Purpose To investigate associations between maternal use of selected medications during early pregnancy and the risk of hypospadias in male infants. Methods We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1,537 case infants with second or third degree isolated hypospadias and 4,314 male control infants born from 1997-2007. Exposure was based on reported use of any prescription or over-the-counter medication or herbal product, for which there were at least 5 exposed cases, from 1 month before to 4 months after conception, excluding topicals, vitamins, minerals, and products for which the components were unknown. Adjusted odds ratios (aORs) and 95% confidence intervals (CI) were estimated using multivariable logistic regression, adjusting for several confounders. Results Of the 195 medication components with at least 5 exposed cases, 89 components met the inclusion criteria and were assessed-28 herbal and 61 non-herbal components. Hypospadias was associated with reported use of cephalexin (aOR 3.06; 95% CI 1.02, 9.18), phenylpropanolamine HCl (aOR 2.68; 95% CI 1.06, 6.80), and ibuprofen (aOR 1.16; 95% CI 1.00, 1.34), in primary analyses. Conclusions We replicated a previously observed association between maternal exposure to phenylpropanolamine HCl and hypospadias. The associations with cephalexin and ibuprofen have not previously been reported. Given the exploratory nature of the analyses, these results should be considered hypothesis-generating. Better understanding of the potential fetal effects will allow clinicians and women of childbearing age to make more informed decisions regarding the use of medications during pregnancy.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

<p>Chromosomal abnormalities are defined as changes in the chromosome structure and fall in one of two categories. The first category is numerical alterations while the second category consists of structural abnormalities. Structural chromosomal abnormalities do not always interrupt genes in order to cause disease. They can also affect gene expression by separating a gene and its promoter element from distant regulatory elements. We have used characterisation of structural chromosomal abnormalities to identify the genetic bases for several congenital disorders.</p><p>In papers I-III, we have applied molecular characterisation of chromosomal translocations in order to identify candidate genes involved in mental retardation, hypospadias and anal malformation and premature ovarian failure. In paper I, we localised the chromosome X translocation breakpoint in a t(X;15) to be in the immediate proximity of the gene <i>ZDHHC15 </i>in a patient with severe mental retardation. Subsequent experiments revealed loss of <i>ZDHHC15</i> transcription in the patient which suggests this gene to be involved in the aetiology of the patient’s phenotype. In paper II, we show that a balanced translocation between chromosomes 6 and 17 in a patient with urogential malformation disrupts 2 genes, one at each translocation breakpoint. We also identified a fusion-gene as a result of the translocation. Our hypethesis is that the translocation together with its molecular consequences is important for the phenotype in the patient. Similarly, in paper III, we have used molecular characterisation of the breakpoints in a balanced translocation between chromosomes X and 11 in order to localise candidate genes in ovarian function. Our results indicate a number of genes affected by the translocation. In paper IV, we have used array-based comparative genomic hybridisation (array-CGH) in order to investigate a cohort of autistic sib-pairs for submicroscopic chromosomal alterations. We have identified several novel duplications and one novel deletion with strong association with autism.</p>

Chromosomal abnormalities are defined as changes in the chromosome structure and fall in one of two categories. The first category is numerical alterations while the second category consists of structural abnormalities. Structural chromosomal abnormalities do not always interrupt genes in order to cause disease. They can also affect gene expression by separating a gene and its promoter element from distant regulatory elements. We have used characterisation of structural chromosomal abnormalities to identify the genetic bases for several congenital disorders. In papers I-III, we have applied molecular characterisation of chromosomal translocations in order to identify candidate genes involved in mental retardation, hypospadias and anal malformation and premature ovarian failure. In paper I, we localised the chromosome X translocation breakpoint in a t(X;15) to be in the immediate proximity of the gene ZDHHC15 in a patient with severe mental retardation. Subsequent experiments revealed loss of ZDHHC15 transcription in the patient which suggests this gene to be involved in the aetiology of the patient’s phenotype. In paper II, we show that a balanced translocation between chromosomes 6 and 17 in a patient with urogential malformation disrupts 2 genes, one at each translocation breakpoint. We also identified a fusion-gene as a result of the translocation. Our hypethesis is that the translocation together with its molecular consequences is important for the phenotype in the patient. Similarly, in paper III, we have used molecular characterisation of the breakpoints in a balanced translocation between chromosomes X and 11 in order to localise candidate genes in ovarian function. Our results indicate a number of genes affected by the translocation. In paper IV, we have used array-based comparative genomic hybridisation (array-CGH) in order to investigate a cohort of autistic sib-pairs for submicroscopic chromosomal alterations. We have identified several novel duplications and one novel deletion with strong association with autism.