturbed by TCDD in short-term cultures. Life Sciences 77(12):1351–1366. Infante-Rivard C, Labuda D, Krajinovic M, Sinnett D. 1999. Risk of childhood leukemia associated with exposure to pesticides and with gene polymorphisms. Epidemiology 10:481–487. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2002. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leuke- mia in the Children of Vietnam Veterans. Washington, DC: National Academy Press. IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. IOM. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. IOM. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. Jaenisch R, Bird A. 2003. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nature Genetics 33:245–354. James WH. 2006. Offspring sex ratios at birth as markers of paternal endocrine disruption. Eniron- mental Research 100:77–85.

OCR for page 435
02 VETERANS AND AGENT ORANGE: UPDATE 2008 Jang JY, Shin S, Choi BI, Park D, Jeon JH, Hwang SY, Kim JC, Kim YB, Nahm SS. 2007. Antiterato - genic effects of alpha-naphthoflavone on 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) exposed mice in utero. Reproductie Toxicology 24(3-4):303–309. Jang JY, Park D, Shin S, Jeon JH, Choi Bi, Joo SS, Hwang SY, Nahm SS, Kim YB. 2008. Antitera- togenic effect of resveratrol in mice exposed in utero to 2,3,7,8-tetrachlorodibenzo- p-dioxin. European Journal of Pharmacology 591(1-3):280–283. Jiang YH, Bressler J, Beaudet AL. 2004. Epigenetics and human disease. Annual Reiew of Genomics and Human Genetics 5:479–510. John-Greene JA, Ouellette JH, Jeffries TK, Johnson KA, Rao KS. 1985. Teratological evaluation of picloram potassium salt in rabbits. Food and Chemical Toxicology 23(8):753–756. Johnson KL, Cummings AM, Birnbaum LS. 1997. Promotion of endometriosis in mice by polychlo- rinated dibenzo-p-dioxins, dibenzofurans, and biphenyls. Enironmental Health Perspecties 105(7):750–755. Kallen B. 1988. Epidemiology of Human Reproduction. Boca Raton, FL: CRC Press. Kalter H, Warkany J. 1983. Congenital malformations. Etiologic factors and their role in prevention (first of two parts). New England Journal of Medicine 308:424–431. Kang HK, Mahan CM, Lee KY, Magee CA, Mather SH, Matanoski G. 2000. Pregnancy out- comes among US women Vietnam veterans. American Journal of Industrial Medicine 38(4): 447–454. Karmaus W, Huang S, Cameron L. 2002 Parental concentration of dichlorodiphenyl dichloroethene and polychlorinated biphenyls in Michigan fish eaters and sex ratio in offspring. Journal of Occupational and Enironmental Medicine 44(1):8–13. Keller JM, Allen DE, Davis CR, Leamy LJ. 2007a. 2,3,7,8-Tetrachlorodibenzo-p-dioxin affects fluc- tuating asymmetry of molar shape in mice, and an epistatic interaction of two genes for molar size. Heredity 98(5):259–267. Keller JM, Huang JC, Huet-Hudson Y, Leamy LJ. 2007b. The effects of 2,3,7,8-tetrachlorodibenzo- p-dioxin on molar and mandible traits in congenic mice: A test of the role of the Ahr locus. Toxicology 242(1-3):52–62. Keller JM, Huet-Hudson YM, Leamy LJ. 2007c. Qualitative effects of dioxin on molars vary among inbred mouse strains. Archies of Oral Biology 52(5):450–454. Keller JM, Huet-Hudson Y, Leamy LJ. 2008. Effects of 2,3,7,8-tetrachlorodibenzo- p-dioxin on molar development among non-resistant inbred strains of mice: A geometric morphometric analysis. Growth, Deelopment, and Aging 71(1):3–16. Kerr M, Nasca PC, Mundt KA, Michalek AM, Baptiste MS, Mahoney MC. 2000. Parental occu- pational exposures and risk of neuroblastoma: A case–control study (United States). Cancer Causes and Control 11:635–643. Khorram O, Garthwaite M, 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. Molecular Human Reproduction 8(1):75–80. Khorram O, Garthwaite M, Jones J, Golos T. 2004. Expression of aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) mRNA expression in human sper- matozoa. Medical Science Monitor 10(5):BR135–BR138. Kline J, Stein Z, Susser M. 1989. Conception to Birth: Epidemiology of Prenatal Deelopment. New York: Oxford University Press. Knobil E, Neill JD, Greenwald GS, Markert CL, Pfaff DW, eds. 1994. The Physiology of Reproduc- tion. New York: Raven Press. Koopman-Esseboom C, Huisman M, Weisglas-Kuperus N, Van der Paauw CG, Tuinstra L, Boersma ER, Sauer PJJ. 1994. PCB, dioxin levels in plasma and human milk of 418 Dutch women and their infants. Predictive value of PCB congener levels in maternal plasma for fetal and infant’s exposure to PCBs and dioxins. Chemosphere 28:1721–1732.

