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The "Gardner hypothesis" suggests that an excess of childhood leukaemia near a nuclear reprocessing plant is caused by paternal exposure to ionizing radiation. But the evidence shows that this explanation is wrong.
Paternal occupational data already collected as part of the Oxford Survey of Childhood Cancers have been reviewed. Information on paternal occupation was available for 14,869 children dying from cancer in England, Wales, and Scotland in the period 1953-81 and for an equal number of matched controls. The importance of fathers working, at any time before or after conception of the survey child, in any of the following occupations was assessed: radiologists (clinical), surgeons and anesthetists, veterinary surgeons, dental surgeons, nuclear industry workers, industrial radiographers. There was no indication that preconception employment in any of these occupations was more important than postconception employment with regard to the risks of all childhood cancers or all childhood leukemias. Findings were consistent with neither paternal preconception exposure to external ionizing radiation nor exposure to unsealed sources of radionuclides being an important risk factor for childhood leukemia or for the overall grouping of all childhood cancers.
The present study describes birth defects and health status of offspring of men with dibromochloropropane (DBCP) induced testicular dysfunction. One case with a major anomaly (urinary bladder extrophy and epispadias) and 2 cases of minor birth defects were observed among the 34 children evaluated. This rate was similar and not significantly different (p = 0.80) from that observed in a control group of 51 children conceived during pre-exposure in the same families. The health status of all the children was unremarkable. It is concluded that paternal exposure to DBCP, severe enough to cause azoospermia or oligozoospermia, did not increase the rate of congenital malformations or of impaired health status of offspring conceived during or after exposure.
AIMS: To study the association between fetal death and paternal agricultural occupation in areas and time periods with different levels of use of agricultural pesticides. METHODS: A total of 1 473 146 stillbirths and births occurring in Spain between 1995 and 1999 were analysed. RESULTS: The offspring of agricultural workers had the highest risk of fetal death from congenital anomalies in the southern and eastern area (where pesticide use is greatest) and the lowest risk in the rest of Spain. In both areas the offspring of agricultural workers had a similar excess risk of fetal death from the remaining causes of death. The relative risk of fetal death from congenital anomalies in infants conceived between April and September (the months of greater use of pesticides) in the southern and eastern area was 0.90 in manual workers and 1.62 in agricultural workers, compared to non-manual workers; in individuals who were conceived during the rest of the year, the relative risk was 0.87 and 0.85, respectively. In both periods the offspring of agricultural workers had an excess risk of fetal death from the remaining causes of death. CONCLUSIONS: Paternal agricultural work in the areas where pesticides are massively used increases the risk of fetal death from congenital anomalies. The risk is also increased for fetuses conceived during the time periods of maximum use of pesticides The higher risk of fetal death from the remaining causes of death in the offspring of agricultural workers seems unrelated to pesticide exposure.
We report seven cases of newborns conceived within 6 months from the end or during paternal ribavirin exposure.
OBJECTIVE: We analyzed the association between fetal death from congenital anomalies and paternal agricultural occupation in mothers who were employed and in housewives. MATERIALS AND METHODS: The data consist of individual records from the Spanish Birth Register (1995-1999). RESULTS: The adjusted relative risk of fetal death in agricultural workers compared with nonagricultural was 1.24 (95% confidence interval = 0.38- 4.02) in mothers who were employed and 1.68 (95% confidence interval = 1.03-2.73) in housewives. CONCLUSION: The risk of fetal death in the offspring of agricultural workers exposed to pesticides around the time of conception was higher than in the offspring of nonagricultural workers in mothers who were housewives but not in mothers who worked outside the home.
