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PubMed2006

Transgenerational effects of betel-quid chewing on the development of the metabolic syndrome in the Keelung Community-based Integrated Screening Program.

BACKGROUND: The transgenerational metabolic effects of betel-quid chewing have been reported in mice but not in humans. OBJECTIVE: This study aimed to determine whether exposure to paternal chewing of betel nut quids led to an increased risk of early manifestation of the metabolic syndrome (MetS) in human offspring. DESIGN: The subjects were selected from 66,971 residents aged >19 y who attended a community-based Integrated Screening Program in Taiwan and who were identified as parent-child trios (n = 5037). Using a population-based, parent-child study design, we compared the mean ages of offspring with MetS at entry between those who were exposed and those who were unexposed to paternal chewing of quids containing betel nut. Cox proportional hazards regression models were used to estimate adjusted hazard ratios and to assess dose-response relations for paternal betel-quid exposure. RESULTS: The offspring who were exposed to paternal betel-quid chewing were younger than those who were not exposed, regardless of MetS status; they also had a 2.14-fold increase in the risk of early manifestation of MetS (adjusted hazard ratio = 2.14; 95% CI: 1.25, 3.66) after control for environmental and other risk factors, including personal betel chewing. Significant dose-response relations were found between the risk of early MetS and the quantity and duration of paternal exposure to betel quids. In the absence of MetS in either parent and of betel-quid consumption by the offspring, paternal exposure to betel quids increased the risk of early manifestation of MetS in offspring 2.53-fold (95% CI: 1.03, 2.64) compared with paternal nonexposure. CONCLUSION: Our findings suggest that exposure to paternal betel-quid chewing increases the risk of early manifestation of MetS in human offspring in a dose-dependent manner.

Adult↗

PubMed2006

Parental heat exposure and risk of childhood brain tumor: a Children's Oncology Group study.

Medulloblastoma (MB) and primitive neuroectodermal tumor (PNET) are histologically similar brain tumors that occur mostly in children. As part of a comprehensive case-control study of MB/PNET, this study explored parental exposure to heat and electromagnetic fields as potential risk factors. Parents of 318 cases (<6 years of age at diagnosis in 1991-1997 and registered with the Children's Cancer Group) and 318 controls selected by random digit dialing were interviewed. In univariate analyses, moderately strong associations were observed for mother's sauna use close to conception (odds ratio = 3.8, 95% confidence interval (CI): 1.0, 13.7) or in the first trimester (odds ratio = 3.6, 95% CI: 0.7, 17.3) and for father's exposure in the 3 months before the pregnancy to sauna (odds ratio = 2.4, 95% CI: 1.3, 4.5), electric blanket (odds ratio = 2.0, 95% CI: 0.9, 4.3), or any heat source (for higher exposure: odds ratio = 2.5, 95% CI: 1.4, 4.6). In multivariate models, father's sauna use and father's exposure to any heat source were associated with MB/PNET in a dose-response fashion (for high exposure: odds ratio = 3.4, 95% CI: 1.2, 9.7, and odds ratio = 2.1, 95% CI: 1.1, 4.3, respectively). This new observation regarding paternal exposure to heat just prior to the index pregnancy deserves consideration in future animal and human studies of MB/PNET.

Case-Control Studies↗

PubMed1996

Brain tumor risk in offspring of men occupationally exposed to electric and magnetic fields.

OBJECTIVES: The purpose of the study was to address the possible associations between the occupational exposure of men to electromagnetic fields (EMF) and the risk of childhood brain tumors in offspring by reanalyzing case-referent interview data from a study of environmental factors and childhood brain tumors conducted by one of the authors and first reported in 1990. METHODS: Analyses of the case-referent data were limited to the 94 cases and 166 individually-matched referents for whom data on the biological fathers were available. Paternal exposure to occupational EMF was inferred from a list of job titles compiled for that purpose. Mantel-Haenszel odds ratios (OR) for individually matched cases and referents were estimated for different definitions of exposure. RESULTS: The findings suggested at best very small increases in risk for jobs associated with the occupational EMF exposure of fathers during the one-year period prior to conception, the OR values ranging from 1.12 to 1.31. Notably elevated OR values were, however, found in association with any paternal welding in the one-year preconception period (OR 3.8, 95% confidence interval 0.95-15.55). CONCLUSIONS: The results of reanalysis indicate that preconceptional paternal occupational exposure to EMF is at best only weakly associated with a risk of childhood brain tumors. However, the findings for paternal welding are somewhat intriguing since relatively strong EMF have been measured in association with welding. Further study of welding as a potential risk factor is required since welders may be exposed to a wide range of toxic agents in addition to EMF.