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-03-29T18:02:18Z No. of bitstreams: 1 andrenettobastos.pdf: 5066328 bytes, checksum: 5fa19bf9587471962ff6d52065ab0f21 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-03-30T11:23:45Z (GMT) No. of bitstreams: 1 andrenettobastos.pdf: 5066328 bytes, checksum: 5fa19bf9587471962ff6d52065ab0f21 (MD5) / Made available in DSpace on 2017-03-30T11:23:45Z (GMT). No. of bitstreams: 1 andrenettobastos.pdf: 5066328 bytes, checksum: 5fa19bf9587471962ff6d52065ab0f21 (MD5) Previous issue date: 2009-09-09 / O objetivo do presente estudo é analisar e comparar os diferentes aspectos histológicos do prepúcio de crianças com hipospádia, com e sem aplicação prévia de testosterona, comparando com o de crianças postectomizados. O prepúcio de nove crianças postectomizadas (G1), 13 crianças com hipospádia sem uso de testosterona (G2) e 13 com hipospádia que fizeram aplicação tópica de propionato de testosterona a 1% por 30 dias (G3) foram incluídas no estudo. Avaliação histológica dos prepúcios para fibras colágenas foi feita com picrosírius, usado para avaliar densidade dessas fibras. Com o Tricrômio de Masson foi avaliada a homogeneidade das fibras colágenas e sua quantificação através do sistema de arcos ciclóides sobreposto a um sistema de vídeomicroscopia, onde obtive-se a densidade de superfície. Resorcina-fucsina de Weigert foi usada para avaliar a densidade e homogeneidade das fibras elásticas. Com o receptor de andrógeno avaliou-se o número e intensidade das células coradas. Fator de Von Willebrand foi usado para avaliar o número e densidade de volume dos vasos sanguíneos. O picrosírius, não mostrou diferenças entre os grupos estudados (p= 0,905). Com o Tricrômio de Masson, observamos que os pacientes tratados com testosterona (G3) apresentaram uma menor homogeneidade (p= 0,001) e menor densidade de superfície de fibras colágenas (0,3 ± 0,1 fibras colágenas) que aqueles não tratados (0,4 ± 0,1 fibras colágenas) (p< 0,001). As crianças postectomizadas apresentaram um padrão de distribuição de fibras elásticas mais denso (p= 0,003) e menos homogêneo (p= 0,008) que os demais grupos. A marcação para receptor de andrógeno foi maior nas crianças do G1 quando comparadas ao G3 (p=0,011). O prepúcios tratados com testosterona (G3) apresentaram aumento do valor numérico absoluto de vasos (8,5 ± 1,3 vasos/campo) (p< 0,001) e aumento da densidade de volume destes vasos (50,5% ± 7,8 vasos/ponto) quando comparados com o grupo não tratado (G2) (24,8% ± 8,6 vasos/ponto) (p< 0,001). O uso tópico de propionato de testosterona a 1% foi capaz de provocar neovascularização, em número absoluto e densidade de volume, e reduzir o tecido fibroso. Crianças tratadas apresentaram padrão de distribuição de fibras colágenas menos homogêneo próxima aos vasos o que sugere menor maturidade destas fibras com menos deposição de colágeno. / The goal of this study is to analyze the different histological features of the foreskins of children with hypospadia, that has and has not recieved application of testosterone cream, and compare them with circumcised patients. The foreskin of 09 circumcised children (G1), 13 children with hypospadia, who did not receive testosterone (G2), and 13 children who received topical 1% testosterone propionate (G3) were included in this study. The histological evaluation of the collagen fiber was done with Picrosirius staining to analyze the density of these fibers. Masson`s trichrome was used evaluate the homogeneity of the collagen fibers and its quantification as their surface density, which was obtained through a videomicroscopy system superimposed with a cycloid arch test system. Elastic fiber density and homogeneity was evaluated with resorcin-fucsin of Weigert. Androgen receptor histochemistry was used to stain intensity and the number of stained cells. With the von Willebrand factor and the same video-microscopy system superimposed with a cycloid arch test system, the number and volume density of the blood vessels was obtained. Picrosirius histochemistry did not show differences among the study groups (p= 0.905). With Masson`s trichrome, testosterone-treated patients (G3) had lower homogeneity (p=0.001) and surface density of the collagen fibers (0.3 ± 0.1 collagen fibers) than those untreated (G2) (0.4 ± 0.1 collagen fibers) (p<0.001). Circumcised children had a denser pattern of elastic fiber distribution (p=0.003), and the elastic fibers were also less homogeneous (p=0.008) than the other groups. The histochemistry for androgen receptor showed a greater staining pattern in children of G1 compared to G3 (p=0.011). Testosterone-treated foreskins (G3) had an increased absolute numbers of blood vessels (8.5 ± 1.3 vessels/field) (p<0.001) and an increased blood vessel volume density (50.5% ± 7.8 vessel/points) compared to untreated subjects (G2) (24.8% ± 8.6 vessel/points) (p<0.001). Topical 1% testosterone propionate produced neovascularization, in absolute numbers and volume density, and reduced fibrous tissue. Treated children had less homogeneous distribution patterns of vessel-surrounding collagen fibers, suggesting a lower maturity of these fibers, with less collagen deposition.

