【作者】 陈智；

【导师】 孙贵范；

【作者基本信息】 中国医科大学 ， 劳动卫生和环境卫生学， 2006， 博士

【摘要】 前言 生殖细胞肿瘤(germ cell tumors,GCTs)是发生于生殖腺或生殖腺外(与其胞胎发育时期有关的部位)的不正常细胞增生。在胚胎发育时期,生殖细胞由卵黄囊(yolk sac)经由肠系膜,最后降至骨盆腔或阴囊而形成睾丸或卵巢。因此,生殖细胞肿瘤除了好发于睾丸或卵巢外,亦可发生于性腺外的部位,如:后腹腔,骶尾骨,纵膈腔或中枢神经系统等部位。50%的患儿确诊年龄在4岁以下。儿童GCTs的病因还不清楚。从1996年到2003年,我们进行了迄今为止最大样本的儿童GCTs病例对照病因研究,试图寻找儿童GCTs的致病因素。本研究使用专门用于职业研究的调查问卷和一般调查问卷搜集各种信息,包括父母在各个时期的职业与住宅农药暴露,吸烟,饮酒,例如怀孕前,怀孕期间,儿童出生之后以及儿童出生后的住宅农药暴露,目的在于探讨儿童早期的一些暴露因素是否是发生儿童GCTs的危险因素。 实验方法 在本研究中,要求病例是在1993年1月1日到2001年12月31日期间被诊断为GCTs的15岁以下的儿童。其中,344名患者符合本课题的要求。在344名患者中,对278名(80.8%)患者的母亲成功地进行了电话调查,其中包括八名已故患者的母亲。根据患者性别,年龄(±1岁),诊断时所在地,采用随机选择电话号码和频率配对的方法进行选择。配对的比例是男孩1:2,女孩1:1。在634个对照的家庭中,423个家庭的母亲完成了电话调查(66.7%)。信息的采集有两种方法,一种是自填调查问卷,另一种是调查员电话调查填写问卷。首先调查母亲,然后调查父亲。调查问卷包括更多还原

【Abstract】 ObjectiveGerm cell tumors (GCT) originate from pluripotent germ cells of the embryonic yolk sac and are located primarily in the testes and ovaries. However, tumors also can arise in extragonadal sites, including the sacrococcygeal region, anterior mediastinum, neck, retroperitoneum, and brain. More than 50% of children were age less than 4 years when GCT was diagnosed. The etiology of GCTs is unknown. From 1996 to 2003, we conducted a large - scale case - control study of childhood germ - cell tumors, which was a largest sample size on the topic to date. Occupation - specific questionnaires were used to collect parental information on various occupational exposures, including maternal and paternal exposures to pesticides before conception, during gestation, during the early childhood of the index child. Self - administered questionnaires collected general information, including parental and children household exposure to pesticides, parental smoking and drinking, and general information. The purpose of this study was to investigate impacts of some environmental exposures during early childhood on childhood germ cell tumors.MethodsCases were recruited and included children younger than age IS years who had been diagnosed with a germ - cell tumor at any anatomic site. To be eligible for the study, cases must have received a diagnosis of germ - cell carcinoma between January 1, 1993, and December 31, 2001 in United States. Telephone interviews were completed successfully with the mothers of 278 of the 344 eligi-ble cases (80. 8 percent) , including the mothers of eight deceased children. Controls were selected by random digit dialing and were frequency - matched to cases on the basis of the child’s sex, year of birth ( ± 1 year) , and geographic location at diagnosis. The matching ratio was approximately 1:2 for males and 1:1 for females. A telephone interview with the mother was completed successfully for 423 of the 634 potential controls (66.7 percent). Information was obtained from each child s mother through a self - administered questionnaire and a telephone interview. The father was also interviewed when available. The questionnaire included questions about demographic factors, medication use, radio-graphic exposures, personal habits, smoking, drinking, lifetime occupational history, residential pesticide use, and family medical history. The occupational data collected consisted of two parts;a self administered generic work history (job title, type of business, location of employer, job tasks, number of working hours, primary job activities or duties, and chemicals and equipment used for all jobs that parents had held for 6 months or longer since the age of 18) and interviewer - implemented module questionnaires with detailed job - specific questions. Module questionnaire in our study were designed for a variety of jobs and exposures. A total of 63 job module questionnaires were used in the study. Three broad classes of pesticides (i. e. , insecticides, herbicides, and agricultural fungicides) were evaluated using a job exposure matrix approach (JEM). Using the detailed work history, module questionnaire, and job exposure matrix information, we assigned a score for the probability, frequency, and intensity of pesticide exposure and a confidence score for the exposures of interest to each study participant, with case control status masked. We investigated parental occupational and household pesticides exposure, smoking, drinking, and