Adult↗

PubMed2001

Parental occupational exposures to electromagnetic fields and radiation and the incidence of neuroblastoma in offspring.

We examined parental occupational exposures to electromagnetic fields and radiation and the incidence of neuroblastoma in offspring. Cases were 538 children diagnosed with neuroblastoma between 1992 and 1994 in the United States or Canada. Age-matched controls were selected by random-digit dialing. Occupational exposures to electrical equipment and radiation sources were classified by an industrial hygienist, and average exposures to extremely low frequency magnetic fields were estimated using a job exposure matrix. Maternal exposure to a broad grouping of sources that produce radiofrequency radiation was associated with an increased incidence of neuroblastoma (odds ratio = 2.8; 95% confidence interval = 0.9-8.7). Paternal exposure to battery-powered forklifts was positively associated with neuroblastoma (odds ratio = 1.6; 95% confidence interval = 0.8-3.2), as were some types of equipment that emit radiofrequency radiation (odds ratios congruent with 2.0); however, the broad groupings of sources that produce ELF fields, radiofrequency radiation, or ionizing radiation were not associated with neuroblastoma. Paternal average extremely low frequency magnetic field exposure >0.4 microTesla was weakly associated with neuroblastoma (odds ratio = 1.6; 95% confidence interval = 0.9-2.8), whereas maternal exposure was not. Overall, there was scant supportive evidence of strong associations between parental exposures in electromagnetic spectrum and neuroblastoma in offspring.

Case-Control Studies↗

PubMed2002

Number of boys born to men exposed to polychlorinated byphenyls.

We studied the sex of children born to individuals involved in the Yucheng oil disaster, Taiwan, who were exposed to polychlorinated byphenyls (PCBs) after an oil contamination accident in 1979. Men exposed to PCBs before age 20 years had a lower chance of having a baby boy than did age-matched and neighbourhood-matched controls (odds ratio 0.65, 95% CI 0.45-0.93). The male-to-female sex ratio of children born to men exposed to PCBs after age 20 years, however, approached that seen in controls (0.90, 0.59-1.35). We noted no significant difference in the birth ratio of infants born to exposed and unexposed mothers (0.93, 0.77-1.12). Our findings suggest that paternal exposure to PCBs before age 20 years affects the sex of a subsequently born child.

Adult↗

PubMed1995

Validity of mother's report of father's occupation in a study of paternal occupation and congenital malformations.

Agreement between the mother's and father's report of the father's occupation was assessed in a case-control study of paternal occupation and birth defects. Cases were identified from births registered with the Metropolitan Atlanta Congenital Defects Program between 1968 and 1980; controls were selected from liveborn infants without defects. Both parents were sought for interview, and each parent was asked about the father's job history for 2 years prior to the infant's death. This concordance analysis is based on 3,739 case infants and 2,279 control infants for whom both parents were interviewed. The authors considered the father's report of his occupation as correct, and they assessed the ability of the mother to report the same occupation(s) during a 7-month period around conception. The exact agreement between mother's and father's report of the father's occupation was 59%. Agreement improved slightly with increasing family income and when fathers were college graduates. Female partners were not accurate proxy respondents in this study of paternal occupation and birth defects, which suggests that investigators should interview both parents in studies of paternal exposures and reproductive outcomes, i.e., mothers for pregnancy history and maternal confounders and fathers for occupational history and paternal confounders.

Case-Control Studies↗

PubMed1993

Paternal preconceptional radiation exposure in the nuclear industry and leukaemia and non-Hodgkin's lymphoma in young people in Scotland.

