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Maternal Serum Level of 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene and Risk of Cryptorchidism, Hypospadias, and Polythelia among Male Offspring
Abstract
1,1-Dichloro-2,2-bis(p-chlorophenyl))ethylene (p,p'-DDE) is a metabolite of the insecticide 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) and is a ubiquitous environmental contaminant. Nearly everyone in the United States has a detectable serum level of DDE. DDE was recently found to inhibit binding of androgen to its receptor and to block androgen action in rodents. Normal development of male genitalia in mammals depends on androgen action. The authors used stored serum samples to examine the relation between maternal DDE levels during pregnancy and adjusted odds of cryptorchidism (n = 219), hypospadias (n = 199), and polythelia (extra nipples) (n = 167) among male offspring, using a nested case-control design with one control group (n = 552). Subjects were selected from the Collaborative Perinatal Project, a US birth cohort study begun in 1959-1966, when DDE levels were much higher than they are at present. Compared with boys whose mother's recovery-adjusted serum DDE level was less than 21.4 μg/liter, boys with maternal levels greater than or equal to 85.6 μg/liter had adjusted odds ratios of 1.3 (95% confidence interval (Cl): 0.7, 2.4) for cryptorchidism, 1.2 (95% Cl: 0.6, 2.4) for hypospadias, and 1.9 (95% Cl: 0.9, 4.0) for polythelia. For cryptorchidism and polythelia, the results were consistent with a modest-to-moderate association, but in no instance was the estimate very precise. The results were inconclusive.
... For instance, increases in hypertensive disorders have been reported with detectable maternal levels of DDT and its metabolite, dichlorodiphenyldichloroethylene (DDE) (Murray et al., 2018). Furthermore, increased gestational length has been correlated to the maternal presence of DDT (Bravo, Grimalt, Chashchin, Chashchin, & Odland, 2019), whereas the maternal presence of DDE has been linked to increased incidences of PTB (Bergonzi et al., 2011;Tyagi, Garg, Mustafa, Banerjee, & Guleria, 2015;Wood et al., 2007) and in male fetuses, hypospadias and cryptorchidism (Bhatia et al., 2005;Longnecker et al., 2002). Hexachlorocyclohexane (HCH), another commonly encountered environmental organochloride, at detectable levels in neonatal cord blood has been correlated to reduced gestational length (Fang, Liu, Zhao, Zhou, et al., 2019) and LBW in male infants (Fang, Liu, Zhao, Wong, et al., 2019). ...
... " PTB (Sagiv et al., 2018) " low birth weight (Sagiv et al., 2018) Perfluorooctanoic acid ( " gestational length* (Bravo et al., 2019) " birth weight and length (Bravo et al., 2019) " Hypertensive disorders (Murray et al., 2018) Term Placenta " PTB (Tyagi et al., 2015) " neural tube defects (Ren et al., 2011) Term Cord blood # birth weight Dichloro-diphenyldichloroethylene (DDE) TM3/Term Maternal blood " PTB (Bergonzi et al., 2011;Tyagi et al., 2015;Wood et al., 2007) " hypertensive disorders (Murray et al., 2018) " hypospadias, cryptorchidism (Bhatia et al., 2005;Longnecker et al., 2002) Term Cord blood # birth weight Continued Hexachlorocyclohexane (HCH) Term Cord blood # gestational length* (Fang, Liu, Zhao, Zhou, et al., 2019) # birth weight (in ♂) (Fang, Liu, Zhao, Wong, et al., 2019) Term Placenta " neural tube defects (Ren et al., 2011) Chlorpyrifos, diazinon, and propoxur Term Cord blood # birth weight and/or length (Perera et al., 2005) Parathion and diazinon TM1 Maternal blood " low birth weight ( Jaacks et al., 2019) Isopropyl-phenyl phenyl phosphate (IPPP) TM2-TM3 Maternal urine # gestational length* (in ♀) and # PTB (in ♂) (Hoffman et al., 2018) " low birth weight (Hoffman et al., 2018) Bis ( syndrome (Sanchez-Ferrer et al., 2017;Wu et al., 2017), whereas shorter AGD puts males at increased risks for infertility, low sperm count, fewer motile sperm, decreased testosterone levels (Dean & Sharpe, 2013;Eisenberg, Hsieh, Walters, Krasnow, & Lipshultz, 2011), and prostate cancer (Castano-Vinyals et al., 2012). Whereas the resulting adult health consequences for fetal exposure to EDCs remain largely unknown, recent data from animal and human studies have now led to the consideration that a variety of environmental chemicals, including EDCs, can not only disrupt early developmental processes but can also program changes that persist and lead to an increased susceptibility to disease later in life . ...
With the advent of industrialization, humans are exposed to a wide range of environmental chemicals, many with endocrine disrupting potential. As successful maintenance of pregnancy and fetal development are under tight hormonal control, the gestational exposure to environmental endocrine disrupting chemicals (EDC) have the potential to adversely affect the maternal milieu and support to the fetus, fetal developmental trajectory and birth outcomes. This chapter summarizes the impact of exposure to EDCs both individually and as mixtures during pregnancy, the immediate and long-term consequences of such exposures on the mother and fetus, the direct and indirect mechanisms through which they elicit their effects, factors that modify their action, and the research directions to focus future investigations.
... Millions of biological samples have been collected as part of these cohorts and are stored in biorepository freezers for future research [3][4][5][6][7][8][9]. A growing number of studies have now attempted to accurately measure a range of chemical exposures in biobanked maternal biospecimen in order to provide insights into the role of the prenatal environment on offspring health [10][11][12][13][14]. The usefulness of biobanked samples for epidemiological research many years after its collection largely depends on the extent to which sample preservation has affected the chemical levels [15]. ...
Background
Relying on freezer stored biospecimens is preferred in epidemiolocal studies exploring environmental pregnancy exposures and later offspring health. Storage duration may increase the pre-analytical variability, potentially adding measurement uncertainty. We investigated evaporation of maternal serum after long-term biobank storage using ions (sodium, Na ⁺ ; chloride, Cl ⁻ ) recognized for stability and relatively narrow normal biological reference ranges in human serum.
Methods
A chemical analysis study of 275 biobanked second trimester maternal serum from a large Danish pregnancy screening registry. Serum samples were collected between 1985–1995 and stored at -20°C. Ion concentrations were quantified with indirect potentiometry using a Roche Cobas 6000 analyzer and compared according to storage time and normal biological ranges in second trimester. Ion concentrations were also compared with normal biological variation assessed by baseline Na ⁺ and Cl ⁻ serum concentrations from a separate cohort of 24,199 non-pregnant women measured before freezing with the same instrument.
Results
The overall mean ion concentrations in biobanked serum were 147.5 mmol/L for Na ⁺ and 109.7 for Cl ⁻ . No marked linear storage effects were observed according to storage time. Ion concentrations were consistently high across sampling years, especially for specific sampling years, and a relatively large proportion were outside respective normal ranges in second trimester: 38.9% for Na ⁺ and 43.6% for Cl ⁻ . Some variation in concentrations was also evident in baseline serum used as quality controls.
Conclusions
Elevated ion concentrations suggest evaporation, but independent of storage duration in the present study (27–37 years). Any evaporation may have occurred prior to freezer storage or during the first 27 years. Other pre-analytical factors such as low serum volume have likely influenced the concentrations, particularly given the high within year variability. Overall, we consider the biobanked serum samples internally comparable to enable their use in epidemiological studies.
... Evidence collected in human studies, although controversial and with non-univocal results, suggested that endocrine disrupting compounds with mixed estrogenic and anti-androgenic properties might be associated with the risk of TDS development, with some specific differences for the single compounds. Exposure to DDT and DDE, as assessed in pregnant mother's serum samples, was reported to be not associated with an increased risk of hypospadias in studies performed in geographically distinct populations, although a small sample size was included (Raghavan et al. 2018;Flores-Luevano et al. 2003;Longnecker et al. 2002); conversely, a larger study adjusted for potential confounding factors found an increased risk of hypospadias in male offspring of women with serum DDE concentrations in the highest quartile, compared to women in the first quartile during the 14th week of pregnancy (Rignell-Hydbom et al. 2012). Moreover, a study from the Nice area demonstrated that DDE exposure, as assessed in maternal breast milk, was associated with an increased risk of congenital cryptorchidism in male offspring, but no significant association emerged when exposure to DDE was assessed in maternal cord serum samples (Brucker-Davis et al. 2008). ...
In the last 50 years a significant progressive decline of male reproductive health has been documented, with increasing occurrence of semen quality impairment and of some interlinked male genital abnormalities, such as hypospadias, cryptorchidism, and testicular germ-cell cancer, which probably share a common origin during prenatal life and are therefore grouped in a unique pathological condition named testicular dysgenesis syndrome. Since in animal studies endocrine disrupting compounds exerting estrogenic and/or anti-androgenic effects have been demonstrated to significantly impair male reproductive function, a potential etiological role in the occurrence of testicular dysgenesis syndrome has also been postulated. Human studies focusing on the potential role of endocrine disrupting compounds in the development of testicular dysgenesis syndrome are clearly based on prenatal exposure, mainly and heterogeneously assessed by quantification of these compounds in maternal samples at various pregnancy stages; nevertheless, studies are fragmented and very often do not account for multiple exposures, therefore commonly resulting in controversial results. This chapter aimed at providing a summary of available animal and human evidence concerning the association between prenatal exposure to endocrine disrupting compounds, including compounds with estrogenic (diethylstilbestrol, bisphenol A), anti-androgenic (phthalates, pesticides, heavy metals), and mixed estrogenic and anti-androgenic (pesticides dichlorodiphenyltrichloroethane and dichlorodiphenyldichloroethylene, flame retardants, polychlorinated biphenyls, dioxins) properties, and the development of specific components of testicular dysgenesis syndrome, particularly, hypospadias, cryptorchidism, and testicular germ-cell cancer, by outlining their effect per se, independently on genetic and lifestyle factors.
... It exerts a direct influence on the endocrine disruptor in both maternal and fetal tissues. A striking example of the disruption of fetal organ formation by DDT is the malformation of male genitalia reported in numerous publications [21][22][23][24][25]. The dysmorphogenetic effect of DDT on endocrine glands has been less studied. ...
Dichlorodiphenyltrichloroethane (DDT) is the most widespread persistent pollutant with endocrine-disrupting properties. DDT has been shown to disrupt secretory and morphogenetic processes in the adrenal cortex. The present investigation aimed to evaluate transcriptional regulation of postnatal growth of the adrenal medulla and formation of the pools necessary for self-renewal of medullary cells in rats that developed under low-dose exposure to DDT. The study was performed using male Wistar rats exposed to low doses of o,p’-DDT during prenatal and postnatal development. Light microscopy and histomorphometry revealed diminished medulla growth in the DDT-exposed rats. Evaluation of Ki-67 expression in chromaffin cells found later activation of proliferation indicative of retarded growth of the adrenal medulla. All DDT-exposed rats exhibited a gradual decrease in tyrosine hydroxylase production by adrenal chromaffin cells. Immunohistochemical evaluation of nuclear β-catenin, transcription factor Oct4, and ligand of sonic hedgehog revealed increased expression of all factors after termination of growth in the control rats. The DDT-exposed rats demonstrated diminished increases in Oct4 and sonic hedgehog expression and lower levels of canonical Wnt signaling activation. Thus, developmental exposure to the endocrine disruptor o,p’-DDT alters the transcriptional regulation of morphogenetic processes in the adrenal medulla and evokes a slowdown in its growth and in the formation of a reserve pool of cells capable of dedifferentiation and proliferation that maintain cellular homeostasis in adult adrenals.