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Bronchopulmonary dysplasia (BPD) is a major cause of chronic lung disease in both preterm infants and adults, but its etiology remains incompletely understood. In this study, F0 generation mice were exposed to polystyrene nanoplastics (PS-NPs), and F1 to F3 generations were obtained by breeding. Multi-omics sequencing including whole genome methylation sequencing, single cell transcriptome sequencing and transcriptome sequencing was performed on the lungs of offspring. The levels of Fe2+, lipid peroxidation products and key gene expression were determined. Male mice exposed to PS-NPs at environmentally relevant doses produced offspring (F1 and F2) that exhibited a typical BPD-like phenotype. Meanwhile, the F0 males showed diminished sperm motility, demonstrating that paternal PS-NPs exposure constituted an etiological factor for BPD in descendants. Mechanistic studies showed that PS-NPs exposure upregulated the expression of DNA methyltransferase Dnmt3a, leading to global hypermethylation of the sperm genome. Importantly, the hypermethylated promoter signature of the mitochondrial ferritin (FtMt) gene partially resisted epigenetic reprogramming and was transmitted to the lungs of offspring, resulting in persistently low FtMt expression in F1 and F2 lungs. This led to increased intracellular Fe2+ levels, subsequently triggered ferroptosis in alveolar epithelial cells, and ultimately impaired alveolarization. Knockdown of FtMt confirmed that FtMt deficiency was sufficient to induce ferroptosis and BPD-like lung injury both in vitro and in vivo. Furthermore, using in vitro fertilization of F0 sperm combined with Dnmt3a siRNA microinjection, we directly demonstrated that Dnmt3a is a key driver for FtMt to escape reprogramming and maintain its hypermethylation. In summary, this study reveals for the first time that paternal PS-NPs exposure causes BPD through a Dnmt3a-FtMt hypermethylation intergenerational and transgenerational axis, providing an epigenetic basis for understanding paternal derived chronic lung disease and potential targets for early intervention.
Chronic low dose treatment of male rats with cyclophosphamide, an anticancer alkylating agent, damages male germ cells, resulting in greater than 80% peri-implantation progeny loss. Little transcription or repair takes place in the DNA of post-meiotic male germ cells. The spermatozoal genome regains its transcriptional capacity in the fertilized oocyte. We hypothesized that as a consequence of exposure of male rats to cyclophosphamide DNA damage to the male genome is transmitted to the conceptus; furthermore, this damage leads to alterations in the expression profiles of DNA repair genes during preimplantation development. Male rats were treated with either saline or cyclophosphamide (6mg/kg/day, 4-6 weeks) and mated to control females; 1-8 cell stage embryos were collected. The alkaline comet assay was used to assess DNA damage in 1-cell embryos. A significantly higher percentage (68%) of the embryos fertilized by cyclophosphamide-exposed spermatozoa displayed a comet indicative of DNA damage, compared to those sired by control males (18%). The in situ transcription/antisense RNA approach was used to determine if DNA damage alters the expression of DNA repair genes in early embryos. Dramatic increases in the transcripts for selected members of the nucleotide excision repair family (XPC, XPE and PCNA), mismatch repair family (PMS1), and recombination repair family (RAD50) were found in 1-cell stage embryos sired by cyclophosphamide-treated males compared to controls, while decreases in the expression of base excision repair family members (UNG1, UNG2, and XRCC1) and in recombination repair transcripts (RAD54) were observed. By the 8-cell stage, transcripts for specific members of the nucleotide excision repair family (XPC) and mismatch repair family (MSH2, PMS2) were elevated greatly in control embryos compared to embryos sired by drug-treated males; in contrast, transcripts for other members of the nucleotide excision repair family (XPE, PCNA), as well as some of the base excision repair family (UNG1), were elevated in embryos sired by drug-treated males. Therefore, DNA damage incurred in spermatozoa, following cyclophosphamide exposure is associated with alterations in the expression profiles of DNA repair genes in preimplantation embryos as early as the 1-cell stage. Genotoxic stress may disturb the nuclear remodeling and reprogramming events that follow fertilization and precede zygotic genome activation.