OBJECTIVE: To determine if a relation exists between paternal exposure to relatively high levels of radiation in the Scottish nuclear industry and the risk of leukaemia and non-Hodgkin's lymphoma is subsequently conceived children. DESIGN: Matched case-control study with three controls for each case. SETTING: The whole of Scotland. SUBJECTS: The fathers of 1024 children with leukaemia and 237 children with non-Hodgkin's lymphoma diagnosed in Scotland below the age of 25 among those born in Scotland since nuclear operations began (in 1958) and the fathers of 3783 randomly chosen controls. The fathers of 80 children with leukaemia and 16 with non-Hodgkin's lymphoma in north Cumbria were also covered since some workers at one Scottish nuclear site live over the border in that area. Details of all fathers were then matched against records of the nuclear industry. MAIN OUTCOME MEASURES: Paternal preconceptional radiation exposures, particularly relatively high levels, both lifetime and in the six and three months before conception. RESULTS: No significant excess was observed in any subgroup and there was no significant trend: fathers of three controls but no cases were exposed to lifetime preconceptional levels of 100 mSv or greater (Fisher's exact p value 0.84). In the six months before conception, fathers of two cases and three controls received 10 mSv or more, odds ratio 2.3 (95% confidence interval 0.31 to 17.24). In the three months before conception the fathers of one case and two controls received 5 mSv or more, odds ratio 1.7 (0.10 to 30.76). The results for leukaemia and non-Hodgkin's lymphoma combined were similar. CONCLUSIONS: No significant excess of leukaemia or of leukaemia and non-Hodgkin's lymphoma was found at any radiation level in any preconceptional period.

Adolescent↗

PubMed1995

Epidemiology of childhood acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is the second most common leukemia in children, with approximately 400 new cases occurring annually in the United States. Worldwide, the highest rates of childhood AML occur in Asia and the lowest rates are reported from India and South America. Numerous genetic risk factors for childhood AML have been defined, including Down syndrome, neurofibromatosis, and Fanconi anemia. Research into environmental risk factors has been limited by the rarity of this disease; however, studies of AML in adults have implicated ionizing radiation, solvents, and petroleum products as potential etiologic agents. The largest analytic study of childhood AML found that occupational exposures of either parent to pesticides, paternal exposure to petroleum products, and postnatal exposures to pesticides are increased in children with AML. In addition, maternal use of marijuana during pregnancy was associated with an increased risk of AML, especially the monocytic subtypes. Further study of childhood AML, including occurrence of the disease as a second malignancy, is needed in order to confirm these findings and to increase our understanding of this leukemia.

Adolescent↗

PubMed2005

Male-mediated developmental toxicity.

In recent years, the public has become more aware that exposure of males to certain agents can adversely affect their offspring and cause infertility and cancer. The hazards associated with exposure to ionising radiation have been recognised for nearly a century, but interest was aroused when a cluster of leukaemia cases was identified in young children living in Seascale, close to the nuclear processing plant at Sellafield in West Cumbria. There was a civil court case on behalf of two of the alleged victims of paternal irradiation at Seascale against British Nuclear Fuels. The case foundered on "the balance of probabilities". Nevertheless, there was support for paternal exposure from Japanese experimental X-ray studies in mice. The tumours were clearly heritable as shown by F2 transmission. Also, effects of a relatively non-toxic dose of radiation (1Gy) on cell proliferation transmitted to the embryo were manifested in the germ line of adult male mice even after two generations. In addition in humans, smoking fathers appear to give rise to tumours in the F(1) generation. Using rodent models, developmental abnormalities/congenital malformations and tumours can be studied after exposure of males in an extended dominant lethal assay and congenital malformations can be determined which have similar manifestations in humans. The foetuses can also be investigated for skeletal malformations and litters can be allowed to develop to adulthood when tumours, if present, can be observed. Karyotype analysis can be performed on foetuses and adult offspring to determine if induced genetic damage can be transmitted. Using this study design, cyclophosphamide, 1,3-butadiene and urethane have been examined and each compound produced positive responses: cyclophosphamide in all endpoints examined, 1,3-butadiene in some and urethane only produced liver tumours in F(1) male offspring. This suggests the endpoints are determined by independent genetic events. The results from heritable studies with 1,3-butadiene have been used in the parallelogram approach to determine a risk assessment for the germ cells in man.

