Article

High prevalence of micropenis in 2710 male newborns from an intensive-use pesticide area of Northeastern Brazil

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Abstract

Exposure to endocrine-disrupting chemicals (EDCs) has been suggested to contribute to the increasing trends of external genital malformation in male newborns. In Northeastern Brazil, the poor sanitary conditions found in the favelas encourage the widespread use of pesticides. This 2-year study of a total birth cohort of full-term male newborns in the regional hospitals of Campina Grande (Paraíba, Brazil) sought to (1) accurately establish for the first time the incidences of neonatal male genital malformations, (2) investigate the endocrine and genetic aetiologies of these malformations, and (3) evaluate their associations with possible prenatal exposure to EDCs. A total of 2710 male newborns were explored for cryptorchidism, hypospadias and micropenis. Cases were referred to the Pediatric Endocrine Clinic for endocrine and genetic investigations, and all parents were interviewed about their environmental/occupational exposure to EDCs before/during pregnancy by paediatric endocrinologists using a detailed questionnaire. We observed 56 cases of genital malformation (2.07%), including 23 cryptorchidism (0.85%), 15 hypospadias (0.55%), and 18 micropenis (0.66%). All cases exhibited normal/subnormal testosterone production and none presented androgen receptor or 5α-reductase gene mutation. More than 92% of these newborns presented foetal contamination by EDCs, as their mothers reported daily domestic use of pesticides (i.e., DDT) and other EDCs. Most of these undervirilized male newborns presented additional EDC contamination, as 80.36% of the mothers and 58.63% of the fathers reported paid or unpaid work that entailed the use of pesticides and other EDCs before/during pregnancy for the mothers and around the time of fertilization for the fathers. The high rate of micropenis in our population associated with an elevated percentage of parental environmental/occupational exposure to EDCs before/during pregnancy indicates that foetal contamination may be a risk factor for the development of male external genital malformation.

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... Tabela 2. Artigos referentes à exposição de agrotóxicos de gestantes e lactantes e o desenvolvimento de defeitos congênitos. [23] -Estudo transversal -Objetivo: investigas a incidência malformações genitais em neonatos. ...
... Em outro estudo que avaliou os impactos da exposição aos agrotóxicos no período gestacional, encontrou-se maior proporção de nascimentos femininos e, entre os masculinos, um maior risco de malformações genitais (micropênis, dentre outros). A hipótese é que isto ocorra em decorrência de alguns agrotóxicos serem desruptores endócrinos e terem efeitos estrogênicos e antiandrogênicos [23] . ...
... Resultados de outro estudo ecológico, que buscou conhecer a relação entre o uso de agrotóxicos e efeitos adversos nos desfechos gestacionais, apontam associação positiva com a mortalidade por anormalidades congênitas em menores de um ano [23] . Em relação ao efeito no peso ao nascer, em dois [25,31] de três [25,31,26] estudos, encontrou-se associação entre a exposição materna e menor peso. ...
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Os resíduos de alguns agrotóxicos podem ser detectados muitos anos após a exposição devido a sua alta estabilidade e característica lipossolúvel. O leite humano é um bom indicador da exposição ambiental e materna em decorrência da sua representativa fração lipídica e consequente presença de diversos xenobióticos. O objetivo deste artigo foi sistematizar os estudos brasileiros que avaliaram os resíduos de agrotóxicos no leite humano, que estimaram a exposição de gestantes e lactantes aos agrotóxicos e sua relação com desenvolvimento de defeitos congênitos. Os estudos foram identificados utilizando-se as seguintes palavras-chave (e seus equivalentes em inglês): “agrotóxicos”, “pesticidas”, “leite materno”, “leite humano”, “gestante”, “recém nascido” e “Brasil”. Foram selecionados 21 estudos, e em todos foi detectada a presença de ao menos um resíduo de agrotóxico no leite humano. Mulheres que tiveram maior número de gestações e que amamentaram por período mais longo apresentaram menores quantidades de resíduos. Exposição ocupacional e dieta rica em alimentos de origem animal, assim como a menor renda e escolaridade dos pais, estão possivelmente associadas a maiores concentrações de resíduos. A exposição durante a gestação mostra-se mais nociva ao desenvolvimento fetal.
... Recent epidemiological, toxicological and molecular biology studies have shown an increased prevalence of male reproductive disorders, related to testicular cancer, decrease in the number of sperm and male congenital genitourinary malformations [18]. The origin of the latter abnormalities is likely related to various factors, including exposure to endocrine-active pesticides used in agriculture, which have been linked to cryptorchidism [19][20][21], hypospadias [22][23][24] and micropenis [25][26][27]. All these abnormalities represent an underlying developmental disease, the testicular dysgenesis syndrome [28]. ...
... In our study, a higher prevalence and risk of micropenis was observed in children of parents living in areas of high pesticide exposure as compared to those of low exposure (OR: 4.06; Table 3). The prevalence of micropenis varies from 0.015% in the USA to 0.66% in French male newborns [25,26]. Previous studies also reported a higher prevalence of micropenis in newborns of parents with environmental and occupational exposure to endocrine-active pesticides before and during pregnancy [25][26][27]. ...
... The prevalence of micropenis varies from 0.015% in the USA to 0.66% in French male newborns [25,26]. Previous studies also reported a higher prevalence of micropenis in newborns of parents with environmental and occupational exposure to endocrine-active pesticides before and during pregnancy [25][26][27]. ...
Article
There is growing evidence that environmental exposure to pesticides may increase the risk of developing reproductive and developmental disorders. This study determined the prevalence and risk of developing gestational disorders and male congenital genitourinary malformations in areas with distinct exposure to pesticides, many of them with potential endocrine disrupting properties. A population–based case–control study was carried out on pregnant women and male children living in ten health districts of Andalusia classified as areas of high and low environmental exposure to pesticides according to agronomic criteria. The study population included 45,050 cases and 950,620 controls matched for age and health district. Data were collected from computerized hospital records between 1998 and 2005. Prevalence rates and risk of miscarriage, low birth weight, hypospadias, cryptorchidism and micropenis were significantly greater in areas with higher use of pesticides in relation to those with lower use, thus supporting and extending previous information.
... Gaspari et al. (2012)[81]Cross-sectional study Objective: To analyze the incidence of genital malformations in male newborns n = 2710 neonates admitted to the hospital, whose parents had direct contact with pesticides, city of Campina Grande, State of Paraíba ...
... Gaspari et al. (2012)[81]Cross-sectional study Objective: To analyze the incidence of genital malformations in male newborns n = 2710 neonates admitted to the hospital, whose parents had direct contact with pesticides, city of Campina Grande, State of Paraíba ...
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The article aims to present an overview of pesticide usage and population exposure, focusing on the impact on health and the correlation with food and nutrition security (FNS). This review is relevant due to the extensive use of pesticides in food production, which exposes individuals in various ways, including the ingestion of contaminated food, with adverse health effects. Brazil is one of the largest consumers of pesticides in the world, with product sale growth above 200% from 2000 to 2013, increasing the predisposition of the population and environment to the impacts caused by these compounds. The country has weaknesses regarding the monitoring of pesticide usage, besides its vulnerable population affected by social and economic problems. Studies on the correlation between pesticides and diseases have shown potential health risks, including birth defects, hearing loss, cancer, and infertility, in addition to symptoms related to acute intoxication, such as weakness, vomiting, seizures, difficulty breathing, loss of appetite, and nosebleed, among others. Reduction policies in pesticide usage and the encouragement for the sustainable agricultural practices should be prioritized by public managers. It is also essential to improve the monitoring and surveillance programs and research on the topic, as well as training of health professionals to identify and report the cases of pesticide poisoning.
... Almost all of them described the occurrence of effects due to the parents' exposure. The exposure to pesticides before and during the pregnancy, and on the breastfeeding, was associated with higher risk of leukemia 102 , adverse pregnancy outcomes 103,104,105,106 , and congenital abnormalities 107,108 . Some studies investigated the exposure through consumption of pesticides 103,105,106,109 and others estimating the domestic and occupational use 124,104,107,108 . ...
... The exposure to pesticides before and during the pregnancy, and on the breastfeeding, was associated with higher risk of leukemia 102 , adverse pregnancy outcomes 103,104,105,106 , and congenital abnormalities 107,108 . Some studies investigated the exposure through consumption of pesticides 103,105,106,109 and others estimating the domestic and occupational use 124,104,107,108 . The studies and their main results are presented in the Figure 5. ...
Article
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Background: In the region of the Americas, approximately 100.000 children under age of 5 years die each year due to environmental hazards. Brazil, due to its size and wide-range of environmental challenges, presents numerous hazards to children's health. Objective: to review the scientific literature about the exposure of children to environmental pollutants in Brazil, having as core question the existence, or not, of a broad and solid knowledge about this exposure and its impact on Brazilian children's health. Methods: A systematic review of the scientific literature was done without language restrictions and time of publication (years). The literature search was conducted in the following key resources: PubMed (MEDLINE), Scopus and Web of Science with the MeSH Terms: Environmental exposure AND Brazil (filters: Human, Child (birth-18 years) and Affiliation Author). The Virtual Health Library was also employed to access the databases Scielo and Lilacs. The search strategy was [DeCS Terms]: Child OR adolescent AND Environmental exposure AND Brazil. Findings: Health effects associated with exposure to environmental pollutants were reported in 74 studies, during the period between 1995 and 2015. The most frequently cited effect was hospital admission for respiratory causes including wheezing, asthma and pneumonia in children living in areas with high concentrations of air pollutants. A broad spectrum of possible health effects was found such as prematurity, low birth weight, congenital abnormality (cryptorchidism, hypospadia, micropenis), poor performance in tests of psychomotor and mental development and behavioral problems. Exposure to pesticides in uterus and postnatal was associated with a high risk of leukemia in children younger than 2 years old. Conclusions: Results show that there is a need in Brazil for stricter monitoring of pollutant emissions and for health surveillance actions especially among vulnerable populations such as these children.
... The female germline and reproductive health have also been shown to be sensitive to the endocrine disrupting action of pesticides, with long-term adverse effects to offspring [12]. Accordingly, epidemiologic studies have linked parental occupation-and associated pesticide exposure-to cancer and other diseases in their children [13][14][15][16]. ...
... Exposure to mancozeb, a fungicide with wide agricultural and industrial use, is associated with epigenetic changes in the female germline and abnormal reproductive outcomes [12]. Accordingly, epidemiologic studies have linked paternal occupation-and associated pesticide exposure-to cancer and other diseases in their children [13][14][15][16] as discussed in Section 3. ...
Article
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Parental environmental experiences affect disease susceptibility in the progeny through epigenetic inheritance. Pesticides are substances or mixtures of chemicals—some of which are persistent environmental pollutants—that are used to control pests. This review explores the evidence linking parental exposure to pesticides and endocrine disruptors to intergenerational and transgenerational susceptibility of cancer in population studies and animal models. We also discuss the impact of pesticides and other endocrine disruptors on the germline epigenome as well as the emerging evidence for how epigenetic information is transmitted between generations. Finally, we discuss the importance of this mode of inheritance in the context of cancer prevention and the challenges ahead.
... Recreational drugs, smoking, alcohol and obesity impair male fertility. The fetal testis is a major target for endocrine disruptors: herbicides, pesticides, PCBs, plasticizers (Gaspari et al., 2012;Sultan et al., 2001). These can induce a syndrome known as testis dysgenesis syndrome, associated with hypospadias, low sperm counts, testicular cancer, cryptorchidism and ambiguous genitalia. ...