... The levels of these chemicals are declining, but because of the persistence of the compounds they continue to add to the contaminant load of children in future generations. The associations for individual chemicals, such as DDT or DDE, are not apparent (Damgaard et al., 2006;Longnecker et al., 2002), emphasizing the need to integrate data and use bioinformatic tools to analyze complex data sets. Already rather simple principal component analyses can demonstrate distinct chemical signatures between different regions as exemplified by contrasts between Denmark and Finland (Krysiak-Baltyn et al., 2010). ...
... Third, exposure of humans to DDT is associated with an increased incidence of IUGR 102 (see Fig. 2) and a mild increase in the incidence of hypospadias and cryptorchidism 103 . This is consistent with the demonstration that the main metabolite of DDT is a potent anti-androgen that blocks the androgen receptor and induces these abnormalities in animals 104 . ...
The effects of adult lifestyle - primarily smoking and diet in women, and sedentary habits generally - are important factors affecting the fertility of men and women, and can also impact the fertility of their children. This review summarizes the effects of season, modern lifestyles and environmental chemicals on human fertility, and discusses the implications of these effects for future generations.
... Rather than indirectly measure exposure to potential endocrine-disrupting chemicals via a proxy such as geographical location or occupation, a number of researchers have collected biological specimens and directly tested for the presence of these chemicals. The medium for this analysis varies: many studies have used maternal blood taken during pregnancy, [152][153][154][155][156][157][158] although neonatal serum, 159,160 amniotic fluid, 60 breast milk, 159,161-166 placental tissue/cord blood [159][160][161][162][166][167][168][169][170][171][172] and adipose tissue biopsy from the child 173,174 have also been employed. Those studies investigating early-life environmental exposure to endocrinedisrupting chemicals as a risk factor for cryptorchidism have generally drawn blood from the children themselves. ...
Undescended testis - known as cryptorchidism - is one of the most common congenital abnormalities observed in boys, and is one of the few known risk factors for testicular cancer. The key factors that contribute to the occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur during two hormonally-controlled phases in fetal development - between 8-15 weeks (the first phase of decent) and 25-35 weeks gestation (the second phase of descent); the failure of a testis to descend permanently is probably caused by disruptions to one or both of these phases, but the causes and mechanisms of such disruptions are still unclear. A broad range of putative risk factors have been evaluated in relation to the development of cryptorchidism but their plausibility is still in question. Consistent evidence of an association with cryptorchidism exists for only a few factors, and in those cases in which evidence seems unequivocal the factor is likely to be a surrogate for the true causal exposure. The relative importance of each risk factor could vary considerably between mother-son pairs depending on an array of genetic, maternal, placental and fetal factors - all of which could vary between regions. Thus, the role of causative factors in aetiology of cryptorchidism requires further research.
... Penelitian terdahulu menyatakan paparan pestisida pada awal kehidupan anak dapat mengubah pola perkembangan anak, dan berpengaruh pada disfungsi kesehatan dan beresiko penyakit seusia hidup. Paparan bahan kimia diidentifikasi berpotensi berbahaya bagi perkembangan awal anak diantaranya adalah radiasi ozon (Newcombe & McGregor, 1971), pestisida organoklorin (Longnecker et al., 2002), polusi udara di luar ruangan (Trasande, Landrigan, & Schechter, 2005), dan pestisida tertentu lainnya (Gray et al., 2001), terutama insektisida organofosfat (NRC, 1993). Anak-anak lebih rentan untuk terkena paparan pestisida (NRC, 1993). ...
In achieving better child well-being, international and Indonesia have agreed to increase efforts in the protection of children, including increasing the capacity of parents to perform better parenting. Time-shared activities among parent and children are important factor to create qualified parenting. The purpose of this study was to analyze the time-shared activities among parents-children and child protection in the family and its influence on children’s subjective well-being. This study was a cross-sectional design. Study sites were selected
purposively at Ciputri Village, Pacet Sub District; and Sindang Jaya Village, Cipanas Sub District, Cianjur DistrictWest Java Province. One hundred and twenty families were purposively chosen among farmer families. Findings
showed that the time-shared activities among parents-children were categorized as in low level. Child protection in physical aspect was in the low category but the environmental protection of child was in high category. Children’s subjective well-being was in the high category. Independent variables that influenced the children’s subjective well-being were time-shared activities among parents-children and physical protection. It was recommended to conduct socialization about the importance of child protection and time-shared activities among
parents-children on improving children’s subjective well-being among farmer families.
... 32 Otro estudio realizado por Matthew et al., mostró un aumento en la incidencia de hipospadias en los pacientes expuestos in útero a antagonistas androgénicos como contaminantes ambientales usados en insecticidas. 33 Alteraciones en la producción de Dehidrotestosterona La conversión de testosterona a dehidrotestosterona es catalizada por la acción de la enzima 5á-reductasa. Existen dos isoenzimas conocidas como tipo 1 y 2, que corresponden a dos diferentes genes, el SDR5A1 y SDR5A2 respectivamente. ...
The ever-increasing number of chemicals to which humans are exposed, together with a recognition that some of them are potentially harmful to the male reproductive system, have driven the development of male reproductive toxicology. This was given a boost in 1992 when a 50% decline in sperm counts over the preceding 50 years was reported (Carlsen et al., Br Med J 305:609–613, 1992), stimulating a huge amount of research into adverse effects on the male reproductive system. Somewhat contentious at the time, the claim has nevertheless been supported by similar, subsequent research (Levine et al., Hum Reprod Update 23:646–659, 2017) that was specifically designed to avoid the problems with the earlier study. Even so, no clear cause for the decline has yet been established. In general, adverse effects on the reproductive system have been found experimentally with a wide range of chemicals but relatively rarely under conditions comparable to human exposure. Population-wide monitoring bears this out with only very small effects on reproductive parameters detectable. The nematocide dibromochloropropane is the classic example of an industrial compound that affects the male reproductive system but there is little evidence that many other toxic agents (e.g. metals, complex organochlorine compounds, alcohol, electromagnetic radiation, heat) have comparable effects at normal exposure and adult susceptibility levels. Certain other agents, particularly smoking and ionising radiation, only show limited heritable effects under certain (usually chronic) exposures. The principal risk to sperm production is from anti-cancer therapies, although the available (albeit limited) evidence indicates no heritable effects, perhaps because the exposures are high dose and acute or sub-chronic. Nevertheless, there is considerable concern that unknown factors in the environment, possibly with endocrine disrupting characteristics, are capable of inducing a range of effects sometimes now grouped together as testicular dysgenesis syndrome. Although there is abundant experimental and environmental evidence that a wide range of specific toxins, especially endocrine-disrupting compounds, can induce such effects, epidemiological evidence in humans is mixed (Rodprasert et al., Front Endocrinol 12:706532, 2021). Consequently, the current legislative framework for regulating exposures that could harm the male reproductive system, has not substantively altered in recent years: with the one exception that guidelines have been introduced for the testing of endocrine disruptors. This is also because the roots of male reproductive toxicity in humans are still only poorly understood. Exciting developments over the last decade however, may be pointing the way towards a better understanding of the mechanisms involved.
Die ständig wachsende Zahl von Chemikalien, denen der Mensch ausgesetzt ist, und die Erkenntnis, dass einige von ihnen potenziell schädlich für das männliche Fortpflanzungssystem sind, haben die Entwicklung der männlichen Reproduktionstoxikologie vorangetrieben. Diese Entwicklung erhielt 1992 Auftrieb, als über einen Rückgang der Spermienzahl um 50 % in den vorangegangenen 50 Jahren berichtet wurde (Carlsen et al. 1992, Evidence for decreasing quality of semen during past 50 years. Br Med J 305:609–613), was einen enormen Forschungsaufwand für die Erforschung schädlicher Auswirkungen auf das männliche Fortpflanzungssystem auslöste. Die damals umstrittene Behauptung wurde jedoch durch ähnliche, spätere Untersuchungen (Levine et al. 2017, Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update 23:646–659) gestützt, die speziell darauf ausgerichtet waren, die Probleme der früheren Studie zu vermeiden. Dennoch konnte bisher keine eindeutige Ursache für den Rückgang festgestellt werden. Im Allgemeinen wurden bei einer Vielzahl von Chemikalien experimentell schädliche Auswirkungen auf das Fortpflanzungssystem festgestellt, jedoch relativ selten unter Bedingungen, die mit der Exposition des Menschen vergleichbar sind. Die bevölkerungsweite Überwachung bestätigt dies, wobei nur sehr geringe Auswirkungen auf die Fortpflanzungsparameter feststellbar sind. Das Nematozid Dibromchlorpropan ist das klassische Beispiel für eine industrielle Verbindung, die sich auf das männliche Fortpflanzungssystem auswirkt, aber es gibt kaum Hinweise darauf, dass viele andere toxische Stoffe (z. B. Metalle, komplexe chlororganische Verbindungen, Alkohol, elektromagnetische Strahlung, Wärme) bei normaler Exposition und Empfindlichkeit von Erwachsenen vergleichbare Auswirkungen haben. Bestimmte andere Agenzien, insbesondere Rauchen und ionisierende Strahlung, zeigen nur begrenzte vererbbare Auswirkungen bei bestimmten (meist chronischen) Expositionen. Das größte Risiko für die Spermienproduktion geht von Krebstherapien aus, obwohl die verfügbaren (wenn auch begrenzten) Nachweise darauf hindeuten, dass es keine vererbbaren Auswirkungen gibt, vielleicht weil die Exposition hoch dosiert und akut oder subchronisch ist. Dennoch besteht große Besorgnis darüber, dass unbekannte Faktoren in der Umwelt, die möglicherweise endokrin wirksame Eigenschaften haben, eine Reihe von Wirkungen hervorrufen können, die heute manchmal unter dem Begriff testikuläres Dysgenesiesyndrom zusammengefasst werden. Obwohl es zahlreiche experimentelle und umweltbezogene Beweise dafür gibt, dass eine breite Palette spezifischer Toxine, insbesondere endokrin wirksame Verbindungen, derartige Wirkungen hervorrufen können, stehen vergleichbare Beweise beim Menschen noch aus. Infolgedessen hat sich der derzeitige Rechtsrahmen für die Regulierung von Expositionen, die das männliche Fortpflanzungssystem schädigen könnten, in den letzten Jahren nicht wesentlich geändert, mit der einzigen Ausnahme, dass Leitlinien für die Prüfung von endokrin wirksamen Stoffen eingeführt wurden.¬ Dies liegt auch daran, dass die Ursachen der männlichen Fortpflanzungstoxizität beim Menschen noch immer nur unzureichend bekannt sind. Die aufregenden Entwicklungen des letzten Jahrzehnts könnten jedoch den Weg zu einem besseren Verständnis der beteiligten Mechanismen weisen.
Hypospadias is a congenital malformation of penile urethra with unknown etiology in most cases. Persistent organic pollutant (POP) exposure may disrupt endocrine function during a critical window of development of male genitalia. In animal studies, POPs have been associated with male reproductive disorders, including hypospadias, but only few studies have assessed this relationship in humans. The aim of this study is to investigate the association between hypospadias and POP concentration levels in breast milk, as a proxy for prenatal exposure. This is a nested case-control study of Danish and Finnish mother-son pairs. Maternal breast milk samples were collected between 1997 and 2002, and they represent infant boys born with hypospadias [n = 33 (n = 22 Danish and n = 11 Finnish)] and their 1:1 matched controls. Breast milk samples were analyzed for six classes of POPs [including dioxins, polychlorinated biphenyls, flame retardants and perfluorinated alkylated substances (PFAS)]. We estimated odds ratios (ORs) and 95% confidence intervals (CI) for each chemical class using conditional logistic regression. In addition, a composite exposure score system was used to explore the effect of a POP mixture (four chemical classes): The composite score was categorized as low, moderate, or high exposure, and differences between cases and controls were tested with conditional logistic regression. No statistically significant associations were observed between the sums of the chemical classes and hypospadias in either country. The composite score was unable to detect differences in the risk of hypospadias between the tertiles of POP exposure. Levels of PFAS were significantly higher in Danish than in Finnish breast milk samples. This small study does not provide evidence for an association between hypospadias and exposure to POPs but adds information on quantitative exposures. Further development of multi-exposure models is needed for assessing the potential mixture effect associated with multiple chemical exposures.