OCR for page 435
0 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS Kransler KM, McGarrigle BP, Russell RJ, Olson JR. 2008. Effects of Helicobacter infection on developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Holtzman rats. Lab Animal 37(4):171–175. Kristensen P, Andersen A, Irgens LM, Bye AS, Sundheim L. 1996. Cancer in offspring of parents engaged in agricultural activities in Norway: Incidence and risk factors in the farm environment. International Journal of Cancer 65(1):39–50. Kristensen P, Irgens LM, Andersen A, Bye AS, Sundheim L. 1997. Birth defects among offspring of Norwegian farmers, 1967–1991. Epidemiology 8(5):537–544. Kuroda M, Oikawa K, Ohbayashi T, Yoshida K, Yamada K, Mimura J, Matsuda Y, Fujii-Kuriyama Y, Mukai K. 2005. A dioxin sensitive gene, mammalian WAPL, is implicated in spermatogenesis. FEBS Letters 579(1):167–172. Lacasana M, Vazquez-Grameix H, Borja-Aburto VH, Blanco-Munoz J, Romieu I, Aguilar-Garduno C, Garcia AM. 2006. Maternal and paternal occupational exposure to agricultural work and the risk of anencephaly. Occupational and Enironmental Medicine 63(10):649–656. Lahvis GP, Lindell SL, Thomas RS, McCuskey RS, Murphy C, Glover E, Bentz M, Southard J, Bradfield CA. 2000. Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor–deficient mice. Proceedings of the National Academy of Sciences of the United States of America 97(19):10442–10447. Lamb JC 4th, Moore JA, Marks TA, Haseman JK. 1981. Development and viability of offspring of male mice treated with chlorinated phenoxy acids and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Toxicology and Enironmental Health 8(5-6):835–844. Landrigan P, Garg A, Droller DBJ. 2003. Assessing the effects of endocrine disruptors in the National Children’s Study. Enironmental Health Perspecties 111(13):1678–1682. Larsen SB, Joffe M, Bonde JP. 1998. Time to pregnancy and exposure to pesticides in Danish farmers. Occupational and Enironmental Medicine 55(4):278–283. Lawson CC, Schnorr TM, Whelan EA, Deddens JA, Dankovic DA, Piacitelli LA, Sweeney MH, Connally LB. 2004. Paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin and birth outcomes of offspring: Birth weight, preterm delivery, and birth defects. Enironmental Health Perspecties 112(14):1403–1408. Lerda D, Rizzi R. 1991. Study of reproductive function in persons occupationally exposed to 2,4- dichlorophenoxyacetic acid (2,4-D). Mutation Research 262(1):47–50. Lind PM, Eriksen EF, Sahlin L, Edlund M, Örberg J. 1999. Effects of the antiestrogenic environmental pollutant 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) in rat bone and uterus: Diverging effects in ovariectomized and intact animals. Toxicology and Applied Pharmacology 154(3):236–244. Lind PM, Larsson S, Oxlund H, Hakansson H, Nyberg K, Eklund T, Örberg J. 2000a. Change in bone tissue composition and impaired bone strength in rats exposed to 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Toxicology 150:41–51. Lind PM, Örberg J, Edlund U-B, Sjöblom L, Lind L. 2000b. Bone tissue composition, dimensions and strength in rats an increased dietary level of vitamin A or exposed to 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) alone or in combination with vitamin C. Toxicology 151:11–23. Loffredo CA, Silbergeld EK, Ferencz C, Zhang J. 2001. Association of transposition of the great arteries in infants with maternal exposures to herbicides and rodenticides. American Journal of Epidemiology 153(6):529–536. Lorber M, Phillips L. 2002. Infant exposure to dioxin-like compounds in breast milk. Enironmental Health Perspecties 110(6):A325–A332. Lucifero D, Mann MR, Bartolomei MS, Trasler JM. 2004. Gene-specific timing and epigenetic memory in oocyte imprinting. Human Molecular Genetics 13:839–849. Mably TA, Moore RW, Goy RW, Peterson RE. 1992. In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 2. Effects on sexual behavior and the regulation of lutein- izing hormone secretion in adulthood. Toxicology and Applied Pharmacology 114:108–117.