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The negative effect of oxidative stress on the human reproductive process is no longer a matter for debate. Oxidative stress affects female and male gametes and the developmental capacity of embryos. Its effect can continue through late stages of pregnancy. Metabolic disorders and psychiatric problems can also be caued by DNA methylation and epigenetic errors. Age has a negative effect on oxidative stress and DNA methylation, and recent observations suggest that older men are at risk of transmitting epigenetic disorders to their offspring. Environmental endocrine disruptors can also increase oxidative stress and methylation errors. Oxidative stress and DNA methylation feature a common denominator: the one carbon cycle. This important metabolic pathway stimulates glutathione synthesis and recycles homocysteine, a molecule that interferes with the process of methylation. Glutathione plays a pivotal role during oocyte activation, protecting against reactive oxygen species. Assisted reproductive techniques may exacerbate defects in methylation and epigenesis. Antioxidant supplements are proposed to reduce the risk of potentially harmful effects, but their use has failed to prevent problems and may sometimes be detrimental. New concepts reveal a significant correlation between oxidative stress, methylation processes and epigenesis, and have led to changes in media composition with positive preliminary clinical consequences.
... A robust literature has developed exploring the relationship between non-occupational exposure to pesticides and congenital anomalies including developmental abnormalities of the male reproductive tract (Fernandez et al. 2007;Gaspari et al. 2011;Rignell-Hydbom et al. 2012), neural tube defects (Rull et al. 2006;Yang et al. 2014) and oral clefts (Yang et al. 2014). Studies examining the relationship between pesticide exposure and hypospadias have so far yielded equivocal results with several finding an association (Fernandez et al. 2007;Gaspari et al. 2011;Gaspari et al. 2012;Agopian et al. 2013) whereas others have been unable to show a convincing link between exposure and development of hypospadias (Shekharyadav et al. 2011;Rignell-Hydbom et al. 2012). ...
Article
Congenital anomalies are an important cause of infant mortality and disability. Developmental exposure to environmental contaminants is thought to increase the risk for congenital anomalies. Herein, we describe a critical review of the literature conducted between February and March 2014 yielding 3057 references from which 97 unique relevant articles published from 2003 through 2014 were evaluated. Common congenital anomalies including hypospadias, cryptorchidism, anogenital distance (AGD), congenital heart defects and oral clefts were well represented in the literature whereas other outcomes such as neural tube defects, limb deficiency defects and gastroschisis were rarely described. While definitions used for congenital anomalies and methods of ascertainment were usually consistent across studies, inconsistencies were frequently found in grouping of different congenital heart defects. Despite strong links between some congenital anomalies and parental occupation, these studies are unable to provide clear insight into the specific chemicals responsible owing to lack of direct measures of exposure. In comparison, data are mixed for contaminant exposures at concentrations representative of results from contemporary biomonitoring studies. Of the environmental contaminants studied, the association between phthalate exposures and developmental abnormalities of the male reproductive tract received the greatest attention. Important limitations of the literature studied relate to adequacy of sample size, absence of or weaknesses in exposure assessment methodologies, failure to account for biological plausibility and grouping of congenital anomalies with divergent mechanisms. We conclude that the literature is inadequate at this time to support a conclusion that exposure to environmental contaminants are or are not associated with increased risks for congenital anomalies in the general population.
... Adverse birth outcomes data were included as a proxy for exposure to environmental contaminants. Several studies [14][15][16][17] have indicated an association between parental exposure to pesticides and occurrences of congenital defects and exposure to air particulate matter and occurrences of low birth weight. ...
Article
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Background This report presents the Brazilian experience on the elaboration of a matrix of children’s environmental health indicators to the Brazilian Health Surveillance System. This experience was part of a project with the financial support of the Ministry of Health of Brazil to develop appropriate indicators for identification, measuring, and monitoring of the environmental risk factors to the children’s health. Methods The methodology adopted for the development of the matrix of indicators of children’s environmental health to Brazil comprised 3 steps. In the first step, the main causes of morbidity and mortality in the Brazilian population, aged 0-14 years, were identified, according to the data available from the Ministry of Health. The second step consisted of the identification of the Brazilian public-access information systems, with available official data regarding environmental, health, and socioeconomic conditions. In the third step, a preliminary matrix was elaborated. Correlation analyses were done to determine the indicators that would constitute the final matrix. Findings The selected indicators allowed the identification and surveillance of cancer, injuries, adverse birth outcomes, diarrheic and respiratory diseases, associated with environmental risk factors, in the Brazilian child population. The existing Brazilian official information systems provided data with the necessary quality for the construction of children's environmental health indicators. Nevertheless, some official systems on health information presented limitations related to the data availability over the course of time and timeliness of data capture. Concerning the environmental information, the major limitation was accessibility. Conclusions A matrix of indicators of children's environmental health to Brazil can come to contribute to the implementation of a surveillance system of children's exposure to environmental contaminants in Brazil.
... According to epidemiological data, exposure to p,p´-DDT is associated with decreased semen parameters (Jeng 2014;Martenies and Perry 2013). Moreover, cryptorchidism, hypospadias, and micropenis have been reported to be associated with in utero exposure to p,p´-DDT (Damgaard et al. 2006;Gaspari et al. 2012;Hosie et al. 2000;Jeng 2014;Rignell-Hydbom et al. 2012), and the concept of testicular dysgenesis syndrome has been proposed to encompass the spectrum of male reproductive outcomes that have been associated with ED exposure (Wohlfahrt-Veje et al. 2009). In addition, p,p´-DDT has been measured in the ovarian follicular fluids of women (Jarrell et al. 1993;Jirsová et al. 2010), and p,p´-DDT exposures have been associated with evidence of reduced fertility (Jirsová et al. 2010;Venners et al. 2005). ...
Article
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Background: p,p'DDT is an environmental persistent endocrine disruptor (ED). Several studies have shown an association between p,p'DDT exposure and reproductive abnormalities. Objectives: To investigate putative effects of p,p'DDT on the Follitropin receptor (FSHR) function. Methods and results: We investigated the impact of p,p'DDT on the FSHR activity and its interaction with the receptor, using Chinese Hamster Ovary (CHO) cells stably expressing the human FSHR. p,p'DDT, at 5 µM, increased the maximal response of FSHR to follitropin by 32 ± 7.45%.Otherwise, 5µM p,p'DDT decreased the basal activity and didn't influence the maximal response of the closely related LH/hCG receptor to human chorionic gonadotropin hormone. The potentiating effect of p,p'DDT was specific of FSHR. Moreover, in cells, that didn't express FSHR, the p,p'DDT didn't have effect on cAMP response. So, the potenting effect of p,p'DDT was dependent on FSHR. In addition, p,p'DDT increased the sensitivity of FSHR to hCG and to a low molecular weight agonist (16a) of FSHR. Basal activity in response to p,p'DDT and potentiation of the FSHR response to FSH by p,p'DDT varied among FSHR mutants with altered transmembrane domains (TMD), consistent with an effect of p,p'DDT via TMD binding. This was corroborated by the results of docking p,p'DDT and 16a into the FSHR transmembrane bundle simultaneously. Conclusion: p,p'DDT acted as a positive allosteric modulator of FSHR in our experimental model. These findings suggest that G Protein-coupled receptors are additional targets of endocrine disruptors.
... Установлена связь между присутствием в организме беременной и плода пестицидов на северо-востоке Бразилии, где они интенсивно используются, и высокой частотой микропениса и других мальформаций (крипторхизм, гипоспадия) наружных половых органов мальчиков [19]. В результате введения беременным крысам полихлорированных бисфенолов, обладающих, как известно, эстрогеноподобными свойствами, у взрослого потомства женского пола выявлено удлинение эстральных циклов и морфологические изменения в преоптической и медиобазальной областях гипоталамуса, регулирующих половое поведение, гормональный гомеостазис и половую цикличность [20]. ...
... Public concerns over the use of synthetic pesticides are growing since many studies have now shown their impact on human health including different kinds of cancers and neurodegenerative disorders 1,[32][33][34] . Over the last dec- ade, a new environmental movement in the occidental countries, promoting an organic agriculture has allowed the use of some botanical pest control and favoured the rebirth of botanical biopesticides 19 . ...
Article
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Public concerns over the use of synthetic pesticides are growing since many studies have shown their impact on human health. A new environmental movement in occidental countries promoting an organic agriculture favours the rebirth of botanical pesticides. These products confer an effective alternative to chemical pesticides such as glyphosate. Among the biopesticides, the α-terthienyls found in the roots of Tagetes species, are powerful broad-spectrum pesticides. We found that an α-terthienyl analogue with herbicidal properties, called A6, triggers resistant SDS oligomers of the pathogenic prion protein PrPSc (rSDS-PrPSc) in cells. Our main question is to determine if we can induce those rSDS-PrPSc oligomers in vitro and in vivo, and their impact on prion aggregation and propagation. Using wild-type mice challenged with prions, we showed that A6 accelerates or slows down prion disease depending on the concentration used. At 5 mg/kg, A6 is worsening the pathology with a faster accumulation of PrPSc, reminiscent to soluble toxic rSDS-PrPSc oligomers. In contrast, at 10 and 20 mg/kg of A6, prion disease occurred later, with less PrPSc deposits and with rSDS-PrPSc oligomers in the brain reminiscent to non-toxic aggregates. Our results are bringing new openings regarding the impact of biopesticides in prion and prion-like diseases.
... Além de todos esses efeitos já apresentados, os agrotóxicos podem, também, estar relacionados a alterações no binômio mãe-feto, como malformações congênitas 108-111 , nascimentos prematuros, índices de apgar insatisfatórios 9,112 e micropênis em recém-nascidos 113 . ...
Article
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RESUMO Atualmente, o Brasil é o maior consumidor de agrotóxicos do mundo. Diversos estudos comprovam os malefícios para a saúde humana e ambiental da exposição aos agrotóxicos. Realizou-se uma revisão sistemática no período de 2011 a 2017 acerca desse tema em bases de dados científicos. Foram incluídos 116 estudos que demonstraram o impacto negativo para a saúde humana e ambiental. É essencial a realização de estudos sobre os efeitos da exposição crônica e simultânea a diversos agrotóxicos, além de estudos sobre os nexos de determinação estrutural do uso dos venenos e suas consequências.
... They are participating as causal factors in the decrease of sperm count [11]. 92% of newborns with cryptorchidism, hypospadias and/or micropenis presented fetal contamination with EDs (DDT) and their mother (80.36%) and father (58,63%) were involved in works with EDs [12]. ...
... These compounds originated in cow's milk and meat. The fetal testis is a major target for endocrine disruptors: herbicides, pesticides, PCBs, plasticizers (Eladak et al. 2015;Gaspari et al. 2012;Sultan et al. 2001), inducing hypospadias (not impairing "stricto sensu" fertility), low sperm count, testicular cancer, cryptorchidism, undescended testis ambiguous genitalia, in a syndrome called "testis dysgenesis syndrome: TDS": environmental exposures are primary factors involved in the associated trends of the syndrome (Brucker-Davis et al. 2008;Chevalier et al. 2014). They are obviously capable of affecting the adult endocrine system directly or via epigenetic mechanisms (Xing and Bai 2017). ...