Introduction
Male infertility is a widespread disease with an etiology that is not always clear. A number of studies have reported a decrease in sperm production in the last forty years. Although the reasons are still undefined, the change in environmental conditions and the higher exposure to endocrine-disrupting chemicals (EDCs), namely bisphenol A, phthalates, polychlorinated biphenyls, polybrominated diphenyl esters, dichlorodiphenyl-dichloroethylene, pesticides, and herbicides, organophosphates, and heavy metals, starting from prenatal life may represent a possible factor justifying the temporal decline in sperm count.
Aim
The aim of this study is to provide a comprehensive description of the effects of the exposure to EDCs on testicular development, spermatogenesis, the prevalence of malformations of the male genital tract (cryptorchidism, testicular dysgenesis, and hypospadias), testicular tumor, and the mechanisms of testicular EDC-mediated damage.
Narrative review
Animal studies confirm the deleterious impact of EDCs on the male reproductive apparatus. EDCs can compromise male fertility by binding to hormone receptors, dysregulating the expression of receptors, disrupting steroidogenesis and hormonal metabolism, and altering the epigenetic mechanisms. In humans, exposure to EDCs has been associated with poor semen quality, increased sperm DNA fragmentation, increased gonadotropin levels, a slightly increased risk of structural abnormalities of the genital apparatus, such as cryptorchidism and hypospadias, and development of testicular tumor. Finally, maternal exposure to EDCs seems to predispose to the risk of developing testicular tumors.
Conclusion
EDCs negatively impact the testicular function, as suggested by evidence in both experimental animals and humans. A prenatal and postnatal increase to EDC exposure compared to the past may likely represent one of the factors leading to the temporal decline in sperm counts.
Hypospadias is the ectopic opening of the urethra on the penis or scrotum. Exposure to estrogenic and/or anti-androgenic chemicals in utero may play an etiologic role. DDT and the pyrethroids cypermethrin and deltamethrin, are used to control malaria. DDT is estrogenic and its breakdown product DDE is anti-androgenic; cypermethrin and deltamethrin can also disrupt androgen pathways. We examined the relationship between maternal exposure to these insecticides during pregnancy and hypospadias among boys participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) in Limpopo Province, South Africa. We measured peripartum levels of p,p'-DDT and p,p'-DDE in maternal serum and urinary pyrethroid metabolites. We conducted urogenital examination on 359 one-year-old boys. A total of 291 (81.0 %) had phimosis, which prevented full urogenital examination, leaving a final sample of 68 boys for determination of the presence of hypospadias. Diagnosis was based on concordance of two independent physicians. We identified hypospadias in 23 of the 68 boys (34 %). Maternal urinary concentrations of cis-DCCA and trans-DCCA metabolites of cypermethrin and other pyrethroids, were associated with an increased risk for hypospadias, but the other metabolite 3-PBA was not (adjusted relative risk per 10-fold increase = 1.58, 95 % CI 1.07–2.34; 1.61, 95 % CI 1.09–2.36; and 1.48, 95 % CI 0.78–2.78, respectively). No associations were found between p,p'-DDT, p,p'-DDE, 3-PBA or cis-DBCA and hypospadias. We observed a high prevalence of hypospadias among boys without phymosis. Boys with higher prenatal exposure to pyrethroid insecticides were at higher risk of hypospadias. Our findings may have global implications given that pyrethroid insecticides are widely used for malaria control, in agriculture and for home use.
In this chapter, we give a comprehensive review of the currently available literature on environmental factors involved in the etiology of hypospadias. We begin with a description about the prevalence of hypospadias, the clustering of hypospadias in families, the testicular dysgenesis syndrome, and the estrogen hypothesis. We focus the remainder of this chapter on the evidence for environmental factors that may be involved in the etiology of hypospadias and divided the chapter in several parts: exogenous exposure to estrogens, endogenous hormone levels, clinical factors, behavioral factors, occupational factors, and living environment. We summarized the results in a quick overview table. We used the review article that we published in 2012 as basis and updated it with new information and references. We focused on the etiology of isolated hypospadias in humans. Therefore, we did not systematically review animal studies.KeywordsEtiologyAssociationEnvironmentHypospadiasRisk factor
In this chapter, I give an overview of the current knowledge on genes involved in the etiology of hypospadias. I begin with a short description of genes involved in the embryology of the male external genitalia and focus the remainder of this chapter on the evidence for genes relevant to the etiology of hypospadias. I used the review article that we published in 2012 as basis, updated it with new information, and subsequently summarized the main facts in order not to be too detailed. I focus on the etiology of isolated hypospadias in humans. Therefore, I do not review animal studies or syndromic forms of hypospadias.KeywordsEtiologyAssociationGeneHypospadiasMutationPolymorphism
Environmental influences on male reproductive health has been well documented in wildlife and experimental animals, in which mechanisms of action have also been revealed. These examples provide robust evidence of adverse effects of endocrine-disrupting chemicals on male reproductive system. Human effects have been more difficult to pinpoint because of limitations in epidemiological observations, and the best evidence of reproductive toxicity in humans comes from occupational settings and environmental accidents. The general population is exposed to a multitude of chemicals simultaneously—thus mixture effects are of special interest. In utero exposures can cause the most harmful and irreversible effects in postnatal/adult life so that developmental and reproductive toxicities are meaningfully studied in tandem.
Green vegetables, fruits, cereals, and pulses are all rich sources of antioxidants. Retinoic acid, ascorbate, proanthocyanidins, tannins, saponins, melatonin, curcumin, allicin, and alpha-lipoic acid stand documented in plants as bioactive compounds. The international dietary committee advocates a specific quantum of these natural antioxidants through diet. Interestingly, environmental pollution has indeed affected most of these farm products. The use of chemical fertilizers, pesticides and heavy metals in soil has a cumulative effect on human health. Enough evidence is available for the presence of phytoestrogen, xenoestrogen, and a host of other endocrine disruptors in the food. These plant-based nutrients can mimic or enhance the natural hormone's health effects. While endocrine disruptors are found in many everyday products, this review aims to address endocrine disruptors from food in the Asian subcontinent. 'Food for thought' justifies the paradigm shift towards good endocrine health by swaying away from the conventional daily dietary recommendations.
Male reproductive health has declined as indicated by increasing rates of cryptorchidism, i.e., undescended testis, poor semen quality, low serum testosterone level, and testicular cancer. Exposure to endocrine disrupting chemicals (EDCs) has been proposed to have a role in this finding. In utero exposure to antiandrogenic EDCs, particularly at a sensitive period of fetal testicular development, the so-called ‘masculinization programming window (MPW)’, can disturb testicular development and function. Low androgen effect during the MPW can cause both short- and long-term reproductive disorders. A concurrent exposure to EDCs may also affect testicular function or damage testicular cells. Evidence from animal studies supports the role of endocrine disrupting chemicals in development of male reproductive disorders. However, evidence from epidemiological studies is relatively mixed. In this article, we review the current literature that evaluated relationship between prenatal EDC exposures and anogenital distance, cryptorchidism, and congenital penile abnormality called hypospadias. We review also studies on the association between early life and postnatal EDC exposure and semen quality, hypothalamic-pituitary-gonadal axis hormone levels and testicular cancer.
The male reproductive system is exposed to a great number of chemical substances which can interfere with the normal hormonal milieu and reproductive function; these are called endocrine disruptors (EDs). Despite a growing number of studies evaluating the negative effects of EDs, their production is continuously growing although some of which have been prohibited. The prevalence of poor semen quality, hypospadias, cryptorchidism, and testicular cancer have increased in the last decades, and recently, it has been postulated that these could all be part of a unique syndrome called testicular dysgenesis syndrome. This syndrome could be related to exposure to a number of EDs which cause imbalances in the hormonal milieu and oestrogenic over-exposure during the foetal stage. The same EDs can also impair spermatogenesis in offspring and have epigenetic effects. Although studies on animal and in vitro models have raised concerns, data are conflicting. However, these studies must be considered as the basis for future research to promote male reproductive health.
This paper reviews the current knowledge on the environmental effects on penile development in humans. The specific focus is on endocrine-disrupting chemicals (EDCs), a heterogeneous group of natural or manmade substances that interfere with endocrine function, and whether they can induce hypospadias and micropenis in male neonates. Epidemiological data and animal observations first raised suspicions about environmental effects, leading to the testis dysgenesis syndrome (TDS) hypothesis. More recent research has provided stronger indications that TDS may indeed be the result of the direct or indirect effects of EDCs. Drawing on epidemiological and toxicological studies, we also report on the effects of maternal diet and substances like pesticides, phthalates, bisphenol A, and polychlorinated biphenyls. Proximity to contamination hazards and occupational exposure are also suspected to contribute to the occurrence of hypospadias and micropenis. Lastly, the cumulative effects of EDCs and the possibility of transgenerational effects, with the penile development of subsequent generations being affected, raise concerns for long-term public health.
Background
Exposure to endocrine-disrupting chemicals (EDCs) during the critical period of testicular descent may increase the risk of cryptorchidism and male fertility.
Objective
To investigate 27 potential EDCs measured in breast milk as a proxy for perinatal exposure and the risk of cryptorchidism in a prospective cohort.
Method
The Norwegian Human Milk Study (2002–2009) enrolled 2606 mother-infant pairs, of which 1326 were mother-son pairs. In a case-cohort design, we studied 641 male infants who had 27 EDCs already quantified in milk samples: 5 organochlorine pesticides, 14 polychlorinated biphenyls (PCBs), 6 brominated flame retardants, and 2 poly- and perfluoroalkyl substances. We defined cases of congenital, recurrent, persistent and ever-reported cryptorchidism based on questionnaires mothers completed when children were 1, 6, 12 and 24 months old. Variable selection via elastic net logistic regression identified the best cryptorchidism predictors while multivariable logistic regression models determined their effect estimates.
Results
The prevalence of reported congenital cryptorchidism was 6.1%, with half spontaneously descending within six months of birth, after which prevalence stabilized between 2.2 and 2.4%. The ever-reported prevalence of cryptorchidism at 1, 6, 12, or 24 months was 12.2%. Elastic net models identified PCB-74 (OR = 1.31, 95% CI: 1.001–1.703), PCB-114 (OR = 1.36, 95% CI: 1.05–1.77), PCB-194 (OR = 1.28, 95% CI: 1.03–1.53) and β-HCH (OR = 1.26, 95% CI: 1.03–1.53 (per interquartile range increase in concentration of EDCs) as best predictors of congenital cryptorchidism. No EDCs were selected for either recurrent or persistent cryptorchidism, and only PCB-194 was selected by elastic net for ever-reported cryptorchidism (OR = 1.23, 95% CI: 1.01–1.51), in contrast to unpenalized multivariable logistic regression, where most of the individual congeners of PCBs showed significant associations.
Conclusion
In the largest multi-pollutant analysis to date considering potential confounding from co-exposure to other chemicals, perinatal exposure to PCB-74, PCB-114, PCB-194 and β-HCH were associated with increased odds of congenital cryptorchidism. Many PCBs may falsely be associated with cryptorchidism when assessed individually, due to confounding by highly correlated chemicals. Experimental studies are warranted to confirm our findings.
