9


Fertility and Gestational Outcomes

Chapter Overview

Based on new evidence and a review of prior studies, the committee for Update 2012 did not find any new significant associations between the relevant exposures and fertility or gestational outcomes. Current evidence supports the findings of earlier studies that

•    None of the fertility or gestational outcomes had sufficient evidence of an association with the chemicals of interest.

•    None of the fertility or gestational outcomes had limited or suggestive evidence of an association between the chemicals of interest.

•    There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and endometriosis; decreased sperm counts or sperm quality, subfertility, or infertility; spontaneous abortion, stillbirth, neonatal death, or infant death; and low birth weight or preterm delivery.

•    There is limited or suggestive evidence of no association between paternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and spontaneous abortion.

This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2010, hereafter referred to as Update 2010 (IOM, 2011), on the association between exposure to herbicides and adverse effects on fertility and during gestation. (Analogous shortened names are used to refer to the updates for 1996, 1998, 2000, 2002, 2004, 2006, and 2008 [IOM, 1996,



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9 Fertility and Gestational Outcomes Chapter Overview Based on new evidence and a review of prior studies, the committee for Update 2012 did not find any new significant associations between the relevant exposures and fertility or gestational outcomes. Current evidence supports the findings of earlier studies that • None of the fertility or gestational outcomes had sufficient evidence of an association with the chemicals of interest. • None of the fertility or gestational outcomes had limited or suggestive evidence of an association between the chemicals of interest. • There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and endometriosis; decreased sperm counts or sperm quality, subfertility, or infertility; spon- taneous abortion, stillbirth, neonatal death, or infant death; and low birth weight or preterm delivery. • There is limited or suggestive evidence of no association between paternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and spontaneous abortion. This chapter summarizes the scientific literature published since Veterans and Agent Orange: Update 2010, hereafter referred to as Update 2010 (IOM, 2011), on the association between exposure to herbicides and adverse effects on fertility and during gestation. (Analogous shortened names are used to refer to the updates for 1996, 1998, 2000, 2002, 2004, 2006, and 2008 [IOM, 1996, 673

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674 VETERANS AND AGENT ORANGE: UPDATE 2012 1999, 2001, 2003, 2005, 2007, 2009] of the original report Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam [VAO; IOM, 1994].) 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 TCDD. Because some polychlorinated biphenyls (PCBs), some polychlorinated dibenzo- furans (PCDFs), and some polychlorinated dibenzodioxins (PCDDs) other than TCDD have dioxin-like biologic activity, studies of populations exposed to PCBs or PCDFs were reviewed if their results were presented in terms of TCDD toxic equivalents (TEQs). Although all studies reporting TEQs based on PCBs were reviewed, studies that reported TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration because mono-ortho PCBs typically contribute less than 10% to total TEQs, based on the World Health Organization’s revised toxicity equiva- lency factors (TEFs) of 2005 (La Rocca et al., 2008; van den Berg et al., 2006). The adverse outcomes evaluated in this chapter include impaired fertility (in which declines in sperm quality may be involved), endometriosis, increased fetal loss (spontaneous abortion and stillbirth), neonatal and infant mortality, and the adverse gestational outcomes of low birth weight or preterm delivery. In this update, consideration of the possibility of adverse health outcomes at any time during the lives of all progeny of Vietnam veterans has been moved to a separate chapter: Chapter 10, “Effects on Future Generations.” Because the vast majority of Vietnam veterans are men, the primary focus of the VAO series has been on potential adverse effects of herbicide exposure on men, and the etiologic importance of the exposed party’s sex does not play the dominant role in nonreproductive outcomes that it does in reproductive outcomes. 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, such as endometriosis, are also included in the present chapter. Whenever the information was available, an attempt was made to evaluate the effects of exposure on adult men and women separately. The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. To reduce repetition throughout the report, Chapter 6 characterizes study populations and presents design information related to new publications that report findings on multiple health outcomes or that revisit study populations considered in earlier updates. BIOLOGIC PLAUSIBILITY OF EFFECTS ON FERTILITY AND REPRODUCTION This chapter opens with a general discussion of factors that influence the plausibility of adverse reproductive effects of TCDD and the four herbicides used in Vietnam. There have been few reproductive studies of the four herbicides in