Animals↗

PubMed1992

Surveillance around hazardous waste sites: geographic information systems and reproductive outcomes.

The purpose of this paper is to discuss the potential for integrating surveillance techniques in reproductive epidemiology with geographic information system technology in order to identify populations at risk around hazardous waste sites. Environmental epidemiologic studies have had problems with estimating or measuring exposures to individuals, and of detecting effects when the exposure is low, but continuous. In addition, exposures around hazardous waste sites are complex and frequently involve chemical mixtures. The birth weight of human babies has been reported to be sensitive to many environmental influences. Birth weight can be analyzed as a continuous variable or as a dichotomous one using the standard cutpoint of 2500 g or less to indicate low birth weight. It has the potential to be a powerful surveillance tool since exposures to the fetus reflect maternal and paternal exposures. The advent of recent environmental regulations pertaining to hazardous waste sites has greatly increased the availability of environmental data for many sites. The major problem with incorporating these data into epidemiologic studies has been with the logistics of data management and analysis. Computer-assisted geographic information systems hold promise in providing capabilities needed to address the data management and analysis requirements for effective epidemiologic studies around to hazardous waste sites.

Environmental Health↗

PubMed2026

Risk of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis: a living meta-analysis-version 1.

OBJECTIVE: To evaluate the association of paternal use of valproate during spermatogenesis compared with paternal use of lamotrigine or levetiracetam on offspring risk of neurodevelopmental disorders (NDDs). METHODS: Eligibility criteria: observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate vs lamotrigine or levetiracetam during spermatogenesis. INFORMATION SOURCES: the databases PubMed, Embase, Cochrane Library and Web of Science were systematically searched from January 1995 to October 2025.Synthesis of results and risk of bias: a random-effects model was used to estimate pooled HRs and 95% CI, with heterogeneity assessed using I2 statistic for any NDD.We present a meta-analysis of observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate versus lamotrigine or levetiracetam during spermatogenesis. Given the major regulatory implications of paternal valproate safety, the recent emergence of new population-based data, and the expectation of further large studies, we designed this work as a living systematic review and meta-analysis that will be updated as new eligible evidence becomes available. RESULTS: We identified three eligible studies based on data from (1) Norway and Sweden, (2) Norway and Taiwan and (3) Denmark. As two studies included Norwegian data, their results are referred to as 'Norway 1' and 'Norway 2' for clarity. In the meta-analysis of data from Denmark, Sweden and Norway 1, the pooled HR of offspring NDDs was 1.05 (95% CI 0.87 to 1.27; I2=0.0%), and in meta-analysis of data from Denmark, Sweden and Norway 2, it was 1.03 (95% CI 0.85 to 1.24; I2=0.0%).In the meta-analysis including Taiwan, Denmark, Sweden and Norway 1, the pooled HR was 1.06 (95% CI 0.88 to 1.27; I2=0.0%), and when including data from Taiwan, Denmark, Sweden and Norway 2, the pooled HR was 1.04 (95% CI 0.87 to 1.25; I2=0.0%). CONCLUSIONS: In this living meta-analysis, we found no evidence that paternal exposure to valproate compared with lamotrigine/levetiracetam during spermatogenesis was associated with increased risk of NDDs in offspring.

Humans↗

PubMedDate not supplied

Cross-species sperm-FISH assays for chemical testing and assessing paternal risk for chromosomally abnormal pregnancies.

The father, like the mother, can transmit genetic defects to his offspring that are detrimental for normal development and a healthy life. Epidemiological studies have identified associations between several paternal exposures and abnormal reproductive outcomes, but these types of studies are inherently complex and expensive, and the risk factors for the paternal contribution to abnormal reproductive outcomes remain poorly understood. Several sensitive methods have been developed for detecting mutations and chromosomal damage directly in sperm. These assays are potential bioindicators for paternal risk factors for infertility, spontaneous abortions, aneuploidy syndromes, and genetic diseases in children. Among these methods, fluorescence in situ hybridization (FISH) has been adapted for the detection of numerical and structural chromosomal abnormalities in the sperm of an expanding number of species, including humans and rodents. Sperm FISH has identified several potential paternal risk factors such as age, drugs, lifestyles, and various environmental/occupational exposures. Here, we summarize the status of the development and usage of these sperm-FISH assays and suggest strategies for prioritizing chemical agents for epidemiological investigations to assess paternal risk for abnormal reproductive outcome.