OCR for page 435
04 VETERANS AND AGENT ORANGE: UPDATE 2008 Mastroiacovo P, Spagnolo A, Marni E, Meazza L, Betrollini R, Segni G, Brogna-Pignatti C. 1988. Birth deffects in Seveso area after TCDD contamination. Journal of American Medical Associa- tion 259:1668–1672 (published erratum appears in JAMA 1988, 260:792). Mayani A, Barel S, Soback S, Almagor M. 1997. Dioxin concentrations in women with endometriosis. Human Reproduction 12(2):373–375. Mehta V, Peterson RE, Heideman W. 2008. 2,3,7,8-Tetrachlorodibenzo-p-dioxin exposure prevents cardiac valve formation in developing zebrafish. Toxicological Sciences 104(2):303–311. Meinert R, Schüz J, Kaletsch U, Kaatsch P, Michaelis J. 2000. Leukemia and non-Hodgkin’s lym- phoma in childhood and exposure to pesticides: Results of a register-based case–control study in Germany. American Journal of Epidemiology 151(7):639–646. Meyer KJ, Reif JS, Veeramachaneni DN, Luben TJ, Mosley BS, Nuckols JR. 2006. Agricultural pesticide use and hypospadias in eastern Arkansas. Enironmental Health Perspecties 114(10): 1589–1595. Michalek JE, Albanese RA, Wolfe WH. 1998a. Project Ranch Hand II: An Epidemiologic Inestiga- tion of Health Effects in Air Force Personnel Following Exposure to Herbicides—Reproductie Outcome Update. US Department of Commerce, National Technical Information Service. Report number AFRL-HE-BR-TR-1998-0073. Michalek JE, Rahe AJ, Boyle CA. 1998b. Paternal dioxin, preterm birth, intrauterine growth retarda- tion, and infant death. Epidemiology 9(2):161–167. Miettinen HM, Pulkkinen P, Jamsa T, Koistinen J, Simanainen U, Tuomisto J, Tuukkanen J, Viluksela M. 2005. Effects of in utero and lactational TCDD exposure on bone development in differen- tially sensitive rat lines. Toxicological Sciences 85(2):1003–1012. Miettinen HM, Sorvari R, Alaluusua S, Murtomaa M, Tuukkanen J, Viluksela M. 2006. The effect of perinatal TCDD exposure on caries susceptibility in rats. Toxicological Sciences 91(2): 568–575. Mitsui T, Sugiyama N, Maeda S, Tohyama C, Arita J. 2006. Perinatal exposure to 2,3,7,8-tetrachlorod- ibenzo-p-dioxin suppresses contextual fear conditioning-accompanied activation of cyclic AMP response element-binding protein in the hippocampal CA1 region of male rats. Neuroscience Letters 398(3):206–210. Mocarelli P, Brambilla P, Gerthoux PM, Patterson DG Jr, Needham LL. 1996. Change in sex ratio with exposure to dioxin. Lancet 348(9024):409. Mocarelli P, Gerthoux PM, Ferrari E, Patterson DG Jr, Kieszak SM, Brambilla P, Vincoli N, Signorini S, Tramacere P, Carreri V, Sampson EJ, Turner WE, Needham LL. 2000. Paternal concentrations of dioxin and sex ratio of offspring. The Lancet 355:1858–1863. Mocarelli P, Gerthoux PM, Patterson DG Jr, Milani S, Limonta G, Bertona M, Signorini S, Tramacere P, Colombo L, Crespi C, Brambilla P, Sarto C, Carreri V, Sampson EJ, Turner WE, Needham LL. 2008. Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality. Enironmental Health Perspecties 116(1):70–77. Monge P, Wesseling C, Guardado J, Lundberg I, Ahlbom A, Cantor KP, Weiderpass E, Partanen T. 2007. Parental occupational exposure to pesticides and the risk of childhood leukemia in Costa Rica. Scandinaian Journal of Work, Enironment and Health 33(4):293–303. Morgan HD, Santos F, Green K, Dean W, Reik W. 2005. Epigenetic reprogramming in mammals. Human Molecular Genetics 14:R47–R58. Moses M, Lilis R, Crow KD, Thornton J, Fischbein A, Anderson HA, Selikoff IJ. 1984. Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: Comparison of findings with and without chloracne. Ameri- can Journal of Industrial Medicine 5(3):161–182. Moshammer H, Neuberger M. 2000. Sex ratio in the children of the Austrian chloracne cohort. The Lancet 356:1271.