Article
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Life expectancy has increased since World War II and this may be attributed to several aspects of modern lifestyles. However, now we are faced with a downturn, which seems to be the result of environmental issues. This paradigm is paralleled with a reduction in human fertility: decreased sperm quality and increased premature ovarian failure and diminished ovarian reserve syndromes. Endocrine Disruptor Compounds (EDCs) and other toxic chemicals: herbicides, pesticides, plasticizers, to mention a few, are a rising concern in today environment. Some of these are commonly used in the domestic setting: cleaning material and cosmetics and they have a known impact on epigenesis and imprinting via perturbation of methylation processes. Pollution from Poly Aromatic Hydrocarbons (PAH), particulate matter (PM), <10 and <2.5 μm and ozone, released into the air all affect fertility. Poor food processing management is a source DNA adducts formation, impairing gametes quality. An important question to be answered is that of nanoparticles (NPs) that are present in food and which are thought to induce oxidative stress. Now is the time to take a step backwards. Global management of the environment and food production is required urgently in order to protect the fertility of future generations. This article is protected by copyright. All rights reserved.
... (Please see reviews [125][126][127]. Fetal exposure to endocrine disrupting chemicals in humans is associated with phenotypes similar to androgen insensitivity syndromes [128,129]. ...
Article
Alfred Jost's work in 1940s laid the foundation of the current paradigm of sexual differentiation of reproductive tracts, which contends that testicular hormones drive the male patterning of reproductive tract system whereas the female phenotype arises by default. Once established, the sex-specific reproductive tracts undergo morphogenesis, giving rise to anatomically and functionally distinct tubular organs along the rostral-caudal axis. Impairment of sexual differentiation of reproductive tracts by genetic alteration and environmental exposure are the main causes of disorders of sex development, and infertility at adulthood. This review covers past and present work on sexual differentiation and morphogenesis of reproductive tracts, associated human disorders and emerging technologies that have made impacts or could radically expand our knowledge in this field.
... In the case of somatic mutations, the patient has 2 cell populations, one carrying the mutation, the other normal [22]. When none of these anomalies are found, prenatal contamination by environmental endocrine pollutants could be discussed [23] [24]. The management of CAIS covers both psychological support and the question of the choice of sexual orientation, the risk of degeneration and, therefore, the need or not for a gonadectomy, hormone replacement therapy, treatment of gynecomastia in the event of PAIS and family genetic counseling [18]. ...
... Similarly, Gaspari et al. studied a unique population in northeastern Brazil where poor sanitation has encouraged widespread pesticide use (49). Over 2 years, the total birth cohort of full-term newborns from a regional hospital was analyzed. ...
Article
Introduction: Endocrine disruptors or environmental agents, disrupt the endocrine system, leading to various adverse effects in humans and animals. Although the phenomenon has been noted historically in the cases of diethylstilbestrol (DES) and dichlorodiphenyltrichloroethane (DDT), the term "endocrine disruptor" is relatively new. Endocrine disruptors can have a variety of hormonal activities such as estrogenicity or anti-androgenicity. The focus of this review concerns on the induction of hypospadias by exogenous estrogenic endocrine disruptors. This has been a particular clinical concern secondary to reported increased incidence of hypospadias. Herein, the recent literature is reviewed as to whether endocrine disruptors cause hypospadias. Methods: A literature search was performed for studies involving both humans and animals. Studies within the past 5 years were reviewed and categorized into basic science, clinical science, epidemiologic, or review studies. Results: Forty-three scientific articles were identified. Relevant sentinel articles were also reviewed. Additional pertinent studies were extracted from the reference of the articles that obtained from initial search results. Each article was reviewed and results presented. Overall, there were no studies which definitely stated that endocrine disruptors caused hypospadias. However, there were multiple studies which implicated endocrine disruptors as one component of a multifactorial model for hypospadias. Conclusions: Endocrine disruption may be one of the many critical steps in aberrant development that manifests as hypospadias.
... Estudo de coorte realizado por Gaspari et al. (2012) em hospitais regionais da cidade de Campina Grande, no estado da Paraíba, avaliou a associação entre malformações congênitas masculinas e possível exposição pré-natal a disruptores endócrinos. Foram avaliados 2.710 recém-nascidos quanto à criptorquidia, hipospádia e micropênis. ...
... Prenatal exposure to DDT has been linked to abnormalities in male sexual development like hypospadias and micropenis (Gaspari et al. 2012). DDT has also been detected in the ovarian follicular fluids of women (Jarrell et al. 1993;Jirsová et al. 2010) and has been associated with lower implantation rate (Al-Hussaini et al. 2018) and reduced fertility. ...
Article
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Dichlorodiphenyltrichloroethane (p,p′DDT) is an endocrine-disrupting chemical (EDC). Several studies showed an association between p,p′DDT exposure and reprotoxic effects. We showed that p,p′DDT was a positive allosteric modulator of human follitropin receptor (FSHR). In contrast, we demonstrated that p,p′DDT decreased the cyclic AMP (cAMP) production induced by human choriogonadotropin (hCG). This study evaluated further the effects of p,p′DDT on Gs-, β-arrestin 2- and steroidogenesis pathways induced by hCG or luteinizing hormone (LH). We used Chinese hamster ovary cells line stably expressing hCG/LHR. The effects of 10–100 µM p,p′DDT on cAMP production and on β-arrestin 2 recruitment were measured using bioluminescence and time-resolved resonance energy transfer technology. The impact of 100 µM of p,p′DDT on steroid secretion was analysed in murine Leydig tumor cell line (mLTC-1). In cAMP assays, 100 µM p,p′DDT increased the EC50 by more than 300% and reduced the maximum response of the hCG/LHR to hCG and hLH by 30%. This inhibitory effect was also found in human granulosa cells line and in mLTC-1 cells. Likewise, 100 µM p,p′DDT decreased the hCG- and hLH-promoted β-arrestin 2 recruitment down to 14.2 and 26.6%, respectively. Moreover, 100 µM p,p′DDT decreased by 30 and 47% the progesterone secretion induced by hCG or hLH, respectively, without affecting testosterone secretion. This negative effect of p,p'DDT was independent of cytotoxicity. p,p′DDT acted as a negative allosteric modulator of the hCG/LHR signalling. This emphasizes the importance of analyzing all receptor-downstream pathways to fully understand the deleterious effects of EDC on human health.
... Cette même étude avait démontré une relation significative entre les malformations génitales suscitées et l'exposition professionnelle des parents aux pesticides avec un odds ratio (OR) de 4,41 avec un intervalle de confiance à 95 %, de 1,21 à 16,00 [8]. Une cohorte brésilienne publiée en 2012 portant sur 2710 nouveau-nés de sexe masculin avait objectivé un taux élevé de malformations génitales externes de l'ordre de 2,07 % dont 0,85 % cas de cryptorchidie, 0,55 % cas d'hypospadias et 0,66 % cas de micropénis ; 92 % de ces nouveau-nés avaient des parents ayant une exposition environnementale et/ou professionnelle aux perturbateurs endocriniens, en particulier des pesticides avant et/ou pendant la grossesse [9]. ...
Article
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Déterminer la prévalence et le profil étiologique du micropénis.
... This complicates an assessment of the TDS hypothesis, not least because only a limited range of chemicals have been investigated. Studies of paternal and maternal pesticide exposures in agricultural occupational settings have reported associations with cryptorchidisms and hypospadias, but due to their design, could not pinpoint specific chemicals (Pierik et al. 2004, Carbone et al. 2006, Gaspari et al. 2012. There is evidence for associations of DES (Palmer et al. 2009) and polybromi-Q2 nated diphenyl ethers (Carmichael et al. 2010) with the risk of developing cryptorchidisms. ...
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It has been hypothesized that the rise in male reproductive disorders over recent decades may at least be partially attributable to environmental factors, including chemical exposures, but observed associations with single chemicals were rather weak. The aim of this case–control study was to explore the relationship between exposure to mixtures of (anti-)androgenic chemicals during pregnancy and the risk of cryptorchidism and/or hypospadias in offspring, using the total effective xenobiotic burden of anti-androgens (TEXB-AA) as a biomarker. A subsample of 29 cases (16 of cryptorchidism, 12 of hypospadias, and one of both disorders) and 60 healthy controls was nested in a cohort of male newborns recruited between October 2000 and July 2002. The (anti-)androgenic activity of placenta samples collected at delivery was assessed using TEXB-AA biomarker, combined with a bioassay-directed fractionation protocol that separated endogenous hormones from most (anti-)androgenic chemicals by normal-phase HPLC. The bioassay measures the androgen-induced luciferase activity and the inhibition of this pathway by (anti-)androgens. First, we collected 27 HPLC fractions in each placenta extract, which were all tested in the bioassay. The multivariable statistical analyses indicated a statistically significant positive dose–response association between the potent anti-androgenic activity of the HPLC fraction collected during minutes 1–2 (F2) and the risk of malformations (odds ratio: 2.33, 95% CI: 1.04–5.23). This study represents a novel approach for the estimation of combined effects of the total anti-androgenic load and the associations suggest an effect of environmental pollutants on the development of fetal reproductive tract. Free Spanish abstract : A Spanish translation of this abstract is freely available at http://www.reproduction-online.org/content/149/6/605/suppl/DC1 .
... Hay pacientes con fenotipo PAIS que algunos autores denominan "idiopáticos" ya que no se ha detectado ninguna alteración genética. En algunos casos se ha demostrado que la causa podía ser la exposición fetal a agentes terapéuticos administrados a la madre (entre ellos el dietilsilbestrol o el clomifeno) o a contaminantes medioambientales que ejercen acciones anti-androgénicas [41][42][43][44]. ...
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Resumen Objetivos El desarrollo sexual anómalo o diferente (DSD) con cariotipo 46,XY incluye anomalías en el desarrollo gonadal y/o genital (externo y/o interno). Contenido Los marcadores bioquímicos útiles para el diagnóstico diferencial de los DSD con cariotipo 46,XY incluyen las hormonas del eje hipotálamo-hipófiso gonadal como son las gonadotropinas LH y FSH (en condiciones basales o tras la estimulación con LHRH), la hormona anti-Mülleriana, la inhibina B, el factor insulinoide tipo 3 y las hormonas esteroideas de origen suprarrenal (se incluirá la hormona hipofisaria ACTH) y testicular (cortisol, aldosterona y sus precursores, testosterona y sus precursores, dihidrotestosterona y estradiol). Las hormonas esteroideas se analizarán en condiciones basales o tras la estimulación con ACTH (hormonas adrenales) y/o con HCG (hormonas testiculares). Los patrones de variación de las distintas hormonas dependerán de la causa y la edad de cada paciente. El diagnóstico molecular debe incluir el análisis de un gen candidato, un panel de genes o el análisis de un exoma completo. Perspectivas El diagnóstico diferencial de los DSD con cariotipos 46,XX ó 46,XY debe ser multidisciplinar, incluyendo los antecedentes clínicos, morfológicos, de imagen, bioquímicos y genéticos. Se han elaborado numerosos algoritmos diagnósticos.
... There are patients with the PAIS phenotype that some authors call "idiopathic" since it is not associated with any genetic alteration. In some cases, it has been possible to demonstrate that the cause of this phenotype was fetal exposure to therapeutic agents administered to the mother (estrogens, including clomiphene) or to environmental pollutants that exert anti-androgenic actions [41][42][43][44]. ...