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FERTILITY AND GESTATIONAL OUTCOMES 675 question, particularly picloram and cacodylic acid, and those studies generally have shown toxicity only at very high doses, so the preponderance of the fol- lowing discussion concerns TCDD, which other than in controlled experimental circumstances usually occurred in a mixture of dioxins (dioxin congeners in addition to TCDD). TCDD is stored in fat tissue and has a long biologic half-life, so internal exposure at generally constant concentrations may continue after episodic, high- level exposure to external sources ceases. If a person had high exposure, high amounts of dioxins may still be stored in fat tissue and be mobilized, particularly at times of weight loss. That would not be expected to be the case for nonlipo- philic chemicals, such as cacodylic acid. Dioxin exposure has the potential to disrupt male reproductive function by altering gene expression that is pertinent to spermatogenesis and by altering steroidogenesis (Wong and Cheng, 2011) and to disrupt female reproductive function by altering gene expression pertinent to ovarian follicle growth and maturation, uterine function, placental development, and fetal morphogenesis and growth. A father’s direct contribution to a pregnancy is limited to the contents of the sperm that fertilizes an egg; those contents had long been thought to consist of greatly condensed, transcriptionally inert deoxyribonucleic acid (DNA) consti- tuting half the paternal genome (a haploid set of chromosomes). Consequently, it was believed that paternally-derived damage to the embryo or offspring could only result from changes in sperm DNA, but dioxins have not been shown to mutate DNA sequence. More recently, however, it has been recognized that sperm also carry a considerable collection of ribonucleic acid (RNA) fragments (Kramer and Krawetz, 1997; Krawetz et al., 2011). Although ribosomal and messenger RNAs have been detected, as yet, demonstration of an active role has been limited to several of the small RNAs found in mature sperm (Krawetz, 2005), in such functions as fertilization itself (Amanai et al., 2006), early embryonic develop- ment (Hamatani, 2012; Suh and Blelloch, 2011), and epigenetic determinations (Kawano et al., 2012). Epigenetic effects are ones that result in permanent (heri- table) changes in gene expression without a change in DNA sequence arising from modification to DNA (usually involving methylation) or to other cellular components such as histones and RNAs (Jirtle and Skinner, 2007). Therefore, male infertility or fetal loss associated with exposure to the chemicals of interest (COIs) might be mediated by epigenetic modifications to components of sperm other than their DNA (Krawetz, 2005). A mother’s contribution to a pregnancy is obviously more extensive, and damage to an embryo or offspring can result from epigenetic changes of the egg DNA or from direct effects of exposure on placenta formation and the fetus during gestation. Mobilization of dioxin during pregnancy may be increased because the body is drawing on fat stores to supply nutrients to the develop- ing fetus. TCDD has been measured in human circulating maternal blood, cord

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676 VETERANS AND AGENT ORANGE: UPDATE 2012 blood, and placenta. Thus, dioxin in the mother’s bloodstream could cross the placenta and expose the developing embryo and fetus. Data indicate that dioxin can accumulate in placental tissue, but the amount of TCDD that can transfer to the fetus appears to be very limited—TCDD’s transfer index was the lowest of 13 environmental toxicants evaluated in perfusion studies of human placentas (Mose et al., 2012). On the basis of laboratory animal studies, TCDD can affect reproduction, so a connection between TCDD exposure and human reproductive and gestational effects is biologically plausible. However, definitive conclusions based on ani- mal studies about the potential for TCDD to cause reproductive and gestational toxicity in humans are complicated by differences in sensitivity and suscepti- bility among animals, strains, and species; by the lack of strong evidence of organ-specific effects across species; by differences in route, dose, duration, and timing of exposure in experimental protocols and real-world exposure; and by substantial differences between laboratory animals and humans in the toxicoki- netics of TCDD. 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 gestational effects. However, the preponderance of evidence from animal studies indicates that they do not have reproductive effects. There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of their reproductive or gestational effects. The sections on biologic plausibility of the specific outcomes considered in this chapter present more detailed toxicologic findings that are of particular relevance to the outcomes discussed. ENDOMETRIOSIS Endometriosis (International Classification of Diseases, Ninth Revision [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 endometriosis, endometrial cells are found outside the uterus—usually in other parts of the reproductive system, in the abdomen, or on surfaces near the repro- ductive organs. The ectopic 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, blood released from endometrial lesions has no way to leave the body and results in inflammation and internal bleeding. The degeneration of blood and tissue 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-