Hypospadias is a congenital malformation that occurs in 0.3-1% of live births, in which the meatus (the urethral opening) is dorsally malpositioned. Uncorrected hypospadias can cause difficulties in urination, abnormal sexual function, and adverse psychological consequences; surgical correction, though generally successful, constitutes an economic burden for families. Several common classes of pesticides have demonstrated potential to disrupt normal endocrine hormones that regulate fetal genitourinary development. Past epidemiologic studies of pesticide exposure and risk of hypospadias have been limited by limited available data, small sample sizes, or poor ascertainment of pesticide exposure. The objective of this study was to examine the relationship between parental occupational pesticide exposure and risk of hypospadias in their offspring; and further, to assess whether addition of residential pesticide exposure data is feasible and contributes to overall pesticide exposure. We began by conducting a meta-analysis of the current literature, in which summary measures of occupation (such as census occupation code) had been used to assign pesticide exposure. We found elevated but marginally significant risks of hypospadias were associated with maternal occupational exposure (PRR of 1.36, CI = 1.04-1.77), and paternal occupational exposure (PRR of 1.19, CI= 1.00-1.41) in the previously published literature. We then used industrial hygienist review of occupational histories to estimate the relationship between pesticide exposure and risk of hypospadias. We found that maternal occupational exposure to any pesticides (yes/no) was not associated with an increased risk of hypospadias (OR = 0.83, 95% CI = 0.6-1.1), cumulative insecticide (OR = 1.09; 95% CI = 0.9- 1.3), herbicide (OR = 1.05; 95% CI = 0.9- 1.2), or fungicide (OR = 0.91; 95% CI = 0.7-1.2) exposure. These negative findings might be explained by a lack of relationship at the low levels of exposure observed in this study population, in which case another farm exposure could be related to hypospadias; or this negative finding may be due to exposure misclassification. Finally, we evaluated the feasibility and relevance of collecting residential pesticide exposure and direct reports of occupational exposure from fathers. Residential pesticide use during the six months prior to pregnancy and during pregnancy was common among control mothers: 45% reported that their home had been treated for insect or rodent pests; 47% reported that their lawn or garden had been treated for weeds or insect pests; 16% used a lawn service; 26% reported that a pet had been treated for fleas, ticks, or mites (including flea and tick preventives); 17% reported community-wide sprayings for pests; and 16% reported that their workplaces were treated for pests. Case mothers were more likely to report that their home had been treated of insect or rodent pests (50%) or that a pet had been treated for fleas, ticks, or mites (36.5%). Our results suggest that collection of information on residential pesticide use is feasible, and the impact of residential pesticide use on birth defects risk should be assessed in future studies.