Animals↗

PubMed2005

Paternal use of ribavirin-interferon alpha 2B combination therapy before conception.

QUESTION: One of my male patients is receiving ribavirin-interferon alpha 2B (Pegetron) combination therapy for chronic hepatitis C. His wife recently found out she is 6 weeks pregnant. They are concerned that the medications might have affected his sperm. How should I advise them? ANSWER: To the best of our knowledge, paternal exposure to ribavirin-interferon alpha 2B has no adverse effects on reproduction. Although we do not have sufficient information to confirm this, several pregnancies where the father had been exposed to these medications turned out fine. If an unexpected pregnancy occurs while the father is receiving this therapy, there is no medical indication for terminating the pregnancy.

Antiviral Agents↗

PubMed1998

Micronuclei and developmental abnormalities in 4-day mouse embryos after paternal treatment with acrylamide.

The developmental consequences of paternal exposure to acrylamide (50 mg/kg i.p. for 5 days) were assessed in preimplantation embryos. There was a significant increase in the proportion of morphologically abnormal embryos after postmeiotic treatment during spermatogenesis (88.7% vs. 14.8% in control). Abnormal embryos had an average of 1.8 +/- 3.5 cells and > 80% had at least one fragmented nucleus. In addition, morphologically normal embryos were significantly delayed (34.3 +/- 12.8 cells per embryo vs. 57.6 +/- 15.7 in control, P < 0.001). Acrylamide caused 10- and 20-fold increases in frequencies of cells with micronuclei (MN) in morphologically normal and abnormal embryos, respectively (41 and 93 MN per 1,000 cells). Both centromere-negative (MN-) and centromere-positive (MN+) were induced. Nuclei of abnormal embryos were significantly larger (900 microm2 vs. 250 microm2) than controls. In addition, MN of abnormal embryos were larger than those of normal embryos (21.2 microm2 vs. 6.5 microm2, P < 0.01). Among control embryos, MN+ were significantly larger than MN- (P < 0.05). These findings suggest that the preimplantation embryo is a sensitive indicator of paternally transmitted effects on early development. Multiple mechanisms appear to be involved, including cytogenetic damage, proliferation arrest/delay, and fertilization failure. Future studies are needed to establish how induced cytological defects in preimplantation embryos contribute to birth defects and other postimplantation abnormalities.

Abnormalities, Drug-Induced↗

PubMed2006

Risk factors for hypospadias.

Despite being one of the most common congenital defects in boys, the etiology of hypospadias remains largely unknown. In this case-referent study, we evaluated a wide spectrum of potential risk factors for hypospadias. Cases were identified from the hospital information system, and referents were recruited through the parents of the cases. Both parents of cases and referents completed written questionnaires that they received through the mail. Logistic regression analyses were used to assess the independent contribution of different factors to the risk of hypospadias. The final database included 583 cases and 251 referents. Hypospadias more often occurred in children whose father had hypospadias (OR=9.7; 95%CI: 1.3-74.0) and in children with a low birth weight (OR=2.3; 95%CI: 1.2-4.2). Indications for elevated risks were found when mothers were DES-daughters (OR=3.5; 95%CI: 0.8-15.6), fathers were subfertile (OR=1.8; 95%CI: 0.7-4.5), the parents had undergone fertility treatment (OR=2.3; 95%CI: 0.9-5.8), and in twin or triplet pregnancies (OR=2.0; 95%CI: 0.8-5.1). Maternal use of iron supplements (OR=2.2; 95%CI: 0.8-6.0), maternal smoking (OR=1.5; 95%CI: 1.0-2.4), paternal prescriptive drug use (OR=2.6; 95%CI: 1.1-6.6), and paternal exposure to pesticides (OR=2.1; 95%CI: 0.6-7.1) during the 3 months immediately prior to conception or in the first trimester of pregnancy also appeared to increase the risk of hypospadias. The associations found in this study support the hypothesis that genetic predisposition, placental insufficiency, and substances that interfere with natural hormones play a role in the etiology of hypospadias.

