An integration of information from laboratory and epidemiological studies, male reproduction and teratology can be found throughout the volume. The range of topics include parental legacies and genomics, lifestyle, occupational and therapeutic paternal exposures and effects; effects on the gamete-packaging of human sperm; role of DNA repair and germ cell apoptosis; stem cells, epigenetics and closing; model systems and implications to clinicians and general counselors.
Advances In Male Mediated Developmental Toxicity 2003
List of Participants. Gender-Specificity of Gamete Susceptibilities to Exposures. Exposures and Effects: Occupational and Environmental. Bonde, et al. Silbergeld, et al. Sakkas, et al. Aitken, D. Vogel, M.
Epub Advances In Male Mediated Developmental Toxicity 1st Edition Read Online
Marchetti, A. Paternal Occupation and Childhood Cancer; A. Olshan, E. Radiation and Malformations in a Murine Model; W. Robaire, B. Chromosome Abnormalities in Human Sperm; R. Pregnancy Outcome.
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Hewitson, et al. Nagao, et al. Strategies for Prevention. Meistrich, et al. It is only later, in the s, that the possible wider impact of male exposures at environmental levels on developmental alterations has been considered, concretized by the setting of international symposia discussing available evidence [ 3 ]. The length of the spermatogenic cycle in human beings, undergoing a number of developmental phases mitosis, meiosis, differentiation and maturation of various durations, starting with spermatogonial stem cells until the production of differentiated motile spermatozoa, lasts about 74 days [ 5 ].
This period of intense cellular transformation is considered to be highly susceptible to environmental insults. Except for some ecological disasters, environmental exposure of human populations is essentially chronic, from occupational environment, air pollution, lifestyle including diet, and the mechanisms involved have to be inferred from experimental models. One can then consider two different situations models of vulnerability for the male reproductive system with potential consequences on embryonic or child development: i exposure of a male adult before mating; ii prenatal exposure during embryonic development of the reproductive system of male conceptus.
Although there is experimental evidence of functional alterations, such as altered reproductive potential or behavioural deficits resulting from paternal exposures, these consequences have been barely studied in human beings [ 7 ]. Extensive research has been conducted on the impact of male exposure to the anticancer drug cyclophosphamide on progeny. Effects on embryonic loss, malformations, tumour incidence and behavioural abnormalities in several generations have been observed at doses similar to those used in clinical regimens [ 5 ].
A number of experiments have also suggested enhanced susceptibility to cancer following exposure to carcinogens such as urethane or methylnitrosourea after subchronic paternal irradiation [ 8 ]. Evidence for an association with the risk of spontaneous abortions was considered strong for metallic mercury and anaesthetic gases in use at that time, moderate for lead and weak for pesticides.
The likelihood of a causal association between paternal exposure to solvents and spontaneous abortions was considered moderate. Since then, two studies among workers exposed to solvents including painters have not reinforced the strength of evidence for an impact on spontaneous abortions but showed increased risks of birth defects in offspring of fathers exposed to solvents [ 12 , 13 ]. A recent study of laboratory workers reported a moderately increased risk of birth defects [ 14 ]. A possible association between childhood cancer and paternal occupational exposure has been the subject of a large number of investigations since the early publication by Fabia and Thuy in [ 15 ] suggesting the impact of paternal exposure to hydrocarbons on the risk of childhood brain tumours.
Electromagnetic fields have been postulated to be responsible for an increased risk of brain tumours explaining excess risks repeatedly reported among children of electricians, electronic workers or power linemen [ 16 ]. This association does not appear to be confirmed in recent studies [ 19 - 21 ]. The interpretation of these studies is weakened by the imprecision in exposure assessment both in terms of identification of compounds and timing of exposure and the potential simultaneous exposure of the mother. This original report was not confirmed by five subsequent studies among nuclear plant workers in the UK and Canada conducted between and and in a large case—control study on childhood leukaemia conducted in Germany [ 29 ].
Recently, records of 34, childhood cancer cases diagnosed in the UK between and were linked with the registry of radiation workers fathers retrieved using updated dosimetric data. This finding is interpreted by the authors as an argument in favour of the infectious aetiology hypothesis to explain clusters of childhood leukaemia observed around nuclear plants, arising from population mixing. Children of parents exposed to radiation around Chernobyl, however, show an elevated level of minisatellite mutations arising from the germ line of exposed fathers, but not from the germ line of exposed mothers [ 32 ].
These observations in human populations suggest differential effects according to the rate of exposure acute, chronic or subchronic that is in accordance with evidence from experimental studies. Paternal serum TCDD levels were above 15 ppt. No impact of maternal exposure on SSR was observed.
Other epidemiological studies have later investigated this issue with mixed results. American veterans exposed to Agent Orange during defoliant sprayings in Vietnam Operation Ranch Hand with a level of exposure to TCDD of the same order of magnitude as in Seveso, Italy, had slightly more boys than girls [ 34 ]. Other persistent organochlorine compounds such as polychlorobiphenyls PCB have also been studied in particular in the populations highly exposed to contaminated rice oil in Yusho and Yucheng.
This is in accordance with experimental evidence showing until now, inconsistent findings on sex ratio of the offspring of male rats exposed to TCDD in utero [ 41 ]. It affected mostly males showing an impact on fertility, prostate and kidney disease and immune abnormalities.
No major effect was noticed among females [ 43 ]. A recent report from the same team presented the results of exposure of pregnant rats to vinclozolin on mating preference three generations later: F3 females preferred males with no history of exposure while no preference was exhibited by F3 males [ 44 ]. These experiments, if confirmed, suggest transgenerational transmission of epigenetic changes affecting especially males. There are not many human counterparts of the observations described above. Lessons can therefore be drawn from the study of health effects induced by in utero exposure to diethylstilboestrol DES.
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This exposure was soon related to an increased risk of a very rare form of cancer of the reproductive tract vaginal adenocarcinoma among daughters exposed in utero [ 45 ]. Recent epidemiological reports have suggested an increased risk of hypospadias among sons of women exposed to DES in utero [ 46 , 47 ]. Apart from these last observations, to be confirmed, there is no indication of a specific vulnerability, transmissible to subsequent generations, of males exposed in utero to DES. Human evidence on the other hand is still not convincing.
Most studies have focused on birth defects, sex ratio, childhood cancers or spontaneous abortions in association with occupational paternal exposures. Functional alterations such as neurobehavioural parameters or reproductive dysfunction have been barely studied. Thus, there is a need for innovative study designs especially aimed at studying the role of paternal exposures on child development and going beyond the study of fertility.
An example of such design is the Danish First Pregnancy Planner Study following couples starting before conception until pregnancy onset, detecting early embryonic losses [ 48 ]. An ideal design should follow several generations. These cohorts will also have the power to evaluate the specific impact of intrauterine exposure on a number of endpoints of developmental toxicity in males. Volume , Issue 2. The full text of this article hosted at iucr. If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account.
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