children exposure to household pesticide;throughout the entire work history before the reference date (i.e. , the diagnosis date for cases);within 1 month before the index pregnancy;during the index pregnancy;and after the birth of the index child. The reference group consisted of subjects exposed to none of the interested variables. We used the chi - squared test and Fishers exact test for categorical comparisons of data. An unconditional logistic regression model with adjustment for age, sex, and relevant confounders was used to calculate odds ratiosand 95 percent confidence intervals as estimates of the relative risk. Tests for trend were performed by treating levels of categorical variables as units forming a continuous variable in the logistic model. Analyses were performed with all subjects together and then separately by sex to explore differences in associations between boys and girls. Analyses were also conducted by stratifying the data by the children’s age and by the major histologic types of germ - cell tumors. Statistical analyses were performed using the statistical package SAS;All tests were two - tailed.Resultst.Boys (n =73) and girls ( n = 180) accounted for 28. 9 percent and 71. 2 percent of total case subjects, respectively. Approximately 50 percent of cases were younger than age 2 years at diagnosis. More case mothers (37.5 percent) than control mothers (27.9 percent) had ever experienced occupational pesticide exposure during their lifetime. After adjustment for child’s age, childs sex, maternal age at index pregnancy, maternal education, maternal race, and family income, the odds ratio associated with maternal occupational exposure was 1.2 (95 percent confidence interval (CI) : 0.9, 1.5). Cumulative maternal occupational exposure before the index pregnancy, within 1 month before the index pregnancy, during the index pregnancy, or after the birth of the index child did not alter the odds ratio substantially from the null. Similarly, no change in risk was seen when data were analyzed by estimated occupational exposure level in different time windows. For example, the odds ratios associated with maternal exposures at the medium level or higher before and during the index pregnancy were 1.1 (95 percent CI: 0.7, 1.5) and0.9 (95 percent CI: 0.5, 1.7), respectively. A similar pattern was observed for girls and boys. Fewer case fathers (30.7 percent) than control fathers (36.5 percent) reported occupational exposure. Most risk estimates were less than unity for paternal pesticide exposure in the different time windows. For fathers who had ever been exposed to pesticides, the odds ratios were 0.9 (95 percent CI: 0.7, 1.2) before pregnancy, 0.8 (95 percent CI: 0.5, 1.3) within 1 month before pregnancy, 0.8 (95 percent CI:0.5, 1.2) during pregnancy, and 0. 8 (95 percent CI: 0.5, 1.3) after the birth of the index child. When both parents had ever been occupationally exposed to pesticides before the index pregnancy, the odds ratio was 0.8 (95 percent CI: 0.4, 1.3). We also evaluated the effect of paternal occupational pesticide exposure for those with a probability greater than 1, confidence greater than 1, or both (data not shown). Again, fewer case fathers than control fathers had incurred exposure to pesticides. Among fathers who had ever been exposed to pesticides, the odds ratio was 0.7 (95 percent CI: 0.5, 1.1) for a probability greater than 1, 0. 8 (95 percent CI;0. 6, 1.1) for confidence greater than 1, and 0.7 (95 percent CI: 0.5, 1.1) for both probability and confidence greater than 1. Maternal exposure was associated with an approximately twofold, though statistically nonsignificant, increased risk of dysgerminoma (odds ratio = 1.9, 95 percent CI: 0. 9, 4.2). Case mothers were slightly more likely to have ever had a residential exposure to insecticides during the period from 6 months before pregnancy to breastfeeding than control mothers (57.4% vs. 53. 1% ) , OR = 1. 