The etiology of hypospadias and cryptorchidism, which are the two most common genital anomalies in males, has not been elucidated. Although prenatal exposure to endocrine-disrupting chemicals (EDCs) may increase the risks of hypospadias and cryptorchidism, the associations have not been confirmed. Therefore, we performed a meta-analysis to establish the relationships between prenatal exposure to EDCs and male genital anomalies. A systematic search of PubMed, EMbase, and Cochrane Library CENTRAL for relevant published studies providing quantitative data on the associations between prenatal EDCs exposure and hypospadias/cryptorchidism in humans was conducted. In total, sixteen case-controlled studies were included. Prenatal exposure to overall EDCs was associated with an increased risk of hypospadias in males (OR, 1.34, 95 % CI 1.12 to 1.60). Although there was no statistically significant association between overall EDCs exposure and cryptorchidism (OR, 1.11, 95 % CI 0.99 to 1.24), exposure to phenol substances was associated with an increased risk of cryptorchidism (OR, 1.81, 95 % CI, 1.12 to 2.93). Using the GRADE tool, we found the overall evidence to be of moderate certainty. In conclusion, the current evidence suggests prenatal EDCs exposure may increase the risk of hypospadias in males.
Insects are more similar in structure and physiology to mammals than plants or fungi. Consequently, insecticides are often of greater toxicity to mammals than herbicides. This is particularly the case with neurotoxins. However, some insecticides are targeted at structures or hormonal systems specific to insects (insect growth regulators/chitin synthesis inhibitors) so are less harmful but can still be mildly haematotoxic. There are, therefore, issues specific to insecticides, which do not occur with other pesticides - hence the need for a book specifically on insecticide toxicology in mammals. The book starts with general issues relating to the mammalian toxicity of insecticides, including target/non-target specificity, nomenclature and metabolism of insecticides. It then goes on to discuss specific types of insecticides including: organochlorines; anticholinesterases; pyrethrum and synthetic pyrethroids; nicotine and the neonicotinoids; insect growth regulators/ecdysone agonists/chitin synthesis inhibitors; insecticides of natural origin; biological insecticides; and insecticides used in veterinary medicine.
Next Generation Risk Assessment (NGRA) can use the so-called Dietary Comparator Ratio (DCR) to evaluate the safety of a defined exposure to a compound of interest. The DCR compares the Exposure Activity Ratio (EAR) for the compound of interest, to the EAR of an established safe level of human exposure to a comparator compound with the same putative mode of action. A DCR ≤ 1 indicates the exposure evaluated is safe. The present study aimed at defining adequate and safe comparator compound exposures for evaluation of anti-androgenic effects, using 3,3-diindolylmethane (DIM), from cruciferous vegetables, and the anti-androgenic drug bicalutamide (BIC). EAR values for these comparator compounds were defined using the AR-CALUX assay. The adequacy of the new comparator EAR values was evaluated using PBK modelling and by comparing the generated DCRs of a series of test compound exposures to actual knowledge on their safety regarding in vivo anti-androgenicity. Results obtained supported the use of AR-CALUX-based comparator EARs for DCR-based NGRA for putative anti-androgenic compounds. This further validates the DCR approach as an animal free in silico/in vitro 3R compliant method in NGRA.
The burden of adverse pregnancy outcomes such as preterm birth and low birth weight is considerable across the world. Several risk factors for adverse pregnancy outcomes have been identified. One risk factor for adverse pregnancy outcomes that is receiving considerable attention in recent years is gestational exposure to endocrine disrupting chemicals (EDCs). Humans are exposed to multitude of environmental chemicals with known endocrine disrupting properties and evidence suggest that exposure to these EDCs have the potential to disrupt maternal-fetal environment culminating in adverse pregnancy and birth outcomes. This review addresses the impact of maternal and fetal exposure to environmental EDCs of natural and man-made chemicals in disrupting the maternal-fetal milieu in human leading to adverse pregnancy and birth outcomes - a risk factor for adult onset non-communicable diseases, the role lifestyle and environmental factors play in mitigating or amplifying the effects of EDCs, the underlying mechanisms and mediaries involved, and the research directions to focus future investigations on to help alleviate the adverse effects from EDC exposures.
Maternal exposure to endocrine-disrupting chemicals (EDCs) is associated with long-term hormone-dependent effects that are sometimes not revealed until maturity, middle age, or adulthood. The aim of this study was to conduct descriptive reviews on animal experimental and human epidemiological evidence of the adverse health effects of in utero and lactational exposure to selected EDCs on the first generation and subsequent generation of the exposed offspring. PubMed, Web of Science, and Toxline databases were searched for relevant human and experimental animal studies on 29 October 29 2018. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated and qualitative data extracted for analysis. The search yielded 73 relevant human and 113 animal studies. Results from studies show that in utero and lactational exposure to EDCs is associated with impairment of reproductive, immunologic, metabolic, neurobehavioral, and growth physiology of the exposed offspring up to the fourth generation without additional exposure. Little convergence is seen between animal experiments and human studies in terms of the reported adverse health effects which might be associated with methodologic challenges across the studies. Based on the available animal and human evidence, in utero and lactational exposure to EDCs is detrimental to the offspring. However, more human studies are necessary to clarify the toxicological and pathophysiological mechanisms underlying these effects.
The mycotoxins zearalenone (ZEN) and alpha-zearalenone (α-ZOL), which are common contaminants of agri-food products, are known for their oestrogenic potential. In addition to mycotoxins, food may also contain pesticides with oestrogenic properties such as 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane (p,p'-DDT) and 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p'-DDE), raising the question on the potential effects of individual and combinations of these xeno-oestrogens on the action of natural oestrogens. The present study employed a mammalian reporter gene assay to assess the effects individual and binary combinations of these environmental and food-borne contaminants on oestrogen nuclear receptor (ER) transactivation. As expected, α-ZOL and ZEN exhibited the strongest oestrogenic potency (EC50: 0.27 ± 0.121 nM and 1.32 ± 0.0956 nM, respectively) whereas p,p'-DDT and p,p'-DDE had weak ER agonistic activity with the maximal response of 28.70 ± 2.97% and 18.65 ± 1.77%, respectively. Concurrent treatment of the mycotoxins and/or pesticides, individually or in binary combination, with 17β-oestradiol (E2) showed either additive, synergistic or antagonistic interactive effects on E2-mediated ER response, depending on the combination ratios, the concentration range of xeno-oestrogens, and the concentration of E2. This study highlights the importance of assessing the mixture effects of chemical contaminants in risk assessment, especially in the area of reproductive and developmental toxicity.
KEYWORDS:
Mycotoxins
Chemical mixtures
Food-borne chemical contaminants
Reporter gene assay
Endocrine disruptor
Reproductive and developmental toxicity
DOI: https://doi.org/10.1016/j.fct.2019.05.014
Purpose of Review
Endocrine disrupting chemicals (EDCs) potentially have a role in causing hypospadias malformation through modifiable in-utero exposure. Considering the emerging literature on the role of potential endocrine disrupting substances on the occurrence of hypospadias and the potential to inform public health efforts to prevent the occurrence of these malformations, we have summarized the current literature, identified areas of consensus, and highlighted areas that warrant further investigation.
Recent Findings
Pharmaceuticals, such as diethylstilbestrol, progestin fertility treatments, corticosteroids, and valproic acid, have all been associated with hypospadias risk. Data on exposure to dichlorodiphenyltrichloroethane and hexachlorobenzene pesticides, as well as non-persistent pollutants, particularly phthalates, is less consistent but still compelling.
Summary
Improving exposure assessment, standardizing sample timing to relevant developmental windows, using clear case identification and classification schemes, and elucidating dose-response relationships with EDCs will help to provide clearer evidence. Promising directions for future research include identification of subgroups with genetic hypospadias risk factors, measurement of intermediate outcomes, and study of EDC mixtures that will more accurately represent the total fetal environment.
This study investigated the use of androgen receptor (AR) reporter gene assay data in a non-animal exposure-led risk assessment in which in vitro anti-androgenic activity and exposure data were put into context using a naturally occurring comparator substance with a history of dietary consumption. First, several dietary components were screened to identify which selectively interfered with AR signaling in vitro, using the AR CALUX® test. The IC50 values from these dose-response data together with measured or predicted human exposure levels were used to calculate exposure:activity ratios (EARs) for the dietary components and a number of other well-known anti-androgenic substances. Both diindolylmethane (DIM) and resveratrol are specifically-acting dietary anti-androgens. The EARs for several anti-androgens were therefore expressed relative to the EAR of DIM, and how this 'dietary comparator ratio' (DCR) approach may be used to make safety decisions was assessed using an exposure-led case study for an anti-androgenic botanical ingredient. This highlights a pragmatic approach which allows novel chemical exposures to be put into context against dietary exposures to natural anti-androgenic substances. The DCR approach may have utility for other modes of action where appropriate comparators can be identified.
Over the last 25 years, researchers and policy makers have become increasingly aware of the deleterious effects that environmental factors and chemical compounds can have on human development and physiology. When considering the effects of such compounds on men's sexual and reproductive health, keen attention has been paid to a specific class of compounds characterized as endocrine-disrupting chemicals (EDCs). Many of these chemicals were initially described in wildlife population studies and were believed to play a negligible role in human health. However, recent studies involving human subjects have purported that EDCs may play a more sinister role in human physiology and development. One prototypical compound is diethylstilbestrol (DES), an estrogenic agent prescribed to nearly 10. million mothers to prevent miscarriages and preterm (early) births between 1938 and 1971. Postapproval monitoring studies revealed that DES had no effect on the rate of miscarriage or premature birth, but it had caused significant urogenital malformations and increased the risk of early-onset clear cell adenocarcinoma of the vagina in offspring exposed in utero. Although chemicals such as DES have clear contraindications and have been removed from the market, many suspected EDCs are still found in common household items, including industrial solvents, lubricants, plastics, pesticides, fungicides, and even food additives. Chemicals such as bisphenol A, monobenzyl phthalates, vinclozolin, and phytoestrogens have made national headlines and gained notoriety for their EDC effects. As the research surrounding the long-term safety of these compounds continues to mature, health and environmental policies that govern their use will continue to be in flux.
La différenciation sexuelle et la fécondité masculines sont le résultat d’une cascade de signaux qui inclut des facteurs cellulaires, génétiques et endocriniens. Les manifestations cliniques des anomalies du développement sexuel masculin sont l’hypogonadisme, l’inversion sexuelle et l’état intersexué. Elles peuvent être dues à des anomalies de la détermination et de la différenciation des gonades, à des troubles de la régulation hypothalamo-hypophyso-gonadique et de la biosynthèse des hormones stéroïdes, à des syndromes d’insensibilité aux hormones et à des anomalies des voies d’excrétion. Après l’examen clinique, un bilan endocrinologique est nécessaire pour distinguer l’hypogonadisme hypergonadotrophique de l’insuffisance gonadique primaire, de l’hypogonadisme hypogonadotrophique des troubles pituitaires et hypothalamiques. Le bilan génétique comprend l’analyse des chromosomes, et pour un nombre croissant d’anomalies un dépistage est aujourd’hui possible, par génétique moléculaire. Dans de nombreux cas, notamment ceux d’inversion sexuelle et d’état intersexué, une approche interdisciplinaire du diagnostic et du traitement est nécessaire.