Experiments were conducted to determine whether gamma-ray-induced genetic damage in parental rats can lead to the development of cancer in their offspring rats using glutathione S-transferase-positive (GST-P+) hepatic foci with or without the addition of diethylnitrosamine (DEN), a carcinogen. A single 1 Gy whole-body exposure of gamma-rays was given to pregnant rats at day 14 and during postnatal week 3, DEN was intraperitoneally injected twice in 1 week. Female pups from irradiated maternal and paternal rats were also used. Twelve weeks after birth, the rats were sacrificed. GST-P+ foci in animals subjected only to radiation were not different to those of normal control pups, but the incidence of GST-P+ foci was 2.4 times higher in pups treated with DEN alone at 3 weeks after birth than in those irradiated after the onset of pregnancy. In DEN-combined groups, irradiation of post-pregnant or maternal and paternal rats with gamma-rays before mating significantly increased both the incidence and area of GST-P+ foci when compared to those of rats treated with DEN alone. The proliferating cell nuclear antigen (PCNA) labeling index was significantly higher in the offspring of rats subjected to radiation alone or radiation combined with DEN than in normal control pups. Using a rat-liver model, the results of this study indicate that although the dose did not induce phenotypic malformation, exposure to radiation during the embryonic or pre-embryonic stage increases susceptibility to carcinogens.
The potential reproductive toxicity of mercury vapour was investigated by comparing the rate of spontaneous abortions among the wives of 152 workers occupationally exposed to mercury vapour with the rate among the wives of 374 controls in the same plant. The results indicate an increase in the rate of spontaneous abortions with an increasing concentration of mercury in the fathers' urine before pregnancy. At concentrations above 50 micrograms/l the risk of spontaneous abortion doubles (odds ratio (OR) = 2.26; 95% confidence interval (95% CI) = 0.99-5.23). Special care was taken to avoid bias in reporting abortions and known risk factors of spontaneous abortions do not seem to explain the results. Several biological mechanisms might account for them including, in particular, direct action of mercury on the paternal reproductive system and indirect toxicity to the mother or embryo through transport of mercury from the father. These indications could be of practical importance and should therefore be further documented.
Low-dose chronic treatment of the male rat with the antitumor drug cyclophosphamide causes a time- and dose-dependent increase in pre- and post-implantation loss in the untreated females to which he is mated. The objective of the present study was to determine whether such effects are reversed, and if so at what time after cessation of drug treatment. Adult male Sprague-Dawley rats were gavage fed daily, 6 times per week for 9 weeks, with saline (control) or with 1 of 3 doses of cyclophosphamide, 1.4, 3.4 or 5.1 mg/kg/day. After the 9 weeks of treatment and at 2-week intervals thereafter, each male was mated with 2 females in proestrus. The females were caesarian sectioned 20 days later and pregnancy outcome assessed. After 9 weeks of drug treatment, pre-implantation loss increased more than 3-fold from 6% in the control group to 21% in the 5.1 mg/kg/day cyclophosphamide treatment group. Post-implantation loss increased in a dose dependent fashion from 5% in the control group to 74% in the 5.1 mg/kg/day cyclosphosphamide treatment group. Pre-implantation loss rapidly decreased upon cessation of treatment with cyclophosphamide: within 2 weeks it had returned to within the control range. Within just 2 weeks after termination of drug treatment in the 5.1 mg/kg/day cyclophosphamide treatment group, post-implantation loss decreased by half to 44%; it had decreased to 11% by 4 weeks and then was maintained at 4-6% thereafter. In the 3.4 mg/kg/day cyclophosphamide treatment group, post-implantation loss returned to the control range by 4 weeks. Thus, the effects of paternally administered cyclophosphamide on progeny outcome are reversible. The timing of reversal suggests that the effects on pre-implantation loss are due to a drug effect on spermatozoa either in the epididymis or near the time of spermiation while those on post-implantation loss are due to an additional effect on spermatids in the seminiferous tubules.
The effects of ethylene dibromide (EDB) exposure to male rats on several neurotransmitter enzymes have been examined in various brain regions of the F1 progeny, from 7 to 90 days of age. The choline acetyltransferase activity was significantly increased at 21 days old, in most brain regions studied in the F1 progeny of the EDB-treated males, but not at 7, 14 or 90 days old. The acetylcholinesterase activity was altered in different brain regions of the F1 progeny of the EDB-exposed males at both 14 and 21 days old but not at 7 or 90 days old. Glutamic acid decarboxylase activity was increased in corpus striatum but decreased in frontal cortex only at 21 days of age. These neurochemical changes in the developing brain of F1 progeny of EDB-treated males at low doses may be associated with behavioral abnormalities observed early in their development.