Child↗

PubMedDate not supplied

Mutagenic lifestyles? A review of evidence of associations between germ-cell mutations in humans and smoking, alcohol consumption and use of 'recreational' drugs.

In humans, associations between germ-cell mutations and hypothetical aetiological factors can be investigated by (1) examining the relationship between the factor of interest and conditions known to be of genetic aetiology; (2) examining the relationship between conditions of unknown aetiology and route of exposure, especially paternal preconceptional exposure. As regards smoking, alcohol and 'recreational' drugs, the first approach has been applied in studies of retinoblastoma, Wilms' tumour and chromosomal anomalies. Only Down's syndrome has received intensive investigation, in relation to maternal smoking during pregnancy; the relative risks would be compatible with there being no association in all recognized conceptuses. The second approach has been applied in studies of sperm quality, miscarriage, congenital anomalies and childhood cancer. The available studies do not show a consistent relationship between smoking and sperm quality; there are few data on the effects of the other exposures. There are a substantial number of studies of childhood cancer and smoking by the father; the majority do not indicate any relationship. Some studies of childhood cancer suggest a positive association with use of 'recreational' drugs by the parents, but it has not been possible to clarify which route of exposure, or the specific type of drug which may be involved. Use of molecular techniques to detect individual genetic changes should enable progress to be made in elucidating the origin of mutation. In the meantime, public health actions are justified on the basis of the known non-genetic effects of these agents.

Abortion, Spontaneous↗

PubMedDate not supplied

Tumorigenesis in F1 offspring mice following paternal 12.5 cGy 252Cf fission neutron irradiation.

Experiments were conducted to determine whether following genetic damage at germ cell stages induced by paternal exposure to 252Cf fission neutron could lead to tumorigenesis in the offspring. Seven-week-old C3H/HeNCrj male mice were irradiated with 252Cf fission neutrons, at doses of 0 and 12.5 cGy and were mated with nine-week-old C57BL/6NCrj females two weeks after the exposure. Three weeks later, it was found that the proportion of abnormal sperm in the 12.5 cGy-irradiated males was higher than that of 0 cGy-irradiated group. Embryo lethality among the F1 offspring was also found to be higher in the 12.5 cGy group than in the 0 cGy group, while the incidence of liver tumors among the F1 offspring increased in males only. These results suggest that the paternal 12. 5 cGy radiation exposure may have caused genetic transmission of liver tumor-associated traits, which is in line with findings that show steep increase in incidence of tumorigenesis in B6C3F1.

Animals↗

PubMed1996

Paternal Occupational Lead Exposure and Pregnancy Outcome.

Self-reported reproductive histories of male employees of a lead-zinc smelter were related to pre-conception measures of lead exposure to examine associations between paternal occupational lead exposure and adverse pregnancy outcome. The participants reported 2,021 pregnancies which resulted in 1,684 normal live births, 12 stillbirths, 30 birth defects, 203 spontaneous abortions, and 92 "other" outcomes. Birth defects and stillbirths were combined for the analysis. The risk of a stillbirth or birth defect was elevated for pre-conception employment in a high-lead-exposure compared with a low-lead-exposure job (odds ratio = 2.7, 95% confidence interval = 0.7, 9.6). A similar risk was found for pre-conception blood lead levels of 25-39 µg/dL and >/= 40 µg/dL when compared with blood lead levels of < 25 µg/dL (OR = 2.9, 95% CI = 0.6, 13.3, and OR = 2.5, 95% CI = 0.5, 11.6, respectively). No association was found between pre-conception lead exposure and spontaneous abortion. A relatively low response rate to the questionnaire and potentially erroneous reporting of reproductive outcomes by male workers are limitations of the study.

Journal Article↗