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Objectives 46,XY differences/disorders of sex development (DSD) involve an abnormal gonadal and/or genital (external and/or internal) development caused by lack or incomplete intrauterine virilization, with or without the presence of Müllerian ducts remnants. Content Useful biochemical markers for differential diagnosis of 46,XY DSD include hypothalamic-pituitary-gonadal hormones such as luteinizing and follicle-stimulating hormones (LH and FSH; in baseline or after LHRH stimulation conditions), the anti-Müllerian hormone (AMH), inhibin B, insulin-like 3 (INSL3), adrenal and gonadal steroid hormones (including cortisol, aldosterone, testosterone and their precursors, dihydrotestosterone and estradiol) and the pituitary ACTH hormone. Steroid hormones are measured at baseline or after stimulation with ACTH (adrenal hormones) and/or with HCG (gonadal hormones). Summary Different patterns of hormone profiles depend on the etiology and the severity of the underlying disorder and the age of the patient at diagnosis. Molecular diagnosis includes detection of gene dosage or copy number variations, analysis of candidate genes or high-throughput DNA sequencing of panels of candidate genes or the whole exome or genome. Outlook Differential diagnosis of 46,XX or 46,XY DSD requires a multidisciplinary approach, including patient history and clinical, morphological, imaging, biochemical and genetic data. We propose a diagnostic algorithm suitable for a newborn with DSD that focuses mainly on biochemical and genetic data.
... On the other hand, it was recently shown that fetal contamination by endocrine-disrupting chemicals (EDCs) such as DDT, secondary to parental exposure, before or during pregnancy, is associated with the development of genital malformations (Gaspari et al., 2012). Nevertheless, in that study, exposure was documented through questionnaires answered by the parents and not through the determination of EDCs in biological samples. ...
... Segundo esta autora, calcula-se que para cada 1 notificação de intoxicados podem haver mais de 50. Por isso, os agrotóxicos podem ter causado muitos danos à saúde dos brasileiros, como: câncer, problemas reprodutores, respiratórios, físicos -microppênis -e levar a morte (BOMBARDI, 2017;ODENT, 2003;OPAS, 1996;GASPARI et al, 2012). ...
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O objetivo do artigo é realizar uma reflexão acerca do processo de resistência camponesa, levando-se em consideração as formas alternativas de produção e da reforma agrária popular como uma forma de promoção da saúde. Essa resistência se dá frente à produção no campo brasileiro, sobretudo, aqueles iniciados nos anos de 1960, contexto que houve inserção do uso de agrotóxicos e de sementes transgênicas – que tinha a justificativa de controlar pragas e o aumentar a produtividade. Como já é largamente debatido na literatura, a verdade é que essa forma só aumentou as desigualdades, tanto no que se refere à produção, quanto em relação ao uso da terra - a partir da expropriação. A discussão tem como referência o Perímetro Irrigado das Várzeas de Sousa, localizado no estado da Paraíba, mais especificamente os movimentos sociais que ali luta e resistem, por uma reforma agrária popular e por soberania alimentar, através de formas alternativas de produção, assim proporcionando a promoção da saúde. Como metodologia, recorremos à análise de entrevistas para compreensão dos fatos apresentados acima. Previamente, inferimos que a reforma agrária popular e as formas alternativas estão promovendo saúde – a partir do entendimento mais amplo dessa –; além de proporcionarem o real desenvolvimento.
... For instance, many studies showed that contaminations of rivers with estrogenic and androgenic compounds in the ng/L range, are responsible for intersex changes within fish populations [3,4] raising concerns about population-level consequences [5]. In Brazil, a study conducted in 2710 newborn males revealed fetal contamination with organochlorine pesticides (DDT) with a risk factor for external genital malformations [6], whereas in young girls, fetal and/or environmental exposure to endocrine disrupting chemicals (EDCs) led to precocious puberty [7,8]. ...
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Despite the ever-increasing role of pesticides in modern agriculture, their deleterious effects are still underexplored. Here we examine the effect of A6, a pesticide derived from the naturally-occurring α-terthienyl, and structurally related to the endocrine disrupting pesticides anilinopyrimidines, on living zebrafish larvae. We show that both A6 and an anilinopyrimidine, cyprodinyl, decrease larval survival and affect central neurons at micromolar concentrations. Focusing on a superficial and easily observable sensory system, the lateral line system, we found that defects in axonal and sensory cell regeneration can be observed at much lower doses, in the nanomolar range. We also show that A6 accumulates preferentially in lateral line neurons and hair cells. We examined whether A6 affects the expression of putative target genes, and found that genes involved in apoptosis/cell proliferation are down-regulated, as well as genes reflecting estrogen receptor activation, consistent with previous reports that anilinopyrimidines act as endocrine disruptors. On the other hand, canonical targets of endocrine signaling are not affected, suggesting that the neurotoxic effect of A6 may be due to the binding of this compound to a recently identified, neuron-specific estrogen receptor.
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Numerous studies have focused on the association between endocrine-disrupting chemicals (EDCs) and hypospadias. Phenotype variability, the absence of representative comparison groups and concomitant genetic testing prevent any definitive conclusions. To identify the role of occupational and environmental exposures to EDCs in nongenetic isolated hypospadias. A total of 408 consecutive children with isolated hypospadias and 302 normal boys were prospectively included (2009-2014) in a multi-institutional study in the south of France, the area of the country with the highest prevalence of hypospadias surgery. In patients without AR, SRD5A2, and MAMLD1 mutations, parental occupational and professional exposures to EDCs were evaluated based on European questionnaire QLK4-1999-01422 and a validated job-exposure matrix for EDCs. Environmental exposure was estimated using the zip code, the type of surrounding hazards, and distance from these hazards. Multivariate analysis was performed. Fetal exposure to EDCs around the window of genital differentiation was more frequent in the case of hypospadias (40.00% vs 17.55%, odds ratio 3.13, 95% confidence interval 2.11-4.65). The substances were paints/solvents/adhesives (16.0%), detergents (11.0%), pesticides (9.0%), cosmetics (5.6%), and industrial chemicals (4.0%). Jobs with exposure were more frequent in mothers of hypospadiac boys (19.73% vs 10.26%, p=0.0019), especially cleaners, hairdressers, beauticians, and laboratory workers. Paternal job exposure was more frequent in the cases of hypospadias (40.13% vs 27.48%, p=0.02). Industrial areas, incinerators, and waste areas were more frequent within a 3-km radius for mothers of hypospadiac boys (13.29% vs. 6.64%, p<0.00005). Association of occupational and environmental exposures increases this risk. This multicenter prospective controlled study with a homogeneous cohort of hypospadiac boys without genetic defects strongly suggests that EDCs are a risk factor for hypospadias through occupational and environmental exposure during fetal life. The association of various types of exposures may increase this risk. Our multi-institutional study showed that parental professional, occupational, and environmental exposures to chemical products increase the risk of hypospadias in children. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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The relative importance of congenital malformations as a cause of death in the first year of life is increasing along with the control of preventable causes of perinatal mortality. To identify risk factors for congenital malformations. Retrospective case-control study of births registered in the database of The Latin American Collaborative Study of Congenital Malformations (ECLAMC), in the period 2001-2010. Birth weight and gestational age were significantly lower in cases than controls, behaving as risk factors and associated with a greater severity of congenital malformations. The risk and severity of congenital malformations increased along with mother's age. Fetal growth retardation, a history of congenital malformations in the family, physical factors and acute illnesses of the mother in the first trimester of pregnancy were also significant risk factors for congenital malformations and their severity. The educational level of the mother was a protective factor for congenital malformations and their severity. Variables previously identified as risk factors for congenital malformations, were significantly related with the occurrence of congenital malformations and their severity.
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Micropenis represents a clinical sign that should be diagnosed at birth (or in utero) by the detection of a normally structured penis with a length 2.5 SD below the mean for age. Micropenis can be classified as due to deficient testosterone secretion or action. Evaluation of the gonadotropic and testicular function during the mini-puberty is often helpful in evaluating the etiology. Management of micropenis should focus on achieving a suitable penis length, in order to allow an adequate urination, normal sexual intercourses and a good self-body image. Irrespective of the underlying cause, a short course of T should be tried in patients with micropenis to assess the ability of the penis to respond to it. Topical 5a-dihydrotestosterone gel has also been reported to be effective. Children with hypopituitarism and GH deficiency respond to appropriate hormonal therapy. Psychological counseling is helpful and often necessary. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Article
The increased prevalence of certain diseases, along with the development of new technologies and industrialization raised the possibility of the involvement of environmental factors, industrial products, nutritional factors, infections, drugs... and endocrine disruptors. These factors may interfere via signaling pathways specific to the organism. Endocrine Disrupting Chemicals (EDCs) have been redefined by the Endocrine Society in 2012 as "exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action". They have therefore potentially deleterious effects on development, growth, metabolism, reproduction, the nervous, immune and cardiovascular systems. Therefore, they constitute a real public health issue. Their long half-life may explain delayed effects and their often lipophilic character may promote maternofetal transmission. Except diethylstilbestrol (DES), few formal proofs have been made on the direct role of EDCs ; arguments are based on cross-sectional studies, in vitro models and animal models. Basic research puts insight into mechanisms of action of EDCs but many questions remain unanswered. Epidemiological data are difficult to interpret because of interindividual differences in susceptibility to EDCs and of nonlinear/nonmonotonique action (as opposed to toxic dose effect), multiple interactions between environmental agents (additive effects and/or synergistic and/or antagonists), the role of the window of exposure, latency, and the possibility of transgenerational effects. Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Chapter
In the recent years, pesticide research and regulatory efforts have focused on the prevention of acute health effects from pesticide poisonings and pesticide residues on foods, but more attention is being given to the deleterious chronic health effects. Children and pregnant women's exposure to contaminated water in particular are at high risk for subsequent adverse health outcomes. The chapter summaries the health effects of water contamination.
Chapter
Hypospadias is the most frequent congenital penile defect affecting the external male genitalia, with an incidence around 1 in 250 male newborns, although this seems to be increasing. The word hypospadias originates from the Greek (ὑπo σπαδιας) ‘hypo’ meaning ‘under’ and ‘spadias’ meaning ‘opening’. As the word tells, hypospadias is “a congenital condition in males in which the opening of the urethra is on the underside of the penis”.
Chapter
This chapter covers the known effects of endocrine disrupting chemicals (EDCs) on reproductive disorders. The EDCs represented are highly studied, including plasticizers (bisphenols and phthalates), chemicals in personal care products (parabens), persistent environmental contaminants (polychlorinated biphenyls), and chemicals in pesticides or herbicides. Both female and male reproductive disorders are reviewed in the chapter. Female disorders include infertility/subfertility, irregular reproductive cycles, early menopause, premature ovarian insufficiency, polycystic ovarian syndrome, endometriosis, and uterine fibroids. Male disorders include infertility/subfertility, cryptorchidism, and hypospadias. Findings from both human and animal studies are represented.