1, 95% CI =0.9-1.4. OR were not altered significantly from the null for any window of exposure examined, i. e. , neither the exposure frequency nor the type of insecticide was related to risk during the month before the pregnancy, during the pregnancy, during breastfeeding, or during the year after the child was born. Case and control fathers reported very similar exposures to residential insecticides (78.5% vs. 78.9% ) during the period from 6 months prior to the pregnancy to 1 year after the child was born (adjusted OR = 1.0, 95% CI = 0.7-1.4). The OR for paternal exposure to insecticides more than four times during the index pregnancy was 0.5 (95% CI =0. 2 -0. 9, trend test p = 0. 05) for boys, and further analyses showed that OR for paternal exposure to indoor insecticides more than three times was 0. 3 (95% CI = 0.2 -0.8, trend test p =0.02) for boys. Analyses examining the effects of paternal exposure to pesticides, as well as analyses examining combined paternal exposure to residential and occupational pesticides did not find any positive associations. Slightly fewer cases than controls children had been exposed to household insecticides (70.6% vs. 72.4%), with an adjusted OR of 1.0 (95% CI =0.7-1.4). The OR were 0.9 (95% CI =0.6-1.3) for children with exposures more thanseven times and 1.0 (95% CI = 0.7 -1.5) for children who were exposed to more than two types of insecticides, analysis of childrens exposures to indoor or outdoor residential insecticides and analysis by histological type did not show any significant associations with risk.Parents of cases were slightly more likely to smoke cigarettes at some points during their lifetime than control parents (44.9% vs. 42.5% and 51.6% vs. 44.7% for mothers and fathers, respectively) , OR = 1. 0,95% CI = 0. 8 - 1. 3 and OR = 1.2, 95% CI = 0.9 -1.5 for mothers and fathers respectively. Similar patterns were observed for girls and boys. Parental cigarette smoking during the month before the index lpregnancy, during any trimester of pregnancy, during all three trimester combines, or during nursing did not appear to alter Ors substantially from the null. Similarly, no change in risk was observed when we analyzed the number of years of smoking during lifetime or number of years of smoking before and after the ndex birth. For example, Ors associated with paternal smoking for > =16 years before the index pregnancy were 1.3 (95% CI =0. 7 -2.2) forallsubjexts, 1.3 (95%CI =0.5-3.2) for boys, andl.l(95%CI = 0.6-2.3) for girls. Further analyses were performed to examine the effect of maternal passive smoking during the index pregnancy on GCTs risk among offspring. No significant association was found ( passive smoking:OR = 1. 0,95% CI =0.7-1.4,active smoking only: OR =0.9, 95%CI =0. 6 - 1. 3: and active and passive smoking: OR = 1.0, 95%CI=0.7-1.4). Slightly more control mothers (59.4% ) drank than case mothers (53.9% ) from 1 month before pregnancy to nursing, but OR =0. 9, 95% CI =0. 7 -1.2. Few mothers drank alcohol during the second and third trimesters and during nursing, we did not analyze the data by amount consumed during these periods. The drink rate of control fathers (72. 3% ) did not differ statistically from that of case fathers (69.5% ) during the period 1 month before the index pregnancy to nursing. No aspect of drinking was associated with GCTs risk. Analyses also were carried out for girls and boys, separately, and no significant associations were found. Additional analyses stratified by age at diagnosis ( < = 2 years vs. > 2 years old) , histologic type of tumors ( mainly dysgerminoma, yolk sac tumor, and terato-ma), and anatomic sites ( mainly ovary, testis, an dextragonadal) showed nosignificant association between parental smoking and alcohol consumption and childhood GCTs risk.Discussion and ConclusionIn summary, this large case - control study did not show a strong association of increased GCT risk in offspring with parental or child - postnatal residential exposure to pesticides, or occupational exposure to pesticides. We did not find the relationship between parental smoking and drinking and childhood GCTs of their offspring. A few significant associations found in our study should be verified, and possible biological mechanisms be investigated in the future studies. Future study of GCT needs not only to have larger sample sizes to allow an evaluation of etiology by histological subtype, but also needs to incorporate bio-markers of exposure to improve the exposure measurements.更多还原