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FERTILITY AND GESTATIONAL OUTCOMES 677 mune modulation are established features of endometriosis but do not adequately explain its cause. 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 who have immune-system or hormonal problems experience the tissue growth associ- ated with endometriosis. Despite numerous symptoms that can indicate endome- triosis, 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 Previous Updates Endometriosis was first reviewed in this series of reports in Update 2002, which identified two relevant environmental studies. Additional studies consid- ered in later updates have not changed the conclusion that the evidence is inad- equate or insufficient to support an association with herbicide exposure. Table 9-1 provides a summary of relevant studies that have been reviewed. Update of the Epidemiologic Literature No Vietnam-veteran, occupational, or case-control studies of exposure to the COIs and endometriosis have been published since Update 2010. Environmental Studies Cai et al. (2011) recruited 17 women who were undergoing diagnostic lapa- roscopy for infertility in Japan during October 2004–March 2007. Of those women, 10 were found to have endometriosis, and 7 were not. Serum and peri- toneal fluid were collected from each participant during her follicular phase and analyzed for 7 PCDDs, 10 PCDFs, and 12 dioxin-like PCBs. Concentrations adjusted for lipids were measured with gas chromatography–mass spectrometry, and from them, TEQs attributable to dioxins, to furans, and to PCBs and an overall ­otal in serum and peritoneal fluid were calculated for each participant. t There were no differences in lipid-adjusted TEQ for any of the categories in either serum or peritoneal fluid between women who had endometriosis and women who did not. The authors noted that in women who had high PCDD and PCDF simultaneously in the peritoneal fluid, there was an association with endometrio- sis (odds ratio [OR] = 2.5, 95% confidence interval [CI] 1.17–5.34). Although this finding achieved statistical significance by usual standards, the sample studied was very small and the biologic importance of this isolated result is unclear.

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678 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 9-1  Selected Epidemiologic Studies—Endometriosis (Shaded Entry Is New to This Update) Study Population Study Results Reference ENVIRONMENTAL Studies Conducted in the United States Case-control study of women Results for cases vs controls: Niskar et al., in Atlanta, Georgia, with Total TEQ (determined by GC/MS): OR 2009 endometriosis; 60 cases and 64 = 01.0 (95% CI 0.9–1.1) controls Studies Conducted in Belgium 88 matched triads (264 total); Results for pelvic endometriosis vs Heilier et al., patients with deep endometriotic controls: 2007 nodules, pelvic endometriosis, Dietary fat: OR = 1.0 (95% CI 1.0–1.0) controls matched for age, BMI: OR = 1.0 (95% CI 0.9–1.0) gynecologic practice in Belgium; Occupation: OR = 0.5 (95% CI 0.2–1.1) routes of exposure to DLCs Traffic: OR = 1.0 (95% CI 0.3–2.8) examined Incinerator: OR = 1.0 (95% CI 1.0–1.1) Serum DLC and aromatase activity No association between TEQs Heilier et al., in endometriotic tissue from 47 (determined by GC/MS) of DLCs 2006 patients in Belgium in serum and aromatase activity by regression analyses p-values = 0.37–0.90 for different endometriosis subgroups Endometriosis in Belgian women 50 exposed cases, risk of increase Heilier et al., with overnight fasting serum levels of 10 pg/g lipid of TEQ compounds 2005 of PCDD, PCDF, PCB (determined by GC/MS); OR = 2.6 (95% CI 1.3–5.3) Belgian women with environmental Mean concentration of TEQ (determined Fierens et al., exposure to PCDDs, PCDFs; by GC/MS) 2003 compared analyte concentrations in Cases (n = 10), 26.2 (95% CI 18.2–37.7) cases vs controls Controls (n = 132), 25.6 (95% CI 24.3–28.9) No significant difference Patients undergoing infertility Six exposed cases: OR = 4.6 (95% CI Pauwels et treatment in Belgium; compared 0.5–43.6) al., 2001 number of women with, without endometriosis who had serum dioxin levels up to 100 pg TEQ/g of serum lipid (determined by CALUX bioassay)