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In the newborn, penile length is determined by a number of androgen dependent and independent factors. The current literature suggests that there are inter-racial differences in stretched penile length in the newborn and although congenital micropenis should be defined as a stretched penile length of less than 2.5SDS of the mean for the corresponding population and gestation, a pragmatic approach would be to evaluate all boys with a stretched penile length below 2 cm, as congenital micropenis can be a marker for a wide range of endocrine conditions. However, it remains unclear as to whether the state of micropenis, itself, is associated with any long-term consequences. There is a lack of systematic studies comparing the impact of different therapeutic options on long-term outcomes, in terms of genital appearance, quality of life and sexual satisfaction. To date, research has been hampered by a small sample size and inclusion of a wide range of heterogeneous diagnoses; for these reasons, condition specific outcomes have been difficult to compare between studies. Lastly, there is a need for a greater collaborative effort in collecting standardized data so that all real-world or experimental interventions performed at an early age can be studied systematically into adulthood.
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Résumé Depuis une vingtaine d'années, de plus en plus de travaux cliniques, épidémiologiques et expérimentaux confirment l’impact des perturbateurs endocriniens environnementaux (PEE) sur la réduction de la fertilité masculine et féminine. Le concept de l’origine fœtale d’une pathologie à l’âge adulte s’est renforcé plus particulièrement dans le domaine de la reproduction. Il est apparu de plus que cette exposition anténatale constitue un véritable risque pour les générations futures, supportant l’hypothèse d’un effet multi- et trans-générationnel de l’impact des PEE.La mise en évidence d’une contamination environnementale reste actuellement un défi eu égard au nombre considérables de PEE produits et mis sur le marché. La chromatographie en phase gazeuse couplée à la spectrométrie de masse est apparue comme une méthode de référence. L’évaluation de l’action hormonale ou antihormonale sur des lignées cellulaires stablement transfectées est aussi régulièrement utilisée. Sur les trois pistes épigénétiques (variations de méthylation, microARNs, histones), les recherches semblent se focaliser sur l’implication des microARNs : les variations de leur expression dans la régulation de la fertilité offrant de nouvelles perspectives dans la compréhension du mécanisme modulant la réponse cellulaire à l’exposition fœtale aux PEE. Ils ouvrent la voie à l’identification de marqueurs d’exposition et, dans le futur, à des outils thérapeutiques potentiels.
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Objective: to assess whether maternal and paternal exposure to toxic agrochemicals throughout life causes congenital malformations. Method: a scoping review was carried out on the PUBMED, CINAHL, EBSCO, MEDLINE, LILACS, SciELO, BDENF, Web of Science and ATHENA databases between August and September 2019 and updated in December 2020. A cohort and case control study were included, which addressed the effects of parents' exposure throughout their lives to toxic agrochemicals which caused congenital malformation outcomes. Results: the review covered 32 studies published between 2005 and 2020. The main malformations presented are related to the reproductive system, nervous system, musculoskeletal system, transverse limb deficiencies, digestive system and other malformations such as fetal growth restrictions, cleft palate and congenital heart disease. The most investigated toxic agrochemicals in the studies were the herbicides represented by atrazine. Conclusion: maternal and paternal exposure to toxic agrochemicals can be associated with greater chances of children being born with congenital malformations, especially those related to the male reproductive system.
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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.
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Repeated health and environmental scandals, the loss of biodiversity and the recent burst of chronic diseases constantly remind us the inability of public authorities and risk assessment agencies to protect health and the environment. After reviewing the main shortcomings of our evaluation system of chemicals and new technologies, supported by some concrete examples, we develop a number of proposals to reform both the risk assessment agencies and the evaluation processes. We especially propose the establishment of an independent structure, a High Authority of Expertise, supervising, either at European level or at national level, all the evaluation agencies, and ensuring the transparency, the methodology and the deontology of the expertise. In addition to modifying the evaluation protocols, both in their nature and in their content, especially in order to adapt them to current pollutants such as endocrine disruptors, we propose a reform of the expertise processes based on transparency, contradiction, and greater democracy, including close collaboration between the institutional and scientific parties on the one hand and the whole civil society on the other. All the proposals we make are inspired by the desire to prevent, through appropriate mechanisms, the human, health, ecological, but also economic consequences of contemporary technological choices.
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Many conditions involving the male external genitalia make the penis look small. Buried or webbed penis is one of those conditions. Penis size is the reason the parents bring their child to the outpatient clinic. It is important to distinguish those conditions where the penis has a normal size, from micropenis. The term micropenis refers to a penis that is completely normally formed, but is abnormally small.
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RESUMO O objetivo deste artigo foi analisar a tendência de malformações congênitas e a associação entre o uso de agrotóxicos em microrregiões de estados brasileiros que possuem maior produção de commodities agrícolas. Estudo ecológico de análise temporal conduzido com informações dos nascidos vivos (Sinasc/Ministério da Saúde), elaborando-se taxas de anomalias ocorridas entre 2000 e 2016. Foram encontradas taxas mais elevadas de anomalias congênitas nas microrregiões dos estados que apresentavam maiores produções de grãos. Essas anomalias podem ser advindas da exposição da população a agrotóxicos, sendo uma sinalização expressiva nos problemas de saúde pública.
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Coal fly ash (CFA) was used as a catalyst for the synthesis of nitrogen-doped carbon nanotubes (NCNTs) and carbon nanofibers (CNFs) by chemical vapor deposition. The carbon nanomaterials (CNMs) were successfully purified by sequential treatment in 5 % HF and then in dil. HNO3/H2SO4 mixture, as was shown by SEM, TGA, and XRD. The purified NCNTs and CNFs were composited with TiO2 nanoparticles at varying loadings (i.e. 1, 5 and 20 % CNFs/NCNTs loadings) by surfactant wrapping sol-gel/hydrothermal method and used for the photodegradation of bisphenol-A (BPA) in water with light being sourced from a solar simulator. It was shown by TEM that the CNMs were completely coated with TiO2 nanoparticles and interactions between the CNMs and TiO2 were demonstrated using PXRD and laser Raman spectroscopy. Photoluminescence measurements showed that compositing TiO2 with CNMs, especially NCNTs significantly reduced its emission intensity suggesting reduced electron/hole recombination rate. Unbound TiO2 was used to optimize the photodegradation experimental conditions, i.e. solution pH, the mass of photocatalyst, the initial concentration of BPA and solution temperature. The photocatalytic efficiency of the various TIO2 and CNFs/NCNTs was assessed using the optimized conditions where it was observed that the composites containing 1 and 5 % loadings of CNMs outperformed TiO2. The photocatalytic efficiency of NCNTs based was higher than that of CNFs based composites. This work shows that CFA, a toxic material could be used to synthesize materials useful for cleaning water.
Book
This book provides comprehensive but concise data for congenital diseases of the penis, explaining the embryological and anatomical background, incidence, historical background, investigation approaches, imaging and management of each condition. The book is organised in themed parts, starting from embryology and normal anatomy and examining anomalies for each anatomical part: prepuce, penis, urinary meatus, penile urethra with a final part of acquired penile diseases with congenital background. With clear illustrations in each chapter to explain each condition in detail, online animations for the difficult and complex cases are also provided. Practitioners in the field of pediatric urology and surgery will find this highly readable book particularly valuable. The author is a pioneer pediatric surgeon with over 30 years’ experience in the field of genitourinary anomalies.
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Penile chordee is a condition in which the head of the penis curves downward or upward, at the junction of the head and shaft of the penis. The curvature is usually obvious during erection, but resistance to straightening is often apparent in the flaccid state as well. It is a congenital anomaly due to reduced elasticity in one or more of the fascial layers of the penis, leading to shortness of the corpus spongiosum when erection occurs. Usually the bend is ventral but could be dorsal or complex.
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Duplication of the penis, or diphallia, is an extremely rare but a well- documented anomaly resulting from incomplete fusion of the genital tubercle.
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Penis with a stretched length more than 2.5 standard deviations (SD) for the standard size for age is considered as a micropenis, which affect at least one in 200 males, it results from a multiplicity of endocrine and nonendocrine conditions. Microphallus must be differentiate from inconspicuous penis which may be a buried or a webbed penis and cases of intersex and ambiguous genitalia. Topical application of 5 % testosterone cream may be effective in management of some cases, but conservative surgical techniques to improve length or girth like division of the suspensory ligament with or without an inverted V-Y plasty may be indicated in others, additionally, it might be appropriate to perform penoscrotal web excision or supra fat pad excision (lipectomy) in order to maximize the subjective penile length.
Article
Abstract This is an attempt to establish the normal stretched penile length and prevalence of male genital anomalies in full-term neonates and whether they are influenced by prenatal parental exposure to endocrine-disrupting chemicals. A thousand newborns were included; their mothers were subjected to the following questionnaire: parents' age, residence, occupation, contact with insecticides and pesticides, antenatal exposure to cigarette smoke or drugs, family history of genital anomalies, phytoestrogens intake and history of in vitro fertilization or infertility. Free testosterone was measured in 150 neonates in the first day of life. Mean penile length was 3.4±0.37 cm. A penile length <2.5 cm was considered micropenis. Prevalence of genital anomalies was 1.8% (hypospadias 83.33%). There was a higher rate of anomalies in those exposed to endocrine disruptors (EDs; 7.4%) than in the non-exposed (1.2%; p<0.0001; odds ratio 6, 95% confidence interval 2-16). Mean penile length showed a linear relationship with free testosterone and was lower in neonates exposed to EDs.
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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.
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RESUMEN El Instituto de Genética Humana de la Pontificia Universidad Javeriana inició la investigación clínica y epidemiológica de malformaciones congénitas en el Hospital Universitario San Ignacio (HUSI) en asocio con el Estudio Colaborativo Latinoamericano de Malformaciones Congénitas (ECLAMC). Objetivo: determinar la prevalencia global de malformaciones congénitas y que variables del estudio ECLAMC-HUSI tienen mayor fuerza de asociación con la presencia de malformaciones congénitas en el HUSI. Método: se realizó un estudio con dos modalidades operativas caso-control y cohorte histórica durante el período del 1º de junio al 31 de diciembre del 2001. Se consideraron en el programa todos los nacimientos, vivos de cualquier peso o muertos mayores a 500 g ocurridos en la sala de partos del HUSI. No se consideraron los nacimientos ocurridos fuera del hospital. Para cada paciente malformado se diligenció la ficha de caso y la ficha para su respectivo control exceptuando los mortinatos malformados a los cuales solamente se les llenó solamente la ficha de caso.
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This study sets out (a) to estimate the prevalence of admissions by birth defects, using the official database of hospitals of Ecuador; and (b) to set the basis for a new National Register of Birth Defects in Ecuador that works as a program for the clinical and epidemiological investigation of risk factors in the etiology of congenital anomalies in Ecuadorian hospitals, using a case-control methodological approach. This is the first report in their class. The data used in this study are derived from the National Register of Hospital Admission/Discharges of the Instituto Nacional de Estadísticas y Censos; data of the Ministry of Public Health were also used. Ecuador does not have an official Medical Birth Registry or a Congenital Malformations Registry. A total of 51,375 discharges by congenital malformations were registered in a 7-year period. Of these, 16,679 admissions were of children aged less than 1 year of age, with a birth prevalence rate (BPR) of 72.33/10,000 births. 77% of the congenital defects registered comprise the 50 most common birth defects observed in this age group. Cleft lip was the most prevalent birth defect in children less than 1 year of age and the second most common defect in children 1 to 5 years of age. Unilateral cleft lip shows a BPR of 4.57/10,000 births; cardiac birth defects as a group have a BPR of 4.2; hydrocephalus a BPR of 3.77; and Down's syndrome a BPR of 3.70. Undescended testicle was the most prevalent birth defect in children between 1 to 5 years. 9384 children under 1 year of age were male (55.9%) and 7053 were female (42.1%). BPR in males was 40.45 and in females 30.40. This report documents the prevalence estimates for birth defects reported in the hospital discharge data. These estimates are important to 1) plan for health-care and education needs of the Ecuadorian population, 2) identify increased occurrences of birth defects in specific geographic regions, 3) serve as a reference point for assessment of provincial surveillance systems, 4) evaluate national public health interventions, 5) compare Ecuador prevalence estimates with those of other countries, and 6) help determine the appropriate allocation of resources for basic and public health research. There is an urgent need to establish a National Registry of Birth Defects involving different sources of information such as prenatal medical records, birth records and medical records during the first year of life at an early stage, and surveys on cytogenetic prenatal diagnostic surveys and cytogenetics of therapeutic abortions.