OCR for page 435
0 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS Nagasaka T, Koi M, Kloor M, Gebert J, Vilkin A, Nishida N, Shin SK, Sasamoto H, Tanaka N, Matsubara N, Boland CR, Goel A. 2008. Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer. Gastroenterology 134:1950–1960. Nakajima S, Saijo Y, Kato S, Sasaki S, Uno A, Kanagami N, Hirakawa H, Hori T, Tobiishi K, Todaka T, Nakamura Y, Yanagiya S, Sengoku Y, Iida T, Sata F, Kishi R. 2006. Effects of prenatal ex- posure to polychlorinated biphenyls and dioxins on mental and motor development in Japanese children at 6 months of age. Enironmental Health Perspecties 114(5):773–778. Nayyar T, Wu J, Hood DB. 2003. Downregulation of hippocampal NMDA receptor expression by prenatal exposure to dioxin. Cellular and Molecular Biology 49(8):1357–1362. NCI (National Cancer Institute). 2001. Sureillance, Epidemiology, and End Results (SEER) data- base. http://seer.cancer.gov/ScientificSystems/CanQues (Accessed March 19). Negishi T, Shimomura H, Koyama T, Kawasaki K, Ishii Y, Kyuwa S, Yasuda M, Kuroda Y, Yoshikawa Y. 2006. Gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin affects social behaviors between developing rhesus monkeys (Macaca mulatta). Toxicology Letters 160(3):233–244. NICHD (National Institute of Child Health and Human Development). 2007. Endometriosis. Na- tional Institute of Health. http://www.nichd.nih.gov/health/topics/endometriosis.cfm (Accessed December 17, 2008). Nishijo M, Tawara K, Nakagawa H, Honda R, Kido T, Nishijo H, Saito S. 2008. 2,3,7,8-Tetrachloro- dibenzo-p-dioxin in maternal breast milk and newborn head circumference. Journal of Exposure Science and Enironmental Epidemiology 18(3):246–251. Nishimura N, Matsumura F, Vogel CFA, Nishimura H, Yonemoto J, Yoshioka W, Tohyama C. 2008. Critical role of cyclooxygenase-2 activation in pathogenesis of hydronephrosis caused by lacta- tional exposure of mice to dioxin. Toxicology and Applied Pharmacology 231(3):374–383. Oh E, Lee E, Im H, Kang HS, Jung WW, Won NH, Kim EM, Sul D. 2005. Evaluation of immuno- and reproductive toxicities and association between immunotoxicological and genotoxicological parameters in waste incineration workers. Toxicology 210(1):65–80. Ohsako S, Miyabara Y, Sakaue M, Ishimura R, Kakeyama M, Izumi H, Yonemoto J, Tohyama C. 2002. Developmental stage–specific effects of perinatal 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on reproductive organs of male rat offspring. Toxicological Sciences 66(2):283–292. Ohtake F, Baba A, Fujii-Kuriyama Y, Kato S. 2008. Intrinsic AhR function underlies cross-talk of dioxins with sex hormone signalings. Biochemical and Biophysical Research Communications 370(4):541–546. Oikawa K, Ohbayashi T, Mimura J, Fujii-Kuriyama Y, Teshima S, Rokutan K, Mukai K, Kuroda M. 2002. Dioxin stimulates synthesis and secretion of IgE-dependent histamine-releasing factor. Biochemical and Biophysical Research Communications 290(3):984–987. Oikawa K, Kosugi Y, Ohbayashi T, Kameta A, Isaka K, Takayama M, Kuroda M, Mukai K. 2003. Increased expression of IgE-dependent histamine-releasing factor in endometriotic implants. Journal of Pathology 199(3):318–323. Oikawa K, Yoshida K, Takanashi M, Tanabe H, Kiyuna T, Ogura M, Saito A, Umezawa A, Kuroda M. 2008. Dioxin interferes in chromosomal positioning through the aryl hydrocarbon receptor. Biochemical and Biophysical Research Communications 374(2):361–364. Park JS, Hwang SY, Hwang BY, Han K. 2008. The spermatogenic effect