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FERTILITY AND GESTATIONAL OUTCOMES 679 TABLE 9-1  Endometriosis, continued Study Population Study Results Reference Studies Conducted in Italy Case-control study of Italian women Results for endometriosis vs controls: Porpora et with endometriosis; 80 cases and dl PCB118 compared to ≤ 13.2 ng/g: al., 2009 78 controls (TEQs determined by 13.3–24.2 ng/g; OR = 3.17 (95% CI CALUX bioassay) 1.36–7.37) ≥ 24.3 ng/g; OR = 3.79 (95% CI 1.61–8.91) Total TEQ compared to ≤ 15.6 pgC- TEQ/g fat: 15.7–29.5 pgC-TEQ/g fat; OR = 0.52 (95% CI 0.18–1.48) ≥ 29.6 pgC-TEQ/g fat; OR = 0.73 (95% CI 0.26–2.01) Case-control study of Italian women Mean total PCBs (ng/g) Porpora et with endometriosis, measured serum Cases, 410 ng/g al., 2006 PCBs Control, 250 ng/g All PCB congeners: OR = 4.0 (95% CI 1.3–13) Pilot study of Italian, Belgian Mean concentration of TCDD (ppt of De Felip et women of reproductive age; lipid): al., 2004 compared concentrations of TCDD, Italy: total TEQ (determined by GC/ Controls (10 pooled samples), 1.6 MS) in pooled blood samples Cases (2 sets of 6 pooled samples), 2.1, from women who had diagnosis of 1.3 endometriosis with controls Belgium: Controls (7 pooled samples), 2.5 Cases (Set I, 5 pooled samples; Set II, 6 pooled samples), 2.3, 2.3 Mean concentration of TEQ (ppt of lipid): Italy: Controls (10 pooled samples), 8.9 ± 1.3 (99% CI 7.2–11.0) Cases (2 sets of 6 pooled samples), 10.7 ± 1.6; 10.1 ± 1.5 Belgium: Controls (7 pooled samples), 24.7 ± 3.7 (99% CI 20–29) Cases (Set I, 5 pooled samples; Set II, 6 pooled samples), 18.1 ± 2.7; 27.1 ± 4.0 continued

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680 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 9-1  Endometriosis, continued Study Population Study Results Reference Residents of Seveso Zones A and B Serum TCDD (ppt): Eskenazi et up to 30 yrs old in 1976; population- ≤ 20 (n = 2 cases), RR = 1.0 (reference) al., 2002a based historical cohort comparing 20.1–100, (n = 8), RR = 1.2 (90% CI incidence of endometriosis across 0.3–4.5) serum TCDD concentrations > 100, (n = 9), RR = 2.1 (90% CI 0.5–8.0) Studies Conducted in Israel Residents of Jerusalem being 8 exposed cases: OR = 7.6 (95% CI Mayani et al., evaluated for infertility; compared 0.9–169.7) 1997 number of women with high TCDD who had (n = 44), did not have (n = 35) a diagnosis of endometriosis Studies Conducted in Japan 17 women undergoing diagnostic TEQ calculated for each person based Cai et al., laparoscopy for infertility, 10 were on PCDDs, PCDFs, and 12 dl-PCBs. 2011 found to have endometriosis and 7 No difference in lipid-adjusted exposure were not levels between those with and without endometriosis. Association was seen with endometriosis and women with high PCDD and PCDF (OR = 2.5, 95% CI 1.2–5.3) 138 infertility patients in Japan; Results for advanced endometriosis: Tsuchiya et laproscopically confirmed case- Total TEQ: OR = 0.5 (95% CI 0.2–1.7) al., 2007 control status, serum dioxin, PCB Genotype-specific: ORs = 0.3–0.6 TEQ (determined by GC/MS); P450 No significant interaction between genetic polymorphism genotype, dioxin TEQ NOTE: BMI, body mass index; CALUX, chemical activated luciferase gene expression; CI, con- fidence interval; dl, dioxin-like; DLC, dioxin-like compound; GC/MS, gas chromatography/mass spectrometry; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p- dioxin; PCDF, polychlorinated dibenzofuran; RR, relative risk or risk ratio; TCDD, 2,3,7,8-tetra­ chloro­­dibenzo-p-dioxin; TEQ, (total) toxic equivalent. Biologic Plausibility Laboratory studies that used animal models and examined gene-expression changes associated with human endometriosis provide evidence of the biologic plausibility of a link between TCDD exposure and endometriosis. Genetic poly- morphisms in the aryl hydrocarbon receptor (AHR) signaling complex have recently been associated with susceptibility to advanced endometriosis in humans (Wu et al., 2012). The first suggestion that TCDD exposure may be linked to endometriosis came as a secondary finding of a study that exposed female rhesus