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The genetics has been reaching great projection in the current medicine. This prominence is linked to the technical progresses in the area as well as to growing importance that the genetic diseases have been reaching in public health. About 5% of the gestations they result in the children's birth with congenital anomalies (fetal malformations) that commit your development. The present study aimed at to analyze the frequency and the factors predisponers for the occurrence of fetal malformations in born children in the maternity of the Assistencial Foundation of the Paraíba (AFP). Was accomplished it analyzes retrospective, of obstetric handbooks and neonatals, with base in the referring information the pregnancy and to the pregnant women childbirth that you/they gave the light, in the period of January of 2005 to June of 2006. In 2. 859 newly born, 1.19% presented some type of congenital anomaly. The foot-crooked deformity (23.54%) it was the most frequent, being followed to syndrome of Down with a frequency of 17.65%. When analyzing the malformations incidence for the maternal age, it was noticed that there was a larger frequency in the age group from 14 to 20 years (35.29%). And that there was association existence between sex been born and malformations emergence, just for syndrome of Down.
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Se analizaron 5.686 nacimientos (5.597 vivos y 89 muertos) correspondientes a dos series realizadas entre los meses de octubre de 1997 y abril de 1998 y de julio a noviembre de 2000 (12 meses) en el Instituto Materno Infantil de Bogotá. Se detectaron anomalías congénitas en 4,4% de los recién nacidos vivos y en 7,8% de los mortinatos. Las anomalías mayores constituyen el 69% de todas las anomalías y se encuentran en 3% de los recién nacidos vivos. Las anomalías moderadas son el 31% de todas las anomalías y se detectaron en 1,4% de los recién nacidos vivos. Los recién nacidos con anomalías mayores, en comparación con los controles, registran una mayor mortalidad al momento del alta hospitalaria (p=0,0001), menor peso promedio al nacer (p=0,003) y antecedentes de anomalía en la familia (p=0,0001). Las anomalías moderadas están asociadas únicamente con antecedentes de anomalías familiares (p=0,0001). Las anomalías congénitas muestran una frecuencia en nuestro medio semejante a las de otros estudios del país y del exterior, aunque, individualmente, algunas anomalías muestran variaciones significativas en sus frecuencias que pueden deberse a sobre o subregistros o a diferencias metodológicas en su detección. Palabras clave: anomalías congénitas, malformaciones, deformaciones, defectos congénitos, vigilancia epidemiológica, monitorización.
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BACKGROUND Over the past decades, an increasing trend in male external genital malformations such as cryptorchidism and hypospadias has led to the suspicion that environmental chemicals are detrimental to male fetal sexual development. Several environmental pollutants, including organochlorine pesticides, polychlorinated biphenyls, bisphenol A, phthalates, dioxins and furans have estrogenic and anti-androgenic activity and are thus considered as endocrine-disrupting chemicals (EDCs). Since male sex differentiation is critically dependent on the normal production and action of androgens during fetal life, EDCs may be able to alter normal male sex differentiation.
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46,XY disorders of sex differentiation (46,XY DSD) can be due to a testis determination defect, an androgen biosynthesis defect, or androgen resistance (complete or partial androgen insensitivity syndrome (PAIS), or 5α reductase deficiency). We aimed to evaluate the impact of a prenatal contamination by environmental xenoestrogens in 'idiopathic' PAIS-like phenotype. We investigated 28 newborn/infant males with 46,XY DSD, normal androgen production, and no androgen receptor or steroid-5αR type II enzyme (SRD5A2) gene mutations. To exclude other genetic defects, we sequenced the steroidogenic factor 1 (SF1) and mastermind-like domain-containing 1 (MAMLD1) genes, which were recently found to be associated with the PAIS-like phenotype. Parents were interviewed about their environmental/occupational exposure to endocrine disrupting chemicals (EDCs) before/during the patients' fetal life. Total estrogenic bioactivity of patient serum was analyzed by ultrasensitive bioassay. All the patients had normal SF1 sequence and one patient showed a double polymorphism of MAMLD1. Eleven (39.3%) of the 28 patients had reported parental fetal exposure to EDCs. The mean estrogenic bioactivity in these 11 patients with fetal EDC exposure (6.65 ± 8.07 pg/ml) versus 17 cases without contamination (1.27 ± 0.34 pg/ml) and controls (1.06 ± 0.44 pg/ml; P<0.05) was elevated. Our results indicate that the 'idiopathic' PAIS-like phenotype may in some cases be related to EDC contamination during fetal life.
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Fetuses and children are more susceptible to the effects of environmental toxins. The objective of this article is to determine the levels of organochlorine pesticides (HCB, ss-HCH, pp'DDT, op'DDT and pp'DDE) in the serum lipids of mothers of newborns with cryptorchidism and compare the levels to a control group of mothers of newborns with descended testicles. The cases were composed of newborns with cryptorchidism (n=41), and the controls (n=41) newborns with descended testicles. Blood samples from both groups of mothers were used to determine the organochlorine pesticide levels. Cryptorchidism was diagnosed at birth by a neonatologist. The results showed that the organochlorine pesticide residues were found in the serum lipids of both groups of mothers. The median serum lipid levels (mgkg-1 lipid-based) were statistically higher for the metabolites pp'DDT (0.464 vs. 0.269) and ss-HCH (0.263 vs. 0.192) in the cryptorchidism group compared to the control group (p<0.01). It could be concluded that the levels of the metabolites pp'DDT and ss-HCH are higher among mothers of newborns with cryptorchidism. It is possible that substances with anti-androgenic effects could produce endocrine disruption, such as cryptorchidism, during fetal development.
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Mutations in chromosome X open reading frame 6 (CXorf6), a recently described candidate gene involved in the development of male genitalia, have been found in patients with complex 46,XY disorders of sexual development (46,XY DSD) including micropenis, bifid scrotum, and penoscrotal hypospadias. The objective of this work was to identify genomic variants of CXorf6 in patients with isolated hypospadias, severe or non-severe. Forty-one patients with glandular to perineal hypospadias and thirty controls were studied. Direct sequencing for coding exons 3-6 of CXorf6 and their flanking splice sites was performed on DNA extracted from foreskin collected from surgery. Secondary and tertiary structures of the protein were predicted using NNpredict and Protein Homology/analogY Recognition Engine engines. Four mutations (9.7% of cases) were identified. One missense mutation (1295T>C, V432A) and two deletions (325delG, predicted to cause a stop codon L121X) occurred in patients with penoscrotal and proximal hypospadias. One patient with subcoronal hypospadias had CAG-repeat amplification in the second polyglutamine domain of CXorf6. Secondary structure prediction indicated that this insertion occurred in a helix element of the protein. The tertiary structure prediction showed an alteration of the shape of the protein and crowding between domains. CXorf6 mutations are associated with isolated hypospadias of varying severity. However, the pathophysiology of these mutations and the function of the CXorf6 gene product remain to be investigated.
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External genital anomalies are among the most common congenital anomalies. Proper early diagnosis and management of genital abnormalities are of great importance to minimize medical, psychological and social complications. To detect the incidence of external genital anomalies and disorders of sex development (DSD) in Great Cairo and Qalyubiyah governorates. 20,000 newborns and infants up to the age of 6 months coming for compulsory vaccination at primary health care units and centers in Great Cairo and Qalyubiyah governorates were examined in the years 2006-2007 for suspected genital anomalies. There were 187 (93.5/10,000) cases with external genital anomalies among the screened 20,000 participants. Various abnormalities in the form of 46,XY DSD, undescended testis, hydrocele, hypospadias, micropenis, synechia of the labia and other genital anomalies were diagnosed and classified after thorough clinical examination, and hormonal, radiological, and laparoscopic investigations. This first pilot study in Great Cairo and Qalyubiyah governorates showed a relatively high incidence of genital anomalies and DSD. Therefore, we recommend more studies including larger population sizes to detect the actual incidence of genital anomalies and DSD in Egypt in order to serve those patients and their families.
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Partial androgen insensitivity syndrome (PAIS) is the milder variant of androgen receptor (AR) defects. The subtle effects of AR mutations present in a patient with micropenis, peno-scrotal hypospadias, infertility, clitoromegaly and posterior labial fusion. We studied the association of isolated micropenis with the genetic defects resulting in androgen resistance, that is, AR gene defects and 5-alpha reductase type 2 (SRD5A2) deficiency. We describe two cases of isolated micropenis: one in a 14-year-old boy and the other in a 3-year-old boy who was followed until he was 10 years old. There were no findings of hypospadias, cryptorchidism or gynecomastia in either of these patients. Serum gonadotrophin and androgen levels were obtained and karyotyping was done. Human chorionic gonadotropin (hCG) stimulation testing assessed the functional capacity of the testes. DNA was extracted from peripheral leukocytes, and all exons of the SRD5A2 and AR genes were amplified by polymerase chain reaction and sequenced. In both patients, baseline testosterone (T) level was low and the values were elevated after hCG testing. The sequence of the SRD5A2 gene was normal in patient 1, and a heterozygous polymorphism, V89L, was found in patient 2. Two known mutations, P390S and A870V, were identified in patients 1 and 2, respectively. Mutations in the AR gene can be associated with isolated micropenis without other features of PAIS, such as hypospadias or gynecomastia. This underlines the importance of including AR gene analysis in the evaluation of isolated micropenis with normal plasma T to ensure proper management of the patient and appropriate genetic counseling for the family.
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Androgen control of penis development/growth is unclear. In rats, androgen action in a foetal 'masculinisation programming window' (MPW; e15.5-e18.5)' predetermines penile length and hypospadias occurrence. This has implications for humans (e.g. micropenis). Our studies aimed to establish in rats when androgen action/administration affects development/growth of the penis and if deficits in MPW androgen action were rescuable postnatally. Thus, pregnant rats were treated with flutamide during the MPW +/- postnatal testosterone propionate (TP) treatment. To assess penile growth responsiveness, rats were treated with TP in various time windows (late foetal, neonatal through early puberty, puberty onset, or combinations thereof). Phallus length, weight, and morphology, hypospadias and anogenital distance (AGD) were measured in mid-puberty (d25) or adulthood (d90) in males and females, plus serum testosterone in adult males. MPW flutamide exposure reduced adult penile length and induced hypospadias dose-dependently; this was not rescued by postnatal TP treatment. In normal rats, foetal (e14.5-e21.5) TP exposure did not affect male penis size but increased female clitoral size. In males, TP exposure from postnatal d1-24 or at puberty (d15-24), increased penile length at d25, but not ultimately in adulthood. Foetal + postnatal TP (e14-postnatal d24) increased penile size at d25 but reduced it at d90 (due to reduced endogenous testosterone). In females, this treatment caused the biggest increase in adult clitoral size but, unlike in males, phallus size was unaffected by TP during puberty (d15-24). Postnatal TP treatment advanced penile histology at d25 to more resemble adult histology. AGD strongly correlated with final penis length. It is concluded that adult penile size depends critically on androgen action during the MPW but subsequent growth depends on later androgen exposure. Foetal and/or postnatal TP exposure does not increase adult penile size above its 'predetermined' length though its growth towards this maximum is advanced by peripubertal TP treatment.