of 50% ethanol extracts of Yacon and its ameliorative effect against 2,3,7,8-tetrachlorodibenzo-p-dioxin induced testicular toxicity in the rat. Natural Product Sciences 14(2):73–80. Pauwels A, Schepens PJC, Hooghe TD, Delbeke L, Dhont M, Brouwer A, Weyler J. 2001. The risk of endometriosis and exposure to dioxins and polychlorinated biphenyls: A case–control study of infertile women. Human Reproduction 16(10):2050–2055. Pearce MS, Parker L. 2000. Paternal employment in agriculture and childhood kidney cancer. Pedi- atric Hematology and Oncology 17(3):223–230.

OCR for page 435
06 VETERANS AND AGENT ORANGE: UPDATE 2008 Pearce MS, Hammal DM, Dorak MT, McNally RJ, Parker L. 2006. Paternal occupational expo- sure to pesticides or herbicides as risk factors for cancer in children and young adults: A case–control study from the North of England. Archies of Enironmental and Occupational Health 61(3):138–144. Peltier MR. 2003. Immunology of term and preterm labor. Reproductie Biology and Endocrinology 1:122–132. Pesatori AC, Consonni D, Tironi A, Zocchetti C, Fini A, Bertazzi PA. 1993. Cancer in a young popula- tion in a dioxin-contaminated area. International Journal of Epidemiology 22(6):1010–1013. Petrelli G, Figa-Talamanca I, Tropeano R, Tangucci M, Cini C, Aquilini S, Gasperini L, Meli P. 2000. Reproductive male-mediated risk: Spontaneous abortion among wives of pesticide applicators. European Journal of Epidemiology 16(4):391–393. Polsky JY, Aronson KJ, Heaton JP, Adams MA. 2007. Pesticides and polychlorinated biphenyls as potential risk factors for erectile dysfunction. Journal of Andrology 28(1):28–37. Porpora MG, Ingelido AM, di Domenico A, Ferro A, Crobu M, Pallante D, Cardelli M, Cosmi EV, De Felip E. 2006. Increased levels of polychlorobiphenyls in Italian women with endometriosis. Chemosphere 63(8):1361–1367. Ray SS, Swanson HI. 2004. Dioxin-induced immortalization of normal human keratinocytes and silencing of p53 and p16INK4a. Journal of Biological Chemistry 279(26):27187–27193. Reik W, Walter J. 2001. Genomic imprinting: Parental influence on the genome. Nature Reiew Genetics 2:21–32. Reik W, Dean W, Walter J. 2001. Epigenetic reprogramming in mammalian development. Science 293:1089–1093. Revich B, Aksel E, Ushakova T, Ivanova I, Zuchenko N, Lyuev N, Brodsky B, Sotsov Y. 2001. Dioxin exposure and public health in Chapaevsk, Russia. Chemosphere 43(4-7):951–966. Reynolds P, Von Behren J, Gunier RB, Goldberg DE, Harnly M, Hertz A. 2005b. Agricultural pesti- cide use and childhood cancer in California. Epidemiology 16(1):93–100. Rier SE, Martin DC, Bowman RE, Dmowski WP, Becker JL. 1993. Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin. Funda- mental and Applied Toxicology 21(4):433–441. Romo A, Carceller R, Tobajas J. 2009. Intrauterine growth retardation (IUGR): Epidemiology and etiology. Pediatric Endocrinology Reiews 6(Supplement 3):332–336. Roundtree MR, Bachman KE, Herman JG, Baylin SB. 2001. DNA methylation, chromatin inheri- tance, and cancer. Oncogene 20:3156–3165. Rudant J, Menegaux F, Leverger G, Baruchel A, Nelken B, Bertrand Y, Patte C, Pacquement H, Verite C, Robert A, Michel G, Margueritte G, Gandemer V, Hemon D, Clavel J. 2007. Household exposure to pesticides and risk of childhood hematopoietic malignancies: The ESCALE study (SFCE). Enironmental Health Perspecties 115(12):1787–1793. Ryan JJ, Amirova Z, Carrier G. 2002. Sex ratios of children of Russian pesticide producers exposed to dioxin. Enironmental Health