No description available.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-09-20T13:55:36Z No. of bitstreams: 1 elisabethcamposdeandrade.pdf: 10436022 bytes, checksum: ee61c000d375df1c659ffc7041f3103f (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-09-22T15:12:59Z (GMT) No. of bitstreams: 1 elisabethcamposdeandrade.pdf: 10436022 bytes, checksum: ee61c000d375df1c659ffc7041f3103f (MD5) / Made available in DSpace on 2017-09-22T15:12:59Z (GMT). No. of bitstreams: 1 elisabethcamposdeandrade.pdf: 10436022 bytes, checksum: ee61c000d375df1c659ffc7041f3103f (MD5) Previous issue date: 2017-07-31 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / A testosterona é frequentemente utilizada no período pré-operatório da cirurgia nos casos de hipospádia grave. Estudos anteriores demonstraram a presença de receptores androgênicos em miócitos cardíacos que podem modular o fenótipo. O uso de doses suprafisiológicas de andrógenos pode levar à toxicidade no músculo cardíaco e, em alguns casos, à hipertrofia ventricular esquerda. Este ensaio clínico randomizado duplo-cego controlado visa avaliar o efeito do uso de testosterona tópica sobre o pênis no índice de massa ventricular esquerda em meninos com hipospádia. Foram incluídos meninos com hipospádia de 6 meses a 9 anos. Os meninos foram divididos em dois grupos: G1 - meninos que receberam creme de propionato de testosterona 1%, duas vezes ao dia, durante 30 dias e G2 - meninos que receberam creme placebo na mesma posologia. Todos os meninos foram submetidos à avaliação ecocardiográfica bidimensional para medir o índice de massa ventricular esquerda e a exame físico para avaliação da pressão arterial e do índice de massa corporal antes do tratamento, ao seu término e 60 dias após. Foram determinados os níveis de testosterona sérica, LH e FSH. Trinta e cinco meninos foram analisados, sendo 17 no G1 e 18 no G2. Não foram encontradas diferenças no índice de massa do ventrículo esquerdo (massa ventricular esquerda indexada pela área de superfície corporal) antes do tratamento. O índice de massa do ventrículo esquerdo foi de 59,21 ± 11,91 g/m² em G1 e 55,12 ± 8,29 g/m² em G2 (p=0,244) ao final do tratamento e 61,13 ± 11,69 g/m² em G1 e 62,84 ± 35,99 g/m² em G2 (p=0,852) 60 dias após. Os níveis séricos de testosterona foram 12 [7-80] ng/dL em G1 e 5 [5-7] ng/dL em G2 (p=0,018) ao final do tratamento e 10 [5-11] ng/dL em G1 e 5 (4-5) ng/dL em G2 (p=0,155), 60 dias após. Houve um pequeno aumento na pressão arterial sistólica (PAS) ao final do tratamento (83,82 ± 7,18 mmHg) no grupo que recebeu testosterona (G1) comparado com o grupo que recebeu placebo (G2), 77,5 ± 6,69 mmHg (p=0,010). Após 60 dias, os níveis de PAS retornaram aos níveis basais em G1 (82,35 ± 5,62 mmHg) e em G2 (81,38 ± 4,79 mmHg) (p=0,588). A testosterona tópica pode ser considerada segura no período pré-operatório de meninos com hipospádias sem risco de hipertrofia ventricular esquerda. Houve um aumento dos níveis de PAS durante o uso da testosterona, que foi transitório, retornando a níveis normais 60 dias após a suspensão da droga. / Testosterone is often used in the preoperative period of surgery in cases of severe hypospadias. Previous studies have demonstrated the presence of androgen receptors in cardiac myocytes that can modulate the phenotype. The use of supraphysiological doses of androgens can lead to toxicity on the heart muscle and, in some cases, to left ventricular hypertrophy. This randomized double blind controlled clinical trial aims to evaluate the effect of topical testosterone on left ventricular mass index in boys with hypospadias. Boys with hypospadias aged 6 months to 9 years were included. Boys were divided into two groups: G1 - boys who received testosterone propionate 1% ointment twice a day for 30 days, and G2 - boys receiving placebo ointment in the same regimen. All boys were submitted to bidimensional echocardiographic evaluation to compare the left ventricular mass index, blood pressure, and body mass index before treatment, at its ending and 60 days later. Levels of serum testosterone, LH, and FSH were measured. Thirty-five boys were analyzed: 17 in G1 and 18 in G2. No differences were found in left ventricular mass index (left ventricular mass indexed by body surface area) prior to treatment. Left ventricular mass index was 59.21 ± 11.91 g/m² in G1 and 55.12 ± 8.29 g/m² in G2 (p=0.244) at the end of the treatment and 61.13 ± 11.69 g/m² in G1 and 62.84 ± 35.99 g/m² in G2 (p=0.852) 60 days later. Serum testosterone levels were 12[7-80] ng/dL in G1 and 5[5-7] ng/dL in G2 (p=0.018) at the end of the treatment of treatment and 10[5- 11] ng/dL in G1 and 5[4-5] ng/dL in G2 (p=0.155), 60 days later. There was a small increase in systolic blood pressure (SBP) at the end of the treatment (83.82 ± 7.18 mmHg) in the group who receive testosterone (G1) compared with controls (G2), 77.5 ± 6.69 mmHg (p=0.010). Passing 60 days, SBP levels returned to basal levels in G1 (82.35 ± 5.62 mmHg) and in G2 (81.38 ± 4.79 mmHg) (p=0.588). Topical testosterone can be considered safe in the preoperative period of boys with hypospadias with no risk of left ventricular hypertrophy. An increase in systolic blood pressure occurs while using testosterone but it is transitory, returning to normal levels 60 days after the discontinuation of the drug.