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Hypospadias is a congenital displacement of the urethral meatus in male newborns, being either an isolated defect at birth or a sign of sexual development disorders. The aim of this study was to assess the prevalence rate of hypospadias in different Districts of Italy, in order to make a comparison with other countries all over the world. We reviewed all the newborns file records (years 2001-2004) in 15 Italian Hospitals. We found an overall hypospadias prevalence rate of 3.066 +/- 0.99 per 1000 live births (82.48% mild hypospadias, 17.52% moderate-severe). In newborns Small for Gestational Age (birthweight < 10(th )percentile) of any gestational age the prevalence rate of hypospadias was 6.25 per 1000 live births. Performing multivariate logistic regression analysis for different degrees of hypospadias according to severity, being born SGA remained the only risk factor for moderate-severe hypospadias (p = 0.00898) but not for mild forms (p > 0.1). In our sample the prevalence of hypospadias results as high as reported in previous European and American studies (3-4 per 1000 live births). Pathogenesis of isolated hypospadias is multifactorial (genetic, endocrine and environmental factors): however, the prevalence rate of hypospadias is higher in infants born small for gestational age than in newborns with normal birth weight.
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To identify intra-urban differentials and risk factors in low birth weight prevalence. Information was gathered in the live birth declarations made by mothers residing in the city of São Paulo (Southern Brazil), and obtained through the Live Birth Information System and the Seade Foundation, for the period between 2002 and 2003, totaling 388,980 live births. The addresses were georeferenced in census tracts and classified into six vulnerability groups according to the São Paulo State Social Vulnerability Index. To identify potential risk factor logistic regression analysis was performed. A positive growth trend was observed in the prevalence of low birth weight with an increase in the vulnerability rate (from 6.8% to 8.1%). There were significant differences among groups in terms of mothers' demographics, prenatal care and the proportion of non-preterm low weight births. In the low birth weight non-preterm group, a proxy measure to estimate intra-uterine growth delay, residing in vulnerable areas (1.29;1.17-1.43) and unfavorable mothers' demographics, such as teenage mothers (1.13;1.04-1.22), low schooling (1.26;1.17-1.35) and high number of children (1.10;1.01-1.20) were considered risk factors, as were older mothers (1.38;1.30-1.47), and single mothers (1.15;1.11-1.20). The lack of prenatal care produced the highest risk of low weight at birth in preterm (3.39;2.86-4.02) and non-preterm births (2.12;1.87-2.41). There was a decrease in the risk for low birth weight with an increase in prenatal care appointments in preterm and non-preterm births. There are low birth weight prevalence differences across vulnerability groups. Prenatal care proved to be unequal across vulnerability groups and its high risk in terms of low birth weight shows the importance of increasing the access to and the quality of healthcare services.
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A cohort of 5914 liveborns (99% of the city births) was followed up to the age of 4 years in Pelotas, southern Brazil. Besides the perinatal evaluation, the cohort children were examined again at mean ages of 11, 23, and 47 months. During each visit the children were weighed and measured and information on morbidity was collected. Also, multiple sources of information were used for monitoring mortality throughout the study. Of the babies with known gestational age, 9.0% were classified as intrauterine growth-retarded and 6.3% as preterm. Excluding those of unknown gestational age, 62% of low birth weight babies were intrauterine growth-retarded and 36% were preterm. Intrauterine growth retardation was statistically associated with maternal height, prepregnancy weight, birth interval, and smoking, whereas preterm births were associated with maternal prepregnancy weight and maternal age. Preterm babies had a perinatal mortality rate 13 times higher than that of babies of appropriate birth weight and gestational age and 2 times higher than that of intrauterine growth-retarded babies. Infant mortality rates presented a similar pattern, with the differentials being more pronounced during the neonatal than in the postneonatal period. In the first 2 years of life intrauterine growth-retarded children were at almost twice the risk of being hospitalized for diarrhea compared with appropriate birth weight, term children, while preterm children experienced only a slightly greater risk. For pneumonia, however, both groups of children were hospitalized significantly more than appropriate birth weight, term children. In terms of growth, despite their earlier disadvantage, preterm children gradually caught up with their appropriate birth weight, term counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PIP The organochlorines DDT and hexachlorocyclohexane (HCH) were determined in mothers' milk in 21 women from rural towns and 21 from urban Botucatu, Sao Paulo, Brazil, and correlated with environmental factors such as prevalence of house spraying, smoking, and agricultural work. Extraction and gas chromatography methods were those published by the U.S. EPA. Average DDT levels in urban milk samples were 34.9 ppb, and in rural milk 16.5 ppb. Higher meat intake was probably a factor in higher urban yield. In contrast, rural levels of HCH were 46.3 ppb, compared to 14.4 ppb in urban mothers. DDT levels were consistently lower in women who had nursed 3 or more children, than those with 1 or 2. House spraying was related to higher DDT levels in rural areas only. DDT levels were much higher in women who smoked. HCH content was higher in younger women than older, and in houses that had been sprayed, especially in rural zones, where spraying programs are run by the public health authorities. Dieldrin was detected in only 3 urban samples.
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A total of 7441 boys were examined for cryptorchidism at birth and, if present, again at 3 months of age. After excluding boys with severe congenital malformations noted at birth, the cryptorchidism rates at 3 months in babies weighing <2000 g, 2000-2499 g, and ≥2500 g were 7.7%, 2.5%, and 1.41% respectively. The overall rate was 1.55%. The cryptorchidism rate at birth had increased by 35.1% and at 3 months by 92.7%, over Scorer's rates in the 1950s. Part of these increases may be attributable to differences in neonatal mortality, but the increases in babies weighing 2500 g or more of 50.2% at birth and 77.4% at 3 months are unlikely to be overestimates. At birth 1.92% of boys had bilateral cryptorchidism and 3.0% unilateral cryptorchidism. Boys with cryptorchidism at 3 months were more likely to have hypospadias, a small scrotum, and poor scrotal rugation compared with boys having normally descended testes at birth. Factors predicting descent by 3 months in babies cryptorchid at birth are birth weight, laterality and scrotal size, babies with low birth weight, bilateral cryptorchidism, and normal scrotal size being more likely to have normally descended testes by 3 months. Descent by 3 months was more likely the lower the testis along the normal pathway of descent. The orchidopexy rate at an average age of 3 years was 1.24%. This is substantially lower than in other series and lower than our estimated rate of 2.9% using Hospital In-Patient Enquiry data for England and Wales.
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Objetivo. Estimar la frecuencia de 27 anomalías congénitas en 7 regiones geográficas de la Argentina.Material y métodos. Diseño observacional, transversal, descriptivo. Se seleccionó una muestra de 21 844 recién nacidos con malformaciones congénitas, sobre un total de 855 220 nacimientos ocurridos en 59 hospitales, entre 1994-2007. Se definieron 7 regiones geográficas de la Argentina. Para identificar regiones de alta frecuencia se utilizó una regresión de Poisson. El modelo incluyó la variable tiempo y 6 variables simuladas (dummy) para 7 regiones geográficas predefinidas: Metropolitana (MET); Pampa (PAM); Centro (CEN); Cuyo (CUY); Noroeste (NOA); Nordeste (NEA) y Patagonia (PAT).Resultados. El análisis regional de las frecuencias altas mostró los siguientes resultados significativos: PAM: hipospadias graves; CEN: espina bífida, microtia, labio leporino con paladar hendido, poliquistosis renal, polidactilia postaxial y síndrome de Down; CUY: polidactilia postaxial; NOA: onfalocele, gastrosquisis, labio leporino con paladar hendido y sin él, atresia anorrectal, genital ambiguo, polidactilia preaxial y agenesia pectoral; PAT: labio leporino sin paladar hendido.Conclusión. Catorce de las 27 anomalías congénitas estudiadas mostraron frecuencias significativamente aumentadas en una o más regiones.
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Background Results of long-term testosterone treatment of congenital hypoplasia of the penis are sparse; the aim of this work was to evaluate these results according to age at onset of treatment, the presence or absence of hypospadias, and its eventual adverse effect upon growth and bone maturation. Patients and methods Sixty-six children with congenital hypoplasia of the penis, isolated (n = 31) or associated with a hypospadias (n = 35), were evaluated between 1 day and 16 years of age. The prevalence (40% of the cases) of the different malformations and/or syndromes associated with congenital hypoplasia and its severity were not different whether the penis was isolated or associated with hypospadias (male-pseudohermaphroditism). The effect of the testosterone heptylate (IM) was evaluated in 40 children treated before 10 years of age. Results The penis' increase in length was more important in the children with isolated micropenis (+2.1 ± 0.8 SDS) than those with hypospadias (+ 1.3 ± 1.2 SDS) but, in all cases, its increase was better when the treatment was started during the neonatal period, which corresponded to those with the most severe forms of micropenis. A mean regression of the penile volume of −0.7 ± 0.8 SDS was noticed after the end of each stimulation. No long-term secondary effects related to treatment were seen on later growth and bone-maturation. Conclusion Penile length at the last follow-up was not associated with total dose of testosterone but with its length at the first evaluation time (r = 0.52; P = 0.002).
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What do pseudohermaphroditic polar bears and girls with premature breast development have in common? Hormones. Sexual differentiation and the initiation of secondary sexual characteristics, such as breast growth, are under the control of sex hormones, estrogen and androgen. Abnormal differentiation of the internal or external genitalia in bears and early onset of breast development in girls also may have a common element—exposure to environmental hormones. It has been shown that many common pesticides and environmental contaminants can act as estrogens or antiandrogens. Although there may be many factors contributing to sex-reversed animals or early pubescent girls, environmental hormone exposure is certainly one of the possible contributors. Four years ago, Herman-Giddens et al 53 published a provocative article in which they reassessed onset of puberty in US girls and found that thelarche (Tanner stage 2B) occurs much earlier than the previously established norms and that menarche also occurs somewhat earlier, although the difference is not as drastic for this measure. Moreover, the percentage of girls less than 8 years of age with one or more secondary sexual characteristics (27.2% of black girls and 6.7% of white girls) is much higher than previously reported. This information is being viewed by some as a redefinition of normal, but others are calling it precocious puberty and sounding alarms about possible unnatural causes. This study has caused a great deal of debate and led to a joint statement issued by the Endocrine Society and Lawson Wilkins Pediatric Endocrine Society in March 2001 calling for further research to define precocious puberty (www.endo-society.org/pubrelations/pressReleases/puberty.cfm) to determine whether girls really are reaching puberty earlier and, if so, to determine the cause. This reassessment in what is considered normal for hormonally associated physiologic change has many pediatricians searching for an answer: is it real? Some think that it is related to obesity, whereas others believe that a genetic component is primarily responsible. A recent preliminary report 57 on puberty and genes demonstrates a possible link. Within the context of an individual's genetic predisposition in conjunction with factors such as diet and obesity, what role does exposure to endocrine disrupting chemicals have on the normal physiologic process during puberty and reproductive development? In addition to reports of possible increases in precocious puberty, other epidemiologic studies have described early isolated thelarche, globally decreasing sperm counts, and increased rates of congenital malformations of the male reproductive system (reviewed by Safe et al 79 ). Information from studies on wildlife and in the laboratory is sufficient to associate endocrine disruption with the epidemiologic trends described in further detail later, but attributing causation remains difficult.