Perspecties 110(11):A699–A701. Sagiv SK, Tolbert PE, Altshul LM, Korrick SA. 2007. Organochlorine exposures during pregnancy and infant size at birth. Epidemiology 18(1):120–129. Savitz DA, Arbuckle A, Kaczor D, Curtis KM. 1997. Male pesticide exposure and pregnancy out- come. American Journal of Epidemiology 146(12):1025–1036. Schnorr TM, Lawson CC, Whelan EA, Dankovic DA, Deddens JA, Piacitelli LA, Reefhuis J, Sweeney MH, Connally LB, Fingerhut MA. 2001. Spontaneous abortion, sex ratio, and paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Enironmental Health Perspec- ties 109(11):1127–1132. Schreinemachers DM. 2003. Birth malformations and other adverse perinatal outcomes in four US wheat-producing states. Enironmental Health Perspecties 111(9):1259–1264.

OCR for page 435
0 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS Schultz R, Suominen J, Varre T, Hakovirta H, Parvinen M, Toppari J, Pelto-Huikko M. 2003. Expres - sion of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator messenger ribonucleic acids and proteins in rat and human testis. Endocrinology 144(3):767–776. Schwartz LS. 1998. Health Problems of Women Veterans of the Vietnam War. Doctoral dissertation, Yale University. Shi Z, Valdez KE, Ting AY, Franczak A, Gum SL, Petroff BK. 2007. Ovarian endocrine disruption underlies premature reproductive senescence following environmentally relevant chronic ex- posure to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo- p-dioxin. Biology of Reproduction 76(2):198–202. Smith AH, Fisher DO, Pearce N, Chapman CJ. 1982. Congenital defects and miscarriages among New Zealand 2,4,5-T sprayers. Archies of Enironmental Health 37:197–200. Staessen JA, Nawrot T, Hond ED, Thijs L, Fagard R, Hoppenbrouwers K, Koppen G, Nelen V, Schoeters G, Vanderschueren D, Van Hecke E, Verschaeve L, Vlietinck R, Roels HA. 2001. Renal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: A feasibility study of biomarkers. Lancet 357(9269):1660–1669. [Comment in Lancet 2001. 358(9295):1816–1817.] Stellman SD, Stellman JM, Sommer JF Jr. 1988. Health and reproductive outcomes among American Legionnaires in relation to combat and herbicide exposure in Vietnam. Enironmental Research 47:150–174. Stockbauer JW, Hoffman RE, Schramm WF, Edmonds LD. 1988. Reproductive outcomes of mothers with potential exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. American Journal of Epidemiol- ogy 128:410–419. Suskind RR, Hertzberg VS. 1984. Human health effects of 2,4,5-T and its toxic contaminants. Journal of the American Medical Association 251:2372–2380. Suzuki G, Nakano M, Nakano S. 2005. Distribution of PCDDs/PCDFs and Co-PCBs in human maternal blood, cord blood, placenta, milk, and adipose tissue: Dioxins showing high toxic equivalency factor accumulate in the placenta. Bioscience, Biotechnology and Biochemistry 69(10):1836–1847. Swan SH, Kruse RL, Liu F, Barr DB, Drobnis EZ, Redmon JB, Wang C, Brazil C, Overstreet JW; Study for Future Families Research Group. 