This article focuses on testicular cancer and its relation to testicular dysgenesis syndrome (TDS) and reviews the current evidence of environmental factors in TDS pathogenesis. Testicular germ cell tumors (TGCT), cryptorchidism, as well as some forms of hypospadias and male infertility are all components of TDS, and it was proposed that these disorders share a common etiology and pathogenesis. Links between these conditions are provided by epidemiological clues and from direct biological evidence that disruption of early testis development and impaired differentiation of cell populations are common features. Main advances in our understanding of human TDS have arisen from studies of germ cell neoplasia in situ (GCNIS), cells with features of transformed gonocytes which failed to differentiate, most likely due to a functional insufficiency of the somatic niche during fetal development. Direct evidence linking specific chemical exposures and disruption of early testis development is sparse. However the potential for direct impacts of chemical exposures and for interactions between the changing environment and the genomic landscape to result in heritable epigenetic changes in the germline are being explored. Molecular markers indicate that testicular development and differentiation rely on largely conserved processes, so information gained from studies of nonhuman species is highly relevant for understanding human testicular cancer. To date, most available evidence in humans comes from the occurrence of genital malformations, especially cryptorchidism, which occur in early childhood. Toxicological studies of human adult manifestations, especially TGCT, are difficult for ethical reasons, highlighting the need for suitable animal models, such as rabbits or dogs. Although rodents are crucial for studying fundamental processes, their windows of susceptibility to endocrine disrupters appear different and TGCTs of the ‘human type’ do not develop. Further advances will arise from efforts to integrate knowledge of (1) the signaling mechanisms that govern key steps in the development and maturation of testicular cells, (2) the effects of toxicants on these processes in animal models and large case-control studies of human subjects with TDS, and (3) the common and species-specific features of normal and disrupted testicular growth. Herein, several of these facets are briefly reviewed and discussed.
Background:
More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders.
Objective and rationale:
The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism.
Search methods:
A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data.
Outcomes:
The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91-1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p'-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04-1.74). The data did not indicate that this increased risk was driven by any specific disorder.
Wider implications:
The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure-response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure-outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field.
Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The only quantitative summary estimate of the link between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago; other reviews of the link between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α-mediated mode of action was specifically explored. Eight studies were included, investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population.
The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community abouthow environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, andepigeneticchanges, therebyproducingeffects inexposedindividuals as well as theirdescendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in arange that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings canbemuchbetter translated tohumanhealth. Armedwith this information, researchers, physicians, andother healthcare providers can guide regulators and policymakers as they make responsible decisions.
Since 1987, the World Health Organization (WHO) carried out global surveys on polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) in human milk. This study presents a review of the three most recent surveys from 2000 to 2010, including DDT. The objective was to identify global quantitative differences and provide baseline information for 52 countries or provide time-trends for countries with previous data. Individual human milk samples were collected following a WHO-designed procedure and combined to form a national pooled sample. Here, we report global levels for PCDDs, PCDFs, PCBs and the sum of o,p'-DDT, p,p'-DDT, o,p'-DDE, p,p'-DDE, o,p'-DDD and p,p'-DDD (ΣDDTs). A concise risk-benefit evaluation related to human milk contamination with these persistent organic pollutants (POPs) was also done. Large global and regional differences were observed. Levels of PCDDs and PCDFs were highest in India and some European and African countries. PCB levels were highest in East and West Europe. The highest levels of ΣDDTs were found in less industrialized countries. A temporal downward trend for PCDDs, PCDFs and PCBs is indicated. A risk-benefit assessment indicates that human milk levels of PCDDs, PCDFs and PCBs are still significantly above those considered toxicologically safe, while ΣDDTs are below or around those considered safe. With respect to potential adverse health effects, a more dominant role of in utero exposure versus lactational exposure is indicated. If potential adverse effects are balanced against positive health aspects for (breastfed) infants, the advantages of breastfeeding far outweigh the possible disadvantages. Our observations provide a strong argument to plea for further global source-directed measures to reduce human exposure further to dioxin-like compounds.
Background:
The biopersistent organochlorine pollutants dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB) and polychlorinated biphenyls (PCBs) can be detected in humans worldwide. The chemicals can cross the placenta and may interfere with endogenous hormonal homeostasis.
Objectives:
To investigate effects on female reproduction following intrauterine exposure to selected biopersistent organochlorines.
Methods:
We used data from a Danish pregnancy cohort with follow-up on 436 eligible daughters at approximately 20years of age. Information on age of menarche (n=335), menstrual cycle length (n=230) and serum concentrations of reproductive hormones (n=243) was obtained. Number of antral follicles was counted by vaginal ultrasound (n=147). Of 244 daughters who attended clinical examination, 170 used hormonal contraceptives and 74 were non-users. Concentrations of p,p'-DDE, HCB and six PCB congeners were analysed in maternal serum samples obtained in pregnancy week 30.
Results:
Age of menarche and menstrual cycle length were found not to be statistically significant associated with prenatal organochlorine exposure. Among non-users of hormonal contraceptives with information on antral follicle number (n=43), daughters exposed to the highest tertile of p,p'-DDE had 28% (95% confidence interval (95% CI): 5; 46%) lower follicle number compared to the low-level exposed reference group. Those exposed to medium and higher levels of HCB had 30% (95% CI: 5; 48%) and 28% (95% CI: 7; 44%) lower follicle number compared to the reference group. Furthermore, maternal serum HCB concentrations were inversely associated with free androgen index among non-users of hormonal contraceptives (n=73). These associations were not found in users of hormonal contraceptives.
Conclusions:
Among non-users of hormonal contraceptives, we found indications of adverse long-term effects on female reproduction following prenatal exposure to biopersistent organochlorines. These findings may have wide implications for public health as intrauterine exposure occurs worldwide.
Climate change endangers human health, affecting all sectors of society, both domestically and globally. The environmental consequences of climate change, both those already observed and those that are anticipated, such as sea-level rise, changes in precipitation resulting in flooding and drought, heat waves, more intense hurricanes and storms, and degraded air quality, will affect human health both directly and indirectly. Addressing the effects of climate change on human health is especially challenging because both the surrounding environment and the decisions that people make influence health. For example, increases in the frequency and severity of regional heat waves—likely outcomes of climate change—have the potential to harm a lot of people. Certain adverse health effects can probably be avoided if decisions made prior to the heat waves result in such things as identification of vulnerable populations such as children and the elderly and ensured access to preventive measures such as air conditioning. This is a simplified illustration; in real-life situations a host of other factors also come into play in determining vulnerability including biological susceptibility, socioeconomic status, cultural competence, and the built environment. In a world of myriad “what if” scenarios surrounding climate change, it becomes very complicated to create wise health policies for the future because of the uncertainty of predicting environmental change and human decisions. The need for sound science on which to base such policies becomes more critical than ever.
Excluding primary testicular failure and diabetes mellitus, endocrine disorders are uncommon but treatable causes ofmale infertility and erectile dysfunction. After treating the cause if possible, testosterone therapy induces puberty and normalizes erectile function in patients with hypogonadotrophic hypogonadism (HH). Infertility in patients with HH is treated by gonadotrophins, complemented with assisted reproductive techniques if necessary. The choice between dopamine agonists or surgery for the treatment of prolactinoma depends on tumour characteristics. The few studies available indicate that thyroid dysfunction is associated with impaired sperm quality. Recent evidence suggests that impaired spermatogenesis is associated with subclinical Leydig cell dysfunction. In these cases long-term follow-up of serum testosterone is recommended. The progressive increase in the incidence of male genital tract anomalies, male infertility and testicular cancer suggests a deleterious effect of environmental factors. The association of these pathologies is called testicular dysgenesis syndrome, TDS. Many studies suggest that TDS is caused by synthetic endocrine disrupters, mostly chemicals with (anti)oestrogenlike actions (xeno-oestrogens).
Introduction “Epigenetics” has been described as the study of changes in gene expression that occur not due to changes in DNA sequence, but rather due to remodeling of the chromatin or modifications in DNA such as methylation, a process by which methyl groups are added to the base cytosine in DNA. Waddington defined “epigenetics” as “… the interactions of genes with their environment which bring the phenotype into being.” In those days, the gene as the unit of heritable material was a theoretical concept without a physical identity. Holliday and Pugh proposed that covalent chemical DNA modifications, including methylation of cytosine–guanine (CpG) dinucleotides, were the molecular mechanisms behind Waddington's hypothesis. Developmental processes are regulated largely by epigenetics, because different cell types maintain their fate during cell division even though their DNA sequences are essentially the same. The further revelations that X chromosome inactivation in mammals and genomic imprinting are regulated by epigenetic mechanisms highlighted the heritable nature of epigenetic gene-regulation mechanisms. The genomics revolution inspired the investigation of global, rather than local, gene analyses, and the term “epigenomics” was coined as the study of the “ … effects of chromatin structure, including the higher order of chromatin folding and attachment to the nuclear matrix, packaging of DNA around nucleosomes, covalent modifications of histone tails (acetylation, methylation, phosphorylation, ubiquitination), and DNA methylation”. The resistance of some gene loci to methylation reprogramming during embryogenesis revealed the possibility that epigenetic modifications are inherited not only during somatic-cell division, but also in subsequent generations.
Women of child-bearing age can be exposed to environmental chemicals that have adverse effects on their hormone homeostasis. These so-called endocrine disruptor (ED) chemicals interfere with the synthesis, secretion, transport, binding, action, and/or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis (normal cell metabolism), reproduction, development, and/or behavior. Experimental and clinical data have confirmed the presence of numerous EDs in the placenta of pregnant women. Consequently, persistent EDs to which women have been exposed in the past and non-persistent EDs to which they have been recently exposed are detected in the blood circulation and tissues of the fetus, where they may have irreversible deleterious effects. The considerable concerns raised about the sensitivity of the embryo and fetus to EDs have led to major research efforts on this issue. Although the potency of EDs is low in comparison to natural hormones, it has been acknowledged that the response within the organism might be amplified by the combined effect of various chemicals acting via the same mechanism. This chapter describes our current state of knowledge on exposure to EDs during pregnancy. A birth cohort established in Spain was used to investigate prenatal exposure to EDs, including the measurement of levels of organochlorine pesticides (OCs), dioxins and furans, benzophenones, parabens, heavy metals, and bisphenols in placenta tissue. We also assessed the combined effect of environmental estrogens, calculated as total effective xenoestrogen burden (TEXB), in placenta extracts. All placentas investigated were positive for at least one out of 17 OCs, with a mean of eight residues per placenta, with p,p'-DDE being the most frequently identified compound. BPA was identified in 58.5%, but none of the chlorinated derivatives were detected. Placenta samples also had at least one of the four selected parabens investigated, with Methylparaben detected in 92% of samples. Among all six benzophenones investigated, only 4-OH-BP and BP-6 were detected in the samples. PCDD/F and DL-PCB concentrations and the congener profile in our series were similar to those reported in other European countries, with OCDD the most abundant PCDD/F congener detected. Of the heavy metals, Cd and Mn concentrations were present in all placentas, while Cr, Pb and Hg were found in 98.5%, 35.0%, and 30.7% of samples respectively, but As was not detected in any sample. Further studies are required to identify and describe pathways of exposure in order to implement preventive measures.
The third edition of this book reviews the global burden of cancer, causes of cancer, and current priorities and future directions in cancer epidemiology and prevention research. The book maintains the structure of previous editions with seventy-two chapters organized into five major sections: Basic Concepts; The Magnitude of Cancer; The Causes of Cancer; Cancer by Tissue of Origin, and Cancer Prevention and Control. The introductory chapters under Basic Concepts highlight the advances in genomic and molecular biology that have applications in morphologic classification of malignant tumors, and in the elucidation of critical genetic events that result in malignant transformation and tumor invasion. The section on the Magnitude of Cancer reviews global patterns of cancer incidence and mortality in relation to country of residence, age, gender, race and ethnicity, and socioeconomic status. The section on The Causes of Cancer reviews the spectrum of environmental, lifestyle and genetic risk factors that are associated with the origin of human cancers. Chapters on Cancer by Tissue of Origin review systematically the demographic, environmental, and host factors that impact the origin and progression of cell-and organ-specific neoplasms. The concluding section, Cancer Prevention and Control, addresses methods and applications for translating epidemiologic, laboratory, and clinical research observations into preventive interventions. Special emphasis is provided on measuring the impact of behavioral interventions on health-promoting practices, as well as governmental policies that regulate environmental carcinogens.