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FERTILITY AND GESTATIONAL OUTCOMES 681 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 TCDD exposure concentration. The sample was too small to yield a definitive conclusion that TCDD was a causal agent of endometriosis, but it led to numerous studies of the ability of TCDD to promote the growth of preexisting endometriotic lesions. There are a number of mechanisms by which TCDD may promote endo- metrial lesions, which constitute additional support of biologic plausibility of a link between TCDD and endometriosis. Human endometrial tissue and cultured human endometrial epithelial cells both express the AHR; its dimerization part- ner, the aryl hydrocarbon nuclear translocator (Khorram et al., 2002); and three AHR target genes—CYP1A1, 1A2, and 1B1 (Bulun et al., 2000; Willing et al., 2011). That suggests that endometrial tissue is responsive to TCDD. Recently, it was shown that CYP1A1 expression is greater in ectopic endometrial tissue than in eutopic uterine tissue in the absence of TCDD exposure; this suggests that CYP1A1 may play a role in disease etiology (Singh et al., 2008). Other mecha- nisms by which TCDD may promote endometriosis include altering the ratio of progesterone receptor A to B and blocking the ability of progesterone to suppress matrix metalloproteinase expression—actions that promote endometrial-tissue invasion and that are observed in women who have endometriosis (Igarashi et al., 2005). TCDD also induces changes in gene expression that mirror those observed in endometrial lesions. In addition to the induction of CYP1A1 noted above, 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 protein) in endometrial stromal cells, and RANTES concentration and bioactivity are increased in women who have endometriosis (Zhao et al., 2002). The two CC-motif chemokines (chemotactic cytokines), RANTES and macrophage-inflammatory protein 1α (MIP-1α), have been identified as potential contributors to the pathogenesis and progression of endometriosis. Previous studies showed that the combination of 17β-estradiol and TCDD increased the secretion of RANTES and MIP-1α in endometrial stromal cells (Yu et al., 2008), and a more recent study showed that the same combination suppressed the expression of tetraspanin CD82, a tumor-metastasis suppressor, and thus promoted the invasion of endometrial stromal cells (Li et al., 2011). Those results support the idea that TCDD in combination with estradiol may contribute to the development of endometriosis by increasing invasiveness of endometrial cells. Despite that compelling evidence, chronic exposure of rats to TCDD, PCB153, dioxin-like PCB118 or PCB126, or 2,3,4,7,8-PeCDF (the furan congener with the highest TEF) individually or to various mixtures of these chemicals fails to alter endometrial histology in a consistent manner (Yoshizawa

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682 VETERANS AND AGENT ORANGE: UPDATE 2012 et al., 2009). Differences between rodent and human endometrium could account for the lack of observed effects in rats. In summary, experimental studies, particularly ones that used human eutopic and ectopic endometrial tissue, provide evidence of the biologic plausibility of a link between TCDD exposure and endometriosis. Synthesis The studies linking dioxin exposure with endometriosis are few and inconsis- tent. The single new epidemiologic study since Update 2010 found no substantive pattern of dioxin-like activity in serum or in peritoneal fluid that would distin- guish infertile women who do and do not have endometriosis; however, this study was very small and involved a large number of statistical tests. Although animal studies support the biologic plausibility of an association, contemporary human exposures may be too low to show an association consistently. Conclusion On the basis of the evidence reviewed here, in VAO, and in the previous VAO updates, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs 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 Sertoli cells in the seminif- erous tubule epithelium to regulate spermatogenesis. More detailed reviews 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). Recent reviews on the effects of vari- ous environmental toxicants, including TCDD, on testicular steroidogenesis and

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FERTILITY AND GESTATIONAL OUTCOMES 683 spermatogenesis provide insights into potential underlying mechanisms, includ- ing reducing testosterone production in Leydig cells and inhibiting the formation of cyclic adenosine monophosphate (Mathur and D’Cruz, 2011; Svechnikov et al., 2010). Studies of the relationship between chemicals and fertility are less common in women than in men. Some chemicals may disrupt the female hormonal balance 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 that result in menstrual-cycle or ovarian-cycle irregularities, changes in menarche and meno- pause, and impairment of fertility (Bretveld et al., 2006a,b). Conclusions from VAO and Previous Updates The committee responsible for the original VAO report (IOM, 1994) con- cluded that there was inadequate or insufficient evidence of an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and al- terations in sperm characteristics or infertility. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 did not change the conclusion that exposure to the COIs had not been found to be associated with impaired fertility in either men or women. Reviews of the relevant studies are presented in the earlier reports. Tables 9-2 and 9-3 summarize the studies related to male and female fertility, respectively. Update of the Epidemiologic Literature Male Fertility No new epidemiologic studies of exposure to the COIs and effects on male fertility have been published since Update 2010. Female Fertility No Vietnam-veteran, occupational, or case-control studies of exposure to the COIs and female fertility have been published since Update 2010. Environmental Studies The literature searches for Update 2012 identified several studies relating menstrual-cycle characteristics to exposures that might have included COIs.