2003. Semen quality in relation to biomarkers of pesticide exposure. Enironmental Health Perspecties 111(12):1478–1484. Tango T, Fujita T, Tanihata T, Minowa M, Doi Y, Kato N, Kunikane S, Uchiyama I, Tanaka M, Uehata T. 2004. Risk of adverse reproductive outcomes associated with proximity to municipal solid waste incinerators with high dioxin emission levels in Japan. Journal of Epidemiology 14(3):83–93. Tas S, Lauwerys R, Lison D. 1996. Occupational hazards for the male reproductive system. Critical Reiews in Toxicology 26(3):261–307. Teilmann G, Juul A, Skakkebaek NE, Toppari J. 2002. Putative effects of endocrine disrupters on pubertal development in the human. Best Practice and Research Clinical Endocrinology and Metabolism 16(1):105–121. ten Tusscher GW, Stam GA, Koppe JG. 2000. Open chemical combustions resulting in a local in- creased incidence of orofacial clefts. Chemosphere 40(9-11):1263–1270. Toft G, Long M, Kruger T, Hjelmborg PS, Bonde JP, Rignell-Hydbom A, Tyrkiel E, Hagmar L, Giwercman A, Spano M, Bizzaro D, Pedersen HS, Lesovoy V, Ludwicki JK, Bonefeld-Jorgensen EC. 2007. Semen quality in relation to xenohormone and dioxin-like serum activity among Inuits and three European populations. Enironmental Health Perspecties 115 (Supplement 1):15–20. Townsend JC, Bodner KM, Van Peenen PFD, Olson RD, Cook RR. 1982. Survey of reproductive events of wives of employees exposed to chlorinated dioxins. American Journal of Epidemiol- ogy 115:695–713.

OCR for page 435
08 VETERANS AND AGENT ORANGE: UPDATE 2008 Tsuchiya M, Tsukino H, Iwasaki M, Sasaki H, Tanaka T, Katoh T, Patterson DG Jr, Turner W, Needham L, Tsugane S. 2007. Interaction between cytochrome P450 gene polymorphisms and serum organochlorine TEQ levels in the risk of endometriosis. Molecular Human Reproduction 13(6):399–404. Tsukimori K, Tokunaga S, Shibata S, Uchi H, Nakayama D, Ishimaru T, Nakano H, Wake N, Yoshimura T, Furue M. 2008. Long-term effects of polychlorinated biphenyls and dioxins on pregnancy outcomes in women affected by the Yusho incident. Enironmental Health Perspec- ties 116(5):626–630. Tuyet LTN, Johansson A. 2001. Impact of chemical warfare with Agent Orange on women’s reproduc- tive lives in Vietnam: A pilot study. Reproductie Health Matters 9(18):156–164. Van den Berg M, Birnbaum L, Bosveld AT, Brunstrom B, Cook P, Feeley M, Giesy JP, Hanberg A, Hasegawa R, Kennedy SW, et al. 1998. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Enironmental Health Perspecties 106:775–792. Vreugdenhil H, Weisglas-Kuperus N. 2000. Effects of environmental exposure to polychlorinated bi- phenyls and dioxins on cognitive development in young children. NeuroToxicology 21(4):620. Vreugdenhil HJI, Slijper FME, Mulder PGH, Weisglas-Duperus N. 2002. Effects of perinatal ex- posure to PCBs and dioxins on play behavior in Dutch children at school age. Enironmental Health Perspecties 110(10):A593–A598. Vreugdenhil HJ, Mulder PG, Emmen HH, Weisglas-Kuperus N. 2004. Effects of perinatal exposure to PCBs on neuropsychological functions in the Rotterdam cohort at 9 years of age. Neuro- psychology 18(1):185–193. Wang S-L, Chang Y-C, Chao H-R, Li C-M, Li L-A, Lin L-Y, Papke O. 2006. Body burdens of poly- chlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls and their relations to estrogen metabolism in pregnant women. Enironmental Health Perspecties 114(5):740–745. Warner M, Samuels S, Mocarelli P, Gerthoux PM, Needham L, Patterson DG Jr, Eskenazi B. 2004. Serum dioxin concentrations and age at menarche. Enironmental Health Perspecties 112(13):1289–1292. Warner M, Eskenazi B, Olive DL, Samuels S, Quick-Miles S, Vercellini P, Gerthoux PM, Needham L, Patterson DG Jr, Mocarelli P. 2007. Serum dioxin concentrations and quality of ovarian function in women of Seveso. Enironmental Health Perspecties 115(3):336–340. Wen WQ, Shu XO, Steinbuch M, Severson RK, Reaman GH, Buckley JD, Robison LL. 2000. Paternal military service and risk for childhood leukemia in offspring. American