Halogenated organic compounds are highly lipophilic chemicals that are persistent in the environment as a result of their use and chemical stability. Some of these compounds are also present in the environment as metabolites or oxidation products of a parent compound or as by-products formed in the production of chlorinated compounds. Chronic exposure to the general population results mainly through the food chain. Because they are lipophilic, and because many are metabolized slowly, these chemicals tend to concentrate in body fat tissue. This contribution has described these halogenated organic compounds, discussed their use, regulation and prohibition throughout the world, and reviewed published studies on the levels of these chemicals found in the adipose tissue of humans and animals. For many years, residues of halogenated organic compounds have been detected in the human adipose tissue of individuals in a number of countries, including those in Europe, Asia, and Africa, as well as in the U.S. The levels detected have been used as an index of the level of general population exposure of these compounds over time. Over the past two decades, most countries have observed a steady decline of this level of exposure, reflecting a reduction in the use of these compounds, restrictions on or banning of their use, and a corresponding decrease in their environmental levels. The levels of concentrations vary from chemical to chemical as well as from isomer to isomer. Since the use of aldrin and dieldrin has now been banned or restricted in the U.S. and a number of other countries, residue levels have slowly decreased. Mean values in human adipose tissue in the U.S. and some foreign countries ranged from 0.04 to 0.40 ppm for dieldrin. Aldrin was detected only in Argentina and Poland in the 1970s and endrin was not detected anywhere at anytime. By 1978, all products containing BHC registered in the U.S. has been either discontinued or reformulated to incorporate lindane rather than BHC. The potential for exposure to BHC is virtually nonexistent in the U.S.; however, exposure to lindane is possible since products containing this chemical are still marketed, and used particularly in the manufacture of human medicine. DDT was banned for agricultural purposes in the U.S. in 1972, although it is still used elsewhere for public health vector control. Since the decline in use of DDT, however, the average levels of concentration have also declined. Heptachlor, chlordane, and trans-nonachlor (a component of both heptachlor and chlordane) are chlorinated cyclodienes.(ABSTRACT TRUNCATED AT 400 WORDS)
wConcentrations of p, p’-DDT, p, p’-DDE, and p, p’-DDD were determined in serum of members of households of two different areas of KwaZulu. Annual intradomiciliary application of DDT is used for the interruption of malaria transmission in one area (the exposed group) while the other served as the control. Demographic differences between the two groups resulted in significantly more females in the control group. The two groups were comparable with respect to age. Serum from household members living in DDT-treated dwellings had significantly higher (p <.005) levels of ƩDDT and metabolites (mean ƩDDT 140.9 μg/l) than those from the control area (mean ƩDDT 6.04 μg/l). Percentage DDT was also significantly higher (p <.05) in the exposed group (28.9%) than the control group (8.3%). ƩDDT for.
The increase in the number of reports of abnormalities in male sex development in wildlife and humans coincided with the introduction of 'oestrogenic' chemicals such as DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) into the environment. Although these phenotypic alterations are thought to be mediated by the oestrogen receptor, they are also consistent with inhibition of androgen receptor-mediated events. Here we report that the major and persistent DDT metabolite, p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene), has little ability to bind the oestrogen receptor, but inhibits androgen binding to the androgen receptor, androgen-induced transcriptional activity, and androgen action in developing, pubertal and adult male rats. The results suggest that abnormalities in male sex development induced by p,p'-DDE and related environmental chemicals may be mediated at the level of the androgen receptor.
Androgen insensitivity syndrome (AIS) is the most common single entity that results in male under-masculinization, but large cohort studies of AIS have rarely been performed. Over the last decade, nationwide cooperation between pediatric endocrinologists in the United Kingdom has allowed the creation of a database of cases of intersex and ambiguous genitalia where detailed clinical information on every notified case has been collected via a questionnaire. Among the 816 entries recorded by January 1999, there were 105 clinically diagnosed cases of complete AIS (CAIS) and 173 cases of partial AIS (PAIS). A masculinization score was devised by scoring the external phenotype, and a score of 12 represented normal masculinization. Androgen receptor (AR) binding was determined by studying binding capacity (Bmax) and receptor affinity (K(d)), and cases were classified as either zero, abnormal, or normal binding. Mutation screening of all eight exons of the AR gene was performed by single-strand conformational polymorphism analysis, followed by direct DNA sequencing. All cases of PAIS presented within the first month of birth. The median age at presentation of children with CAIS was 1 yr (P10,P90: 0.1,10.4). The testes were palpable in the labioscrotal folds or the inguinal region in 77% and 41% of cases of CAIS and PAIS, respectively. There was marked overlap between the masculinization score of those children with PAIS reared as girls [2.5(P10,P90:1, 6)] and those reared as boys [3(P10,P90:2, 7.5)]. Gonadectomy was performed prepubertally in 66% and postpubertally in 29% of the cases of CAIS. The median age of the latter group was older at 14 yr (P10,P90:0.1,18). No cases of malignancy or carcinoma in situ were reported in the 121 cases of AIS where histology results were available. Biochemical endocrine investigations were reported to have been performed in a greater number of cases of PAIS than CAIS (98% vs. 48%). AR binding was abnormal in 44 of 51 (86%) and 40 of 113 (35%) cases of CAIS and PAIS, respectively. Zero binding was encountered in 29 of 43 (67%) and 1 of 55 (2%) cases of CAIS and PAIS, respectively. Mutational analysis of the AR gene, performed in 102 index cases was positive in 57 of 69 (83%) cases of CAIS and 12 of 43 (28%) cases of PAIS. In 24 of these cases, the mutation identified was novel. The mutations in PAIS cases were all missense, whereas in CAIS the mutations were more diverse. AR binding was only normal in 3 of 69 mutation-positive cases. In the PAIS group, mutation-positive cases had a significantly higher Kd and Bmax compared to the mutation negative cases. The clinical diagnosis of AIS can be confirmed in a significant number of cases by a combination of androgen-binding studies and mutational analysis. There is some correlation between the phenotypic features and the abnormalities discovered on mutational analysis of the AR gene, but there is a need to improve this further by developing optimal bioassays of AR function. The phenotypic heterogeneity among clinically diagnosed cases of AIS emphasizes the need for appropriate comprehensive evaluation of male under-masculinization.
• A high rate of association between supernumerary nipples (SNNs) and hidden renal anomalies has previously been reported. We examined 2035 term infants and detected SNNs in 49. Only one patient, at age 4 months, was found to have a renal anomaly, as determined by ultrasound examination. The likelihood of finding a renal anomaly in a term infant with an SNN is likely to be lower than previously reported.
(AJDC 1987;141:987-988)
• A prospective study on supernumerary nipples (SNNs) was performed on 1,691 consecutively born neonates. We used a new technique for easier routine detection of SNNs. The incidence of this anomaly was one per 40 or 25 per 1,000 live births. Association of other congenital abnormalities with SNNs was not found.
(Am J Dis Child 1983;137:952-953)
Twenty healthy adult humans had serum samples drawn on four occasions within a 24-hr period: after a 12 hr overnight fast, 4–5 hr after a high fat breakfast, at midafternoon, and the next morning after another 12 hr fast. Nonfasting samples had 22% to 29% higher mean concentrations (p < 0.05)="" than="" did="" fasting="" samples="" for="" polychlorinated="" biphenyls="" (pcbs,="" 4.81="" vs="" 3.74="" ng/g="" serum="" wt),="" hexachlorobenzene="" (hcb,="" 0.163="" vs="" 0.134="" ng/g="" serum="" wt),="">p,p-dichlorodiphenyldichloroethylene (p,p-DDE, 6.74 vs 5.37 ng/g serum wt) measured by electron capture gas liquid chromatography. Total serum lipids were estimated from measurements of total cholesterol, free cholesterol, triglycerides, and phospholipids and were 20% higher in nonfasting samples than in fasting samples (7.05 g/L vs 5.86 g/L). When PCBs, HCB, andp,p-DDE concentrations were corrected by total serum lipids, results from fasting and nonfasting samples were not statistically different. Because of the differences in these chlorinated hydrocarbon concentrations observed with different sample collection regimens, meaningful comparison of analytical results requires standardizing collection procedures or correcting by total serum lipid levels.
The population of the Collaborative Study (PRB population) is described and categorized socioeconomically using the technique recently developed by the Bureau of the Census. This combines scores for education, occupation and family income to derive a composite numerical index. Each family is assigned two sets of scores, one derived empirically from the cumulative percentage distribution of these variables in the PRB population and the other from the corresponding scoring system of the Bureau of the Census. The total PRB population and that of the individual institutions are compared socioeconomically with the U.S. population. The various regional differences are discussed. The socioeconomic index devised by the Bureau of the Census is considered an excellent objective and simple descriptive instrument with universal application. Its potentialities as a predictive instrument are discussed.
Studies were performed to compare the effects of 5 alpha-reductase inhibition and antiandrogen receptor blockade on differentiation of male internal and external genital structures and prostate in the rat. Dose-response studies were performed on male rats treated in utero during the period of sexual differentiation with either the potent 5 alpha-reductase inhibitor finasteride or the antiandrogen flutamide. The treated animals were raised to adulthood and killed, and genital structures were evaluated. Treatment with the 5 alpha-reductase inhibitor finasteride at a dose of 25 mg/kg.day resulted in significant feminization of the external genitalia. There was no further feminization of the genitalia at doses up to 300 mg/kg.day. Wolffian ductal differentiation occurred at all doses evaluated. Seminal vesicle weight, however, significantly decreased at 25 mg/kg.day, but without a further decrease at higher doses of the 5 alpha-reductase inhibitor. Vas deferens and epididymal weights were unchanged at all doses evaluated. There was a significant decrease in prostate size at 25 and 50 mg/kg.day, with no further decrease at higher doses. In flutamide-treated animals, complete feminization of the genitalia occurred at 24 mg/kg.day in all animals. At 18 mg/kg.day, Wolffian ductal differentiation occurred, but seminal vesicle weight was decreased. At dosages of 100, 200, and 300 mg/kg.day flutamide, the vas deferens was absent unilaterally or bilaterally, with small remnants of epididymal head and tail present. At dosages of 24 mg/kg.day and above, the prostate was absent. Studies with the 5 alpha-reductase inhibitor finasteride demonstrate the dependency of prostate and male external genital differentiation on dihydrotestosterone (DHT). However, unlike androgen receptor blockade with flutamide, finasteride did not totally abolish prostate differentiation or completely feminize the external genitalia, despite increasingly higher doses. Since there is no evidence of multiple 5 alpha-reductase isoenzymes to date in the rat, these results suggest that testosterone (T) can compensate for DHT to some degree at the level of the androgen receptor. Wolffian differentiation, however, was not affected by inhibition of DHT, demonstrating its T dependency, but seminal vesicle growth was impaired. Thus, inhibition of 5 alpha-reductase activity limits seminal growth potential in adulthood. Studies with the antiandrogen flutamide show that at doses significantly above that required to completely block prostate differentiation and cause genital feminization, Wolffian ductal differentiation is significantly impaired. Thus, higher doses of flutamide are needed to block the paracrine effect of T on the Wolffian ducts.