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FERTILITY AND GESTATIONAL OUTCOMES 715 It is also noteworthy that serum TCDD was not higher in the Yusho mothers than in the general population. Nonetheless, the results raise concerns and in theory would provide some plausibility of later associations with diseases in offspring, from neurodevelopmental impairment to adult-onset chronic diseases. Finally, Kezios et al. (2012) examined the association of maternal exposure to PCBs and infant growth measures in 600 infants (born in 1960–1963) par- ticipating in the Child Health and Development Studies in northern California. Eleven PCB congeners were measured in postpartum maternal seruma, including dioxin-like, mono-ortho PCB 118. Overall, there was no association between PCB 118 concentration and infant birth weight, and no interaction related to infant sex. There was also no association with length of gestation. Biologic Plausibility The available evidence from experimental animal studies indicates that TCDD exposure during pregnancy can reduce body weight at birth but only at high doses. Laboratory studies of the potential male-mediated developmental toxicity of TCDD and herbicides as a result of exposure of adult male animals are inadequate to support conclusions. TCDD and herbicides are known to cross the placenta, and this leads to direct exposure of the fetus. Data from studies of experimental animals also suggest that the preimplantation embryo and devel- oping fetus are sensitive to the toxic effects of 2,4-D and TCDD after maternal exposure. Synthesis Three studies provide some evidence of deficit in birth weight in relation to maternal exposure to DLCs—Konishi et al. (2009, reviewed in Update 2010), Nishijo et al. (2012), and Tsukimori et al (2012b)—some with notably stronger effects in male infants. LBW itself was examined overall only in the Tsukimori study, in which it was found to be significantly increased in association with exposure. None of the studies found associations with prematurity or gestational length continuously. In Tsukimori et al. (2012b), the magnitude of birth weight decrease associated with a 10-fold increase in total TEQ exposure is comparable with that found for maternal active smoking (about a 200-g birth-weight deficit). The implication of this finding is unclear—animal evidence indicates that in utero TCDD exposure can reduce birth weight at high doses in both male and female pups, but there are insufficient data to support conclusions about any sex-specific effects of TCDD. Two older studies had addressed this outcome without reporting separate re- sults by infant sex, and the committee asked researchers from each team whether they could make such a comparison. Both responded to the inquiries, but the information they provided did little to support the hypothesis that there tended

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716 VETERANS AND AGENT ORANGE: UPDATE 2012 to be a lowering of birth weight in male infants. The one previous Vietnam-era study (Kang et al., 2000) reported no association with LBW in 4,140 female military veterans, and Kang replied that a reanalysis showed that the average birth weight of the boys was only slightly lower than that of the girls (see Table 9-7) (H. Kang, US Department of Veterans Affairs, personal communication, February 27, 2013). Eskenazi et al. (2003), in their analysis of the Seveso population that had high TCDD exposures, reported no overall association with SGA and birth weight, although they did not report the results of any analyses that considered effect modification by infant sex; Eskenazi replied to the committee’s question by reporting that the researchers had made the comparison by infant sex but they found nothing of interest and so did not report details (B. Eskenazi, Seveso Women’s Health Study, personal communication, January 30, 2013). There are a number of challenges in conducting these types of epidemiologic studies in a rigorous way. First, the prenatal and immediate postpartum period is not a stable pharmacokinetic state, involving substantial changes in body volume and fat mobilization. Biomarker measures during pregnancy may be substan- tially affected by weight change during pregnancy. Moreover, extrapolation of a more recent biomarker measure back many years to a more relevant period is complicated by intervening pregnancy and breastfeeding events, which result in substantial uncertainty in the index exposure level. Overall, although the commit- tee notes that the animal literature does support an effect of TCDD exposure on birth weight, the epidemiologic literature is insufficiently robust to allow a final determination. However, the committee is concerned about a potential association of maternal exposure with birth weight. Conclusions On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to de- termine whether there is an association between exposure to the COIs and low birth weight or preterm delivery. REFERENCES1 Alberman E. 1984. Low birth weight. In: Bracken MB, ed. Perinatal Epidemiology. New York: Oxford University Press. Pp. 86–98. Alexander GR, Slay M. 2002. Prematurity at birth: Trends, racial disparities, and epidemiology. Men- tal Retardation and Developmental Disabilities Research Reviews 8(4):215–220. 1  Throughout this report, the same alphabetic indicator after year of publication is used consistently for a given reference when there are multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicators in order of citation in a given chapter is not followed.

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