Journal of Epidemiology 151(3):231–240. Weselak M, Arbuckle TE, Wigle DT, Walker MC, Krewski D. 2008. Pre-and post-conception pesti- cide exposure and the risk of birth defects in an Ontario farm population. Reproductie Toxicol- ogy 25(4):472–480. Wikiera B, Basiak A, Barg E, Noczynska A. 2007. Precocious thelarche—Current opinions. Adances in Clinical and Experimental Medicine 16(2):329–334. Wilcox AJ, Weinberg CR, O’Connor JF, Baird DD, Schlatterer JP, Canfield RE, Armstrong EG, Nisula BC. 1988. Incidence of early pregnancy loss. New England Journal of Medicine 319: 189–194. Wolfe WH, Michalek JE, Miner JC, Rahe AJ, Moore CA, Needham LL, Patterson DG Jr. 1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand. Epidemiology 6:17–22. Wu Q, Ohsako S, Ishimura R, Suzuki JS, Tohyama C. 2004. Exposure of mouse preimplantation em- bryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the methylation status of imprinted genes H19 and Igf2. Biological Reproduction 70(6):1790–1797. Yamada T, Fujiwara K, Mishima K, Imura H, Sugahara T. 2007. Effects of 2,3,7,8-tetrachlorodibenzo- p-dioxin on the development of murine palate in organ culture. Asian Journal of Oral and Maxillofacial Surgery 19(4):185–189.

OCR for page 435
09 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS Yamano Y, Ohyama K, Ohta M, Sano T, Ritani A, Shimada J, Ashida N, Yoshida E, Ikehara K, Morishima I. 2005. A novel spermatogenesis related factor-2 (SRF-2) gene expression affected by TCDD treatment. Endocrine Journal 52(1):75–81. Yamauchi M, Kim EY, Iwata H, Shima Y, Tanabe S. 2006. Toxic effects of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in developing red seabream (Pagrus major) embryo: An association of mor- phological deformities with AHR1, AHR2 and CYP1A expressions. Aquatic Toxicology 80(2): 166–179. Yamazaki Y, Mann MR, Lee SS, Marh J, McCarrey JR, Yanagimachi R, Bartolomei MS. 2003. Re- programming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning. Proceedings of the National Academy of Sciences of the United States of America 100:12207–12212. Yang JZ, Agarwal SK, Foster WG. 2000. Subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin modulates the pathophysiology of endometriosis in the cynomolgus monkey. Toxicological Sciences 56:374–381. Yasuda I, Yasuda M, Sumida H, Tsusaki H, Arima A, Ihara T, Kubota S, Asaoka K, Tsuga K, Akagawa Y. 2005. In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) af- fects tooth development in rhesus monkeys. Reproductie Toxicology 20(1):21–30. Ye L, Leung LK. 2008. Effect of dioxin exposure on aromatase expression in ovariectomized rats. Toxicology and Applied Pharmacology 229(1):102–108. Yen SC, Jaffe RB. 1991. Reproductie Endocrinology. Philadelphia: W.B. Saunders Company. Yoshimura T, Kaneko S, Hayabuchi H. 2001. Sex ratio in offspring of those affected by dioxin and dioxin-like compounds: The Yusho, Seveso, and Yucheng incidents. Occupational and Eni- ronmental Medicine 58(8):540–541. Yu J, Wang Y, Zhou W-H, Wang L, He Y-Y, Li D-J. 2008. Combination of estrogen and dioxin is involved in the pathogenesis of endometriosis by promoting chemokine secretion and invasion of endometrial stromal cells. Human Reproduction 23(7):1614–1626. Zhao D, Lebovic DI, Taylor RN. 2002. Long-term progestin treatment inhibits RANTES (regulated on activation, normal T cell expressed and secreted) gene expression in human endometrial stromal cells. Journal of Clinical Endocrinology and Metabolism 87(6):2514–2519.