This study was intended to characterize more fully the distribution of serum concentrations of 16 pesticide residues with regard to key demographic and seasonal variables in a subsample of persons from the Second National Health and Nutrition Examination Survey between the ages of 12 and 74 yr old. Blood sera in 2-ml aliquots were analyzed, and the results were confirmed for 5994 persons. Almost all participants (99.5%) had p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) concentrations greater than or equal to 1 ppb, ranging as high as 378.6 ppb. For the other pesticide residues, only beta-benzene hexachloride (beta-BHC) (quantified in 17.2% of the sera), dieldrin (10.6%), and another DDT-related residue, p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) (35.7%) were found at quantifiable levels in more than 10% of the serum specimens. Of the remaining analytes, hexachlorobenzene (HCB), trans-nonachlor (TNC), and heptachlor epoxide (HE) were found at quantifiable concentrations in 1-10% of the specimens, whereas o,p'-DDT, o,p'-DDE, p,p'-DDD, mirex, alpha-BHC, gamma-BHC, heptachlor, delta-BHC, and aldrin were found in less than 1% of the serum specimens. Results showed that increasing age, residing on a farm, or being a male conferred increased risks of exposure to most of the pesticide residues, independent of all other demographic and seasonal factors. In a pattern less consistent across the different pesticide residues and for fewer of the pesticides, persons who lived below the national poverty level, were nonwhite, resided in the South or West, or were examined in the spring or winter also seemed to have an increased likelihood of having quantifiable serum levels.
The authors measured polychlorinated biphenyls (PCBs) and dichlorodiphenyl dichloroethene (DDE) in maternal serum, cord blood, placenta, and serial samples of breast milk from 868 women. Almost all samples of breast milk showed detectable levels of both chemicals. Overall, values for DDE in this study are within the range of those found previously, whereas those for PCBs are somewhat higher. Possible causes of variation in levels were investigated. For DDE, older women, Black women, cigarette smokers, and women who consumed sport fish during pregnancy had higher levels; only age and race showed large effects. For PCBs, older women, women who regularly drink alcohol, and primiparae had higher levels. In addition, both chemicals showed modest variation across occupational groupings. Casual exposure to a PCB spill did not result in chemical levels different from background. In general, women have higher levels in their first lactation and in the earlier samples of a given lactation, and levels decline both with time spent breast-feeding and with number of children nursed. These striking declines are presumably a measure of exposure to the child.
A high rate of association between supernumerary nipples (SNNs) and hidden renal anomalies has previously been reported. We examined 2035 term infants and detected SNNs in 49. Only one patient, at age 4 months, was found to have a renal anomaly, as determined by ultrasound examination. The likelihood of finding a renal anomaly in a term infant with an SNN is likely to be lower than previously reported.
Paired human serum and adipose tissue samples were analyzed from 50 persons for 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) by high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). On a lipid weight basis, the range of values in adipose tissue spanned approximately 2.5 orders of magnitude, from 3.3 to 969 parts per trillion (ppt). After adjusting the adipose tissue 2,3,7,8-TCDD levels for total lipid content and the serum 2,3,7,8-TCDD levels for total lipid content, the mean of the partitioning ratio of adipose tissue to serum 2,3,7,8-TCDD was 1.09 (standard deviation = 0.385, standard error = 0.060). On this same total lipid weight basis, the adipose tissue and serum levels of 2,3,7,8-TCDD were highly correlated, r = 0.98. The high correlation between adipose tissue and serum 2,3,7,8-TCDD levels in this study indicates that serum 2,3,7,8-TCDD is a valid measurement of 2,3,7,8-TCDD body burden concentration.
Excellent normal ranges for plasma lipid and lipoprotein cholesterol levels have been developed by the Lipid Research Clinics program, standardized by the Centers for Disease Control (CDC). However these values were generated by methods not currently in use in most clinical chemistry laboratories. Automated enzymatic methods for cholesterol, triglycerides and free glycerol determinations, as well as a dextran sulfate-Mg2+ procedure for separation of high density lipoproteins (HDL) with standardization are described. Similar methods for the measurement of unesterified cholesterol and phospholipids are also given. Serum pools for total cholesterol with values ranging from 1220-3490 mg/l produced coefficients of variation (CV) less than or equal to 2.85%; reference values for low total cholesterol samples in a range of 280-727 mg/l gave CV of 4.35% or less; HDL cholesterol reference values of 265-640 mg/l yielded CV less than or equal to 3.70%; and values for triglycerides between 0.74 and 3.05 mmol/l gave CV of 4.22% or less through three to eight testing cycles (9-24 mth). These data indicate that long term CDC standardization of total cholesterol, triglycerides, and HDL cholesterol can be obtained with automated enzymatic methods utilizing commercially available reagents.
A prospective study on supernumerary nipples (SNNs) was performed on 1,691 consecutively born neonates. We used a new technique for easier routine detection of SNNs. The incidence of this anomaly was one per 40 or 25 per 1,000 live births. Association of other congenital abnormalities with SNNs was not found.
In the androgen-induced destruction of the mammary rudiments of 14 day male mouse fetuses, the hormone acts directly only on the mesenchyme, which then condenses around the epithelial gland buds and--in some unknown way--causes their necrosis. In this paper we report that an organ-specific but not species-specific influence of mammary epithelium on the surrounding mesenchyme is required to allow its response to the hormone. This epithelial "signal" has a very short range; its transmission may depend on contact between the two tissues. The requirement for epithelial contact, however, may only exist for those mesenchymal cells that initiate the reaction at the tissue interface, whereas the hormone must act on all the cells that eventually form the mesenchymal condensation. Mesenchyme of the mammary region only is competent to produce this testosterone response. All the mesenchymal cells required for the reaction are already present at the epithelial surface at least 2 days before the hormone response occurs, and our experiments exclude the participation of any cells that could have arrived at the mammary bud through migration from more distant sites.
This article will review the embryology, clinical presentation, diagnosis, treatment, and clinical significance of ectopic breast tissue, supernumerary breasts, and supernumerary nipples. These structures most commonly develop along the embryonic "milk line." Supernumerary nipples can be identified at birth, whereas ectopic breast tissue becomes noticeable only after hormonal stimulation, usually during puberty, pregnancy, or lactation. Axillary ectopic breast tissue may provide a diagnostic challenge, as other benign and malignant lesions occur in this area. Fine needle aspiration is a useful tool. Ectopic breast tissue is subject to the same pathologic events that occur in normally positioned breasts. Excision may be required for diagnosis, treatment of symptoms, or cosmesis. Supernumerary nipples do not themselves pose diagnostic or symptomatic problems, but evidence suggests that they are markers for associated conditions, most notably urologic malformations or urogenital malignancies.
We assessed risk factors for cryptorchidism in a prospective hospital-based cohort study at Mount Sinai Hospital in New York City. We examined at birth 6,699 singleton male neonates who were delivered between October 1987 and October 1990. Follow-up examinations were undertaken at 3 months and 1 year for those diagnosed as cryptorchid at birth. We calculated prevalence ratios and adjusted odds ratios according to selected maternal and neonatal characteristics for those who remained cryptorchid at the 1-year assessment. We found elevated risks for maternal obesity [prevalence ratio = 2.42; 95% confidence interval (CI) = 1.11-5.27], for infants delivered by cesarean section (adjusted odds ratio = 2.17; 95% CI = 1.29-3.65), for low birthweight (adjusted odds ratio = 2.29; 95% CI = 1.12-4.70), for preterm birth (adjusted odds ratio = 2.25; 95% CI = 1.16-4.35), and for infants with congenital malformations (prevalence ratio = 13.97; 95% CI = 1.27-26.67). We observed a seasonal effect, with a peak in births of cryptorchid infants during September through November and a smaller peak during the months of March through May. We found no evidence that young women, white women, or primiparas were at increased risk.
In humans and rodents, exposure to hormonally active chemicals during sex differentiation can produce a wide range of abnormal sexual phenotypes including masculinized and defeminized females and feminized and demasculinized males. Although numerous "environmental estrogens," including pesticides, toxic substances (PCBs), and plant and fungal estrogens, have been shown to alter mammalian sex differentiation, similar information on environmental androgens is lacking. Recently, the fungicide vinclozolin (V) was found to inhibit sexual differentiation in male rats in an antiandrogenic manner. In the present study, V was administered to pregnant rats (p.o.) at 0, 100, or 200 mg/kg/day in corn oil during the period of sex differentiation (Gestational Day 14 to Postnatal Day 3) to examine the demasculinizing effect of this fungicide more closely. In both groups of V-treated male offspring, anogenital distance was female like at birth, and nipple development was prominent at 2 weeks of age. After puberty, most of the V-treated male offspring were unable to attain intromission even though they all mounted sexually receptive females. The V-treated male offspring that appeared to achieve intromission, failed to ejaculate normally, as no sperm were found in the uterus after overnight matings. A factor in the abnormal ejaculation was that all V-treated male offspring had cleft phallus with hypospadias. In addition, a number of unusual reproductive malformations were noted when the males were necropsied at 1 year. Many V-treated male offspring had suprainguinal ectopic scrota/testes, a vaginal pouch, epididymal granulomas, and small to absent sex accessory glands. During the study, about 25% of the V-treated males died as a result of bladder stones, hydroureter, or hydronephrosis, while other males displayed these lesions at necropsy. While some of the above malformations in male offspring can also be produced by perinatal administration of a potent estrogen, like DES, V-treated female offspring did not display any estrogen-like alterations of reproductive development or fecundity. The only change seen in the female offspring was a reduced anogenital distance during neonatal life. Our observation of perinatal-induced agenesis of the prostate and blocked testicular descent, a pattern of malformations nearly identical to that reported for the antiandrogen flutamide, is consistent with other recent evidence that this fungicide is an androgen-receptor antagonist.
Dosemeci et al. (Am J Epidemiol 1990; 132:746-8) gave examples in which nondifferential misclassification of exposure reversed the direction of a trend. Gilbert (Am J Epidemiol 1991; 134:440-1) proposed that these examples occurred because the errors in exposure were systematic, and she pointed out that the relation between the measured and the true exposure was not monotonic. Assuming that the mean response either monotonically increases or decreases with the true exposure and that the exposure misclassification is nondifferential, the authors show that if the mean value of the measured exposure increases with the true exposure, then the direction of the trend cannot be reversed. Consequently, Gilbert's intimation that reversal of trend can only occur when errors are systematic is correct. However, the present authors' result is stronger in that even when errors in assessing exposure do include a systematic component, if monotonicity can be assumed, reversal of trend cannot occur. The weaker condition of positive correlation between the measured and true exposure is not sufficient to guarantee nonreversal of trend, as they show by example.
This paper discusses sampling and design considerations relevant to the estimation of exposure to organochlorine compounds in epidemiological studies. We consider exposures measured directly via biomarkers of exposure in the body. It is critical for the design, implementation, and evaluation of studies that epidemiologists and biostatisticians be familiar with methodological issues relevant to the direct measure of exposure. Etiologic, toxicokinetic, quality control and quality assurance, and statistical sampling are discussed. Finally, the limitations of these studies and the need for complete reporting of methods are discussed.
Maternal serum levels of DDE and polychlorinated biphenyls (PCB) and their congeners were compared for 20 women who had a spontaneous preterm delivery and 20 matched women who had delivered at term at Mount Sinai Medical Center in New York between October 1990 and August 1993. Since no substantial case-control differences were evident, these findings do not indicate that increased DDE or PCB levels are associated with spontaneous preterm birth.
Chlorinated pesticides and polychlorinated biphenyls (PCBs) remain public health concerns because of their unresolved health impact and their persistence in humans. Current epidemiological studies of cancer, non-Hodgkins lymphoma, and endocrine disruption in National Center for Environmental Health (NCEH) laboratories require exposure assessment of many analytes in thousands of people. Previous methods of analyzing pesticides and PCBs in serum have proven inadequate for timely processing of the number of samples required for epidemiological studies. A new method that involves solid-phase extraction (SPE) and cleanup followed by dual-column gas chromatographic separation and electron capture detection has been developed. Nine surrogate compounds were added to the serum prior to sample workup to provide quality assurance for the SPE steps. These surrogates mimic the chemistry of the analytes in the extraction, cleanup, and gas chromatographic analysis steps. To increase selectivity, extracts were injected onto two gas chromatographs with different capillary columns, a DB-1701 and a DB-5. Recoveries of 17 pesticides, 28 PCB congeners, and one polybrominated biphenyl congener ranged from 40 to 80%. Recoveries from this procedure were found to be similar to those from the previously used liquid-liquid extraction method. Correlation of analyte and surrogate recoveries were compared to examine the ruggedness of the technique. The SPE method was found to provide improved sample throughput by a factor of 15.