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In this study, we analyze the association between industrial activity and the occurrence of 34 con- genital anomalies. We selected 21 counties in Argentina during 1982-1994 and examined a total of 614,796 births in these counties in consecutive series. We used the International Standard Industrial Classification of All Economic Activities (United Nations, 1968) as an indicator of expo- sure to 80 specific industrial activities. Incidence rate ratios for each congenital anomaly were adjusted by the socioeconomic level of the county according to a census index of social deprivation. For a given exposure/anomaly association to be considered as significant and relevant, the exposure had to be a statistically significant risk for the occurrence of the anomaly and an increase in the birth prevalence rate of the congenital anomaly type involved had to be observed in those counties where the putative causal activity was being performed. Significant associations (p < 0.01) were identified between textile industry and anencephaly, and between the manufacture of engines and turbines and microcephaly. These observations are consistent with previous reports on occupa-
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Hintergrund: Der Maldescensus testis betrifft 1 % aller einjährigen Jungen. Die Beobachtung familiärer Leistenhoden (LH) beschränkte sich bisher auf die Beschreibung von individuellen Fällen bzw. Familien. Das Ziel der vorliegenden Studie war es, die Häufigkeit einer positiven Familienanamnese sowie den Verwandtschaftsgrad zu evaluieren und darüber hinaus die Häufigkeit von assoziierten urogenitalen Anomalien bei Familienmitgliedern festzustellen. Auf der Basis dieser Daten sollte ein Risikoprofil für das Auftreten eines LH bei Neugeborenen mit positiver Familienanamnese erstellt werden. Patienten und Methoden: 374 Patienten, die an unserer Klinik wegen eines LH operiert wurden, wurden mittels eines speziellen Fragebogens nach Verwandten mit LH und/oder assoziierten urogenitalen Anomalien bzw. Organveränderungen (Varikozele, Hydrozele, Hypospadie, Hodenkarzinom, Nierenmissbildung) gefragt. Die Kontrollgruppe bestand aus 374 Personen, die anamnestisch keinen LH hatten. Zur Berechnung des familiären Clusters wurde das Odds Ratio verwendet. Ergebnisse: 85/374 (22,73 %) Patienten hatten Familienangehörige mit einem LH versus 28/374 (7,5 %) der Kontrollpersonen. Brüder waren in 8,56 % der Fälle betroffen, Väter in 8,02 %, Onkel in 5,35 %, Cousins in 3,74 %, Großcousins in 1,87 % und Großväter in 1,6 % der Fälle. Das Risiko für einen Neugeborenen ebenfalls einen LH zu haben, falls ein Familienangehöriger bereits betroffen ist, liegt insgesamt bei 3,6fach (2,306; 5,727), 6,9fach wenn der Bruder und bei 4,6fach, wenn der Vater betroffen ist. In der Patientengruppe traten assoziierte urogenitale Organalterationen bei Familienangehörigen fast doppelt so häufig auf, wie in der Kontrollgruppe (14 % vs. 7,8 %). Schlussfolgerung: Der familiäre LH tritt bedeutend häufiger auf, als bisher angenommen. Das Erkrankungsrisiko für männliche Nachkommen ist gegenüber der Normalbevölkerung 3,6fach erhöht, wenn bereits ein Familienmitglied erkrankt ist. Aufgrund der hohen familiären Clusters und der höheren Frequenz einer positiven Familienanamnese für den LH und anderer urogenitaler Anomalien bei Patienten mit LH, erscheint eine genetische Disposition wahrscheinlich.
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Reports based on national registers of congenital malformations have suggested that the birth rate of hypospadias has increased during the last few decades. Register-based information may, however, have pitfalls because of changes in diagnostics, reporting accuracy and registration system. The aim of this study was to determine the current birth rate of hypospadias in Turku University Central Hospital (TUCH) in Finland. This was a prospective study on live-born boys born in TUCH from 1997 to 1999. In the total birth cohort (n=5,798) as well as in a special subcohort group (n=1,505) 0.3% of boys had hypospadias. Only one scrotal hypospadias was found in a boy who had a chromosomal anomaly. Other hypospadias were glandular or coronal. No increase was found in the birth rate of hypospadias when comparing our result with register-based data of boys born in Finland during the years 1970 to 1986 and surgically treated for hypospadias by the age of 8 years. No difference was found either from malformation register-based data concerning the nationwide birth rate of hypospadias during the years 1993 to 1998. Due to differences in national registration systems between countries, prospective studies with equal assessment criteria are needed in order to make reliable international comparisons.
Article
Over the past 20 years, the documented increase in the disorders of male sexual differentiation, such as hypospadias, cryptorchidism, and micropenis, has led to the suspicion that environmental chemicals are detrimental to normal male genital development in utero. Male sexual differentiation is critically dependent on the normal action of androgens, and unbalanced androgen/estrogen ratios can disturb it. Environmental xenoestrogens (such as herbicides, pesticides, PCBs, plasticizers, and polystyrenes) that mimic estrogens or environmental antiandrogens (such as polyaromatic hydrocarbons, linuron, vinclozolin, and pp′DDE) that disturb endocrine balance, cause demasculinizing effects in the male foetus. These environmental chemicals are often referred to as endocrine disruptors: they are thought to mimic endogenous estrogens by entering the cell, binding to the receptor and activating transcription, they may also antagonize normal androgen action. We have established numerous cell lines to assess the estrogenicity and antiandrogenicity of compounds found in the environment and to identify new products present in wastewater effluents that are able to disrupt endocrine functions. Several cell lines responding to estrogens have been obtained in our group, including cells with different enzymatic equipment and cells expressing chimeric receptor or natural estrogen receptors α and β. These cell lines have proved to be useful for assessing the biological activity of pesticides, fungicides, and chemicals found in plastic or discarded in the environment. In order to generate a powerful tool for the investigation of androgen action and the rapid screening of potential antagonists, we developed a new stable prostatic cell line. The PALM cell line is an original cellular model to characterize the response of hAR, and it provides an easy and rapid bioluminescent test to identify new antagonists. We also developed a model based on a fusion protein between the androgen receptor (AR) and the green fluorescent protein (GFP) to study the intracellular dynamics of AR. The GFP–AR model was applied to define the ability of several xenoestrogens and antiandrogens to inhibit the nuclear transfer of AR. The ubiquitous presence of endocrine disruptors in the environment and the increased incidence of neonatal genital malformation support the hypothesis that disturbed male sexual differentiation may in some cases be caused by increased exposure to environmental xenoestrogens and/or antiandrogens.
Article
Hypospadias is one of the most frequent genital malformations in the male newborn and results from an abnormal penile and urethral development. This process requires a correct genetic programme, time- and space-adapted cellular differentiation, complex tissue interactions, and hormonal mediation through enzymatic activities and hormonal transduction signals. Any disturbance in these regulations may induce a defect in the virilization of the external genitalia and hypospadias. This malformation thus appears to be at the crossroads of various mechanisms implicating genetic and environmental factors. The genes of penile development (HOX, FGF, Shh) and testicular determination (WT1, SRY) and those regulating the synthesis [luteinizing hormone (LH) receptor] and action of androgen (5alpha reductase, androgen receptor) can cause hypospadias if altered. Several chromosomal abnormalities and malformative syndromes include hypospadias, from anterior to penoscrotal forms. More recently, CXorf6 and ATF3 have been reported to be involved. Besides these genomic and hormonal factors, multiple substances found in the environment can also potentially interfere with male genital development because of their similarity to hormones. The proportion of hypospadias cases for which an aetiology is detected varies with the authors but it nevertheless remains low, especially for less severe cases. An interaction between genetic background and environment is likely.
Article
Experimental animal studies show that measurement of anogenital distance (AGD) and/or penis length may provide lifelong 'read-outs' of foetal androgen exposure during the masculinization programming window (MPW). However, variation in postnatal androgen exposure may complicate interpretation of such measurements. This is important to clarify if such measurements are to be applied to humans. The present aim was to evaluate effects of prenatal and/or postnatal manipulation of androgen production/action on growth of AGD and the penis in rats. Pregnant rats were treated daily before (e13.5-e21.5) and after birth (postnatal days 1-15) with either vehicle, 500 mg/kg di(n-butyl) phthalate (DBP) or 100 mg/kg flutamide (postnatal only) in prenatal + postnatal treatment combinations (N = 6 treatment combinations); DBP impairs androgen production whereas flutamide impairs androgen action. Male offspring were killed on postnatal day 8 (prepuberty), 25 (early puberty) or 90 (adulthood) when AGD was measured, the penis dissected out and its weight and length measured; plasma testosterone and ventral prostate weight were measured at day 90 to assess endogenous androgen exposure. In controls, penis length, girth and AGD increased 2.2-, 5.3-and 5.9-fold respectively from day 8 to day 90. Significant inhibition of penis growth and final length and girth was induced by treatments that inhibited postnatal androgen action. Conversely, growth and ultimate (adult) AGD was inhibited by prenatal inhibition of androgen production whereas postnatal androgen inhibition had negligible effect. Nevertheless, AGD and penis length were highly correlated at every age (R(2) > 0.33; p < 0.0001). However, altered endogenous androgen exposure may confound interpretation of changes in adults exposed prenatally/postnatally to DBP/flutamide. We conclude that AGD provides a lifelong guide to prenatal androgen exposure (in the MPW) whereas penis size reflects both prenatal + postnatal androgen exposure. At the group treatment level, prepubertal measurement of either AGD or penis size accurately predicts their size in adulthood.
Article
Micropenis is defined as a stretched penile length of less than 2-2.5SD for age. Aetiologies include hypogonadotropic hypogonadism, testicular dysgenesis, defects in testosterone synthesis, androgen resistance [5α-reductase (5αR) deficiency or partial androgen insensitivity] and other rare causes like growth hormone GH deficiency. Often, the cause remains unknown. The aim of this study was to determine whether isolated micropenis with normal plasma testosterone could hide a molecular defect in the androgen pathway. Twenty-six boys with isolated micropenis were included in this study. All of them had 46,XY karyotype, normal luteinizing hormone and follicle-stimulating hormone and a normal plasma testosterone response to human chorionic gonadotropin testing. Androgen receptor (AR), 5αR and steroidogenic factor 1 (SF1) genes were sequenced. A mutation in the AR gene was found in two patients, and a new mutation in the SF1 gene was found in one patient who was the only one to have a low level of inhibin B (InhB). This is the first report of isolated micropenis as a revealing symptom of AR and SF1 mutations. Anti-Mullerian hormone and InhB should thus be evaluated in patients with isolated micropenis, even when plasma testosterone is in the normal range. Detection of gene mutations is helpful for diagnosis, treatment and genetic counselling for probands.
Article
Prenatal diethylstilbestrol (DES)-exposed mice have raised the suspicion of a transgenerational effect in the occurrence of genital malformation in males. This nationwide cohort study in collaboration with a French association of DES-exposed women studied 529 families and showed that a significant proportion of boys born to DES daughters exhibited hypospadias with no other molecular defects identified.