Supernumerary nipples and supernumerary breast tissue are often dismissed as cosmetic curiosities. These structures have the potential for pathologic degeneration and may be associated with significant congenital abnormalities. In a prospective comparison of 100 Native American women to 100 non-Native American women, these accessory organs were found much more commonly in Native American women. Careful attention should be given to thorough evaluation and long term follow-up of any patient in whom this anomaly is found.
We determined the incidence of defects in 3 enzymes, namely 3beta-hydroxysteroid dehydrogenase, 17alpha-hydroxylase and 17,20-lyase, on the testosterone biosynthetic pathway in boys with hypospadias.
We evaluated 30 boys with a 46,XY karyotype, fully descended testes and penoscrotal or proximal shaft hypospadias. Serum concentrations of the metabolites mediated by these enzymes were measured, from which the precursor-to-product ratios were calculated. Seven patients underwent adrenocorticotropic hormone stimulation. Findings were compared to previously published data on age matched normal boys.
A total of 11 boys had evidence of impaired function of 3beta-hydroxysteroid dehydrogenase alone or in combination with impaired 17,20-lyase or 17alpha-hydroxylase activity. An additional 4 boys had evidence of isolated 17,20-lyase deficiency. Thus, of the 30 boys studied 15 (50%) had evidence of a testosterone biosynthetic defect. The effect of adrenocorticotropic hormone stimulation varied with widening of the precursor-to-product ratios in some boys and narrowing in others.
A high incidence of 3beta-hydroxysteroid dehydrogenase and 17,20-lyase deficiency was found in boys with proximal hypospadias. The response to adrenocorticotropic hormone stimulation suggests that enzymes in the adrenal glands and testes may be affected independently. Our findings support the hypothesis that hypospadias is the result of fetal endocrinopathy.
Although the pesticide DDT has been banned in the United States for decades, it remains at low levels in the environment. p,p'-DDE, a metabolite of DDT, was recently shown to inhibit the binding of androgens to the androgen receptor and to exert antiandrogenic effects in perinatal Long-Evans (LE) rats at a dose of 100 mg/kg/day administered to pregnant dams. In this study, we compared the effects of p,p'-DDE on male sexual development in offspring of Sprague-Dawley (SD) and LE rats. The chemical was dosed by gavage to pregnant dams at 10 or 100 mg/kg body wt from gestation day 14 to 18. The developing male rats were examined for sexual developmental landmarks, while the effects of p,p'-DDE on androgen receptor expression were evaluated in the testis and other reproductive organs. The tissue dosimetry of p,p'-DDE was also determined at different stages of development following in utero and lactational exposures. The higher p,p'-DDE dose induced a reduction in the male anogenital distance, an increase in retention of male thoracic nipples and alterations in expression of the androgen receptor in either one or both strains. A much weaker response was seen in the lower dose groups. Tissue and body fluid concentrations of p,p'-DDE were similar in the two strains in some tissues but dissimilar in others, particularly in the serum levels. Higher serum p,p'-DDE levels in the LE strain during pregnancy corresponded with an overall greater sensitivity of the LE strain to the antiandrogenic effects of p,p'-DDE. These results support the previous findings of p,p'-DDE antiandrogenicity in LE rats, extend the findings to SD rats, and suggest that the developmental effects of p,p'-DDE on male rat sexual differentiation are minimal at maternal doses below 10 mg/kg/day.
We evaluated predictors of plasma concentrations of dichlorodiphenyldichloroethylene (DDE), a metabolite of dichlorodiphenyltrichloroethane (DDT), and polychlorinated biphenyls (PCBs) in a group of 240 women, controls from a breast cancer case-control study nested in the Nurses' Health Study. We considered personal attributes such as age, serum cholesterol, region of residence, adiposity, lactation, and dietary intake. DDE levels increased 0.17 ppb/year of age (p = 0.0003), and PCBs increased 0.08 ppb (p = 0.0001). DDE and PCBs increased 0.20 (p = 0.02) and 0.13 ppb (p = 0.001), respectively, per 10 mg/dl serum cholesterol. Women living in the western United States had higher levels of DDE (mean = 11.0 ppb; p = 0.003), and women in the Northeast and Midwest had higher levels of PCBs (mean = 5.6 ppb; p = 0.0002) as compared to women from other parts of the country (mean DDE = 6.3; mean PCBs = 4. 5 ppb). Levels of DDE could not be predicted from consumption of meat, fish, poultry, dairy products, vegetables, fruits, and grains. There was a positive association between fish consumption and PCB concentrations among women in the Northeast and Midwest. Using data from the cases in the nested case-control study to assess the predictive ability of the models, we confirmed that the most reliable predictors of DDE were age and serum cholesterol, and the most important predictors of PCBs were age, serum cholesterol, and residence in the Midwest or Northeast. The null results for the majority of the food variables suggest that specific dietary factors, other than fish, are not currently a substantial contributor to human exposure to DDE and PCBs.
Researchers from seven European nations and the United States have published reports of increasing rates of hypospadias during the 1960s, 1970s, and 1980s. Reports of increasing rates of cryptorchidism have come primarily from England. In recent years, these reports have become one focus of the debate over endocrine disruption. This study examines more recent data from a larger number of countries participating in the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS) to address the questions of whether such increases are worldwide and continuing and whether there are geographic patterns to any observed increases. The ICBDMS headquarters and individual systems provided the data. Systems were categorized into five groups based on gross domestic product in 1984. Hypospadias increases were most marked in two American systems and in Scandinavia and Japan. The increases leveled off in many systems after 1985. Increases were not seen in less affluent nations. Cryptorchidism rates were available for 10 systems. Clear increases in this anomaly were seen in two U.S. systems and in the South American system, but not elsewhere. Since 1985, rates declined in most systems. Numerous artifacts may contribute to or cause upward trends in hypospadias. Possible "real" causes include demographic changes and endocrine disruption, among others.
In utero exposure to dichlorodiphenyldichloroethene and polychlorinated biphenyls, within the range found in the general U.S. population, may produce detectable effects in offspring. To design studies of the effects of in utero organochlorine exposure, we obtained data on the relationship between gestational and perinatal maternal levels in females on several occasions. We studied 67 pregnant women in the United States who agreed to have their blood drawn once during each trimester and once postpartum. We examined the Pearson correlation coefficient between the natural logarithm of levels (microg/g serum lipid). The correlation, r, among levels in the first and third trimester was .86 and .77 for dichlorodiphenyldichloroethene and for polychlorinated biphenyls. Correlations among levels determined at other times (i.e., second trimester and postpartum) were similar. On the basis of these results, we suggest that in studies of the effects of in utero or perinatal exposure to the aforementioned compounds, the time when specimens are collected is not critical.
We studied risk factors for cryptorchidism and hypospadias.
We performed a register based, case control study of 6,177 boys with cryptorchidism, 1,345 with hypospadias and 23,273 male controls born live in Denmark from 1983 to 1992 to determine the effects of cryptorchidism and hypospadias on the presence of the other abnormality in an individual, the presence of the abnormalities in an older brother, birth weight, weeks of gestation, maternal history of stillbirth, parity, twin birth, parental age, nationality and professional status. Unconditional logistic regression analysis was used to estimate odds ratios.
In an individual simultaneous cryptorchidism and hypospadias were more common than expected. There was an increased risk of both entities when the same abnormality was present in an older brother. The risk of cryptorchidism and hypospadias increased with decreasing birth weight independent of weeks of gestation. Twins were at lower risk than singletons for both entities in all lower birth weight groups. An increased risk of hypospadias was noted in the sons of women who had had a previous stillbirth. The risk of cryptorchidism and hypospadias slightly increased with decreasing parity.
Birth weight was the principal determinant of cryptorchidism and hypospadias. Twins were at lower risk for both abnormalities than singletons in the same birth weight classes. There are indications of separate genetic as well as common environmental causes of cryptorchidism and hypospadias.
The concentrations of chlorinated biphenyls (CBs), 1, 1-bis(4-chlorophenyl)-2,2-dichloroethene (DDE), hexachlorobenzene (HCB), and the methylsulfonyl metabolites of CBs (MeSO(2)-CBs) and DDE (MeSO(2)-DDE) were determined in human plasma samples and in the fractions obtained by ultracentrifugation of plasma into very-low-density (VLDL), low-density (LDL), high-density (HDL) lipoprotein and lipoprotein depleted (LPDP) fractions (containing primarily albumin). The concentrations of triacylglycerols, cholesterol, phospholipids, and apolipoprotein B (apoB) were determined. The organochlorine compounds were associated with all fractions, but predominantly with the LPDP fraction. On an average 44% of CBs, 61% of MeSO(2)-CBs, 73% of DDE, 77% of MeSO(2)-DDE, and 45% of HCB were distributed in the LPDP fraction. A tendency to greater association of 3-methylsulfonyl substituted than of corresponding 4-methylsulfonyl substituted chlorobiphenyls to the LPDP fraction was noticed. Among the lipoprotein fractions, LDL was the main carrier of HCB, DDE and CBs. MeSO(2)-DDE was predominantly found in HDL and MeSO(2)-CBs were distributed equally among the LDL and HDL fractions. Calculating the concentrations of organochlorine compounds in relation to the content of apoB, the levels were about 10 times higher in VLDL than in LDL.
This article is concerned with relating a response or outcome to an exposure and confounders in the presence of measurement error in one or more of the variables. We focus almost entirely on measurement error in a continuous or measured variable. When categorical variables (exposed or not exposed, case or control, quintiles of fat) are measured with error, they are said to be misclassified [see Misclassification Error]. There are also many links in this topic with methods for handling missing data and with validation studies [see Missing data in Epidemiologic Studies; Validation Study]. For further details and a general overview of the topic, see Carroll, et al. [19]; Fuller [30] should be consulted for the linear model. Before describing the problem, it is useful to first consider a number of specific examples that have had an impact on the development of the field.
- Cryptorchidism
- Hypospadias
for cryptorchidism and hypospadias. Epidemiology 1999;10:
364–9.
Risk factor patterns by guest on
- O Akre
- L Lipworth
- S Cnattingius
Akre O, Lipworth L, Cnattingius S, et al. Risk factor patterns
by guest on November 7, 2015
http://aje.oxfordjournals.org/
Downloaded from
322 Longnecker et al.
Am J Epidemiol Vol. 155, No. 4, 2002
The women and their pregnancies. (Publication no. (NIH) 73–379)
- Kr Niswander
- M Gordon
Niswander KR, Gordon M. The women and their pregnancies.
(Publication no. (NIH) 73–379). Washington, DC: US
Department of Health, Education, and Welfare, 1972.
Measurement error in epidemiologic studies
- Rj Carrol
Carrol RJ. Measurement error in epidemiologic studies. In:
Armitage P, Colton T, eds. Encyclopedia of biostatistics, vol 3.
New York, NY: John Wiley and Sons, Inc, 1998:2491–519.
Analysis of biological materials using plasma atomic emission spectroscopy
- J M Mermet
- J Hubert
Mermet JM, Hubert J. Analysis of biological materials using
plasma atomic emission spectroscopy. Prog Analyt Atom
Spectrosc 1982;5:1-32.
for cryptorchidism and hypospadias
for cryptorchidism and hypospadias. Epidemiology 1999;10:
364-9.