[Age of the father and development potential]. / Age du pere et aptitude au developpement.

PIP: Testicular aging, like ovarian aging, concerns not just the individual but also the quality of the gametes and hence of the offspring. The 1st signs of testicular aging appear early. Beginning around the age of 30, the vascularization begins to thin, with a progressive decline in the density of the capillaries. The membrane of the seminiferous tubules, an essential element of the hematotesticular barrier, begins to thicken and the number of Sertoli cells begins to decline. Endocrine effects usually appear a decade later, but individual variations are considerable. These modifications are accompanied by a slow decline in the number of sperm and alterations in their morphology and motility. Male fertility declines progressively with age. The quality of the gametes is lower among very young males and increases to a maximum at about age 30. Paternal aging may be responsible for well-defined syndromes in the offspring. Paternal aging has long been recognized as a factor in dominant autosomal mutations causing macroscopic malformations such as achondroplasia, Apert syndrome, Marfan's syndrome, fibrodysplasia ossificans progressiva, and others. The frequency of each disorder is very low, but the total number of recognized disorders of this type exceeds 1000, multiplying the risks so that the .3-.5% risk of anomalies due to paternal aging after 40 is comparable to the risk of trisomy 21 for women aged 35-40. Dominant autosomal mutations can also be responsible for less marked anomalies such as Recklinghausen's neurofibromatosis. Some authors believe that recessive mutations linked to the X chromosome causing hemophilia or Duchenne muscular dystrophy can also result from paternal aging. Some evidence suggests that for a given maternal age, paternal age results in subtle and continuous declines in cerebral functioning. A psychometric study of 1700 military recruits in Nancy, France, in 1985 who were 18 years old showed that sons of very young fathers and of older fathers did less well on the tests. The study is being repeated on 12,000 recruits in the Paris area in 1989-90 to verify the results. Efforts will be made to separate the influence of socioeconomic status and birth order on the results.^ieng

[Evolution of male fertility as a function of age and risks in progeny]. / Evolution de la fertilite masculine en fonction de l'age et risques pour la progeniture.

PIP: Testicular aging starts form age 30 with progressive deterioration of vascularization, the density of capillaries, the diminution of the efficacy of the blood-testis barrier, the aging of Sertoli cells, which results in fall of production of androgen-binding protein. These changes lead to a slow reduction of the number of spermatozoa, although it is their quality that is responsible for male fertility. Analysis of the number, morphology, and mobility of spermatozoa of men aged 25-59 showed that the quality varies depending on age: the maximum values are reached between age 25 and 35, decreasing afterwards. The aging finally results in a degradation of the number and especially in the quality of spermatozoa, which is not satisfactory in individuals of very young age either. Whether male of female, parental aging poses a problem, because fertility diminishes and the risk of anomalies of the conceptus increase with the age of parents. It has been demonstrated that the new, autosomal dominant mutations responsible for fetal deaths or the numerous malformation syndromes, such as achondroplasia, Apert's disease, ossifying fibrodysplasia, and Marfan's syndrome, may be linked to paternal aging. The frequency of each of these syndromes is very low: 15-28 cases per million births for achondroplasia. Also, the frequency of anomalies attributable to paternal aging after the 40s reaches .3-.5% of births. Neurofibromatosis or von Recklinghausen's disease, hemophilia A, the myopathy of Duchenne, schizophrenia, and the performance of 18-year-old males on psychometric tests have been associated with paternal aging. The aging of gonads cannot be prevented, but one could avoid the consequences of the aging of gametes by avoiding having children after 35 or 40 years of age. This has been recommended to women for about 15 years, and perhaps should also be recommended to men.^ieng

Is the sperm bacterial ratio a determining factor in impairment of sperm motility: an in-vitro study in man with Escherichia coli.

The effects of urogenital infection on male fertility are controversial. The object of this study was to assess whether contact between E. coli, one of the bacteria encountered most frequently in semen cultures, and sperm was involved in decreasing motility of the sperm. Sperm from healthy donors were therefore incubated at two concentrations (1.10(7) and 4.10(7) ml-1) with bacteria (10(4) and 10(6) bacteria ml-1 respectively). Sperm motility was assessed as a function of time. The endotoxin effect was also evaluated. Aliquots of the sperm were used as controls. The motility of a population of 10(6) sperm ml-1 was reduced significantly more by the presence of 10(6) ml-1 E. coli than a sperm population four times more numerous. Since the endotoxin had no effect on sperm motility, it is possible this phenomenon is due to bacterial adherence to the sperm. From this study, it is therefore probable that the presence of E. coli in semen decreases sperm motility, but that this depends on the sperm:bacterial ratio ml semen-1.

Cyclophosphamide in the male rat: cerebral biochemical changes in progeny.

Adult male Wistar rats were treated with cyclophosphamide either alone or with both cyclophosphamide and vinblastine. They were then mated with virgin non-treated females. Examination of their offspring showed an increased post-natal mortality rate; and diminished learning capacity and spontaneous activity in the adults. These disorders were also found in the second generation, resulting from mating between animals of the first generation. Biochemical analyses of the brains of the offspring of treated males in the first and second generations showed a diminished activity of hippocampal choline acetyl-transferase. Moreover, the second generation showed a diminution of fronto-parietal cortex norepinephrine. These biochemical results may correspond to the observed behavioral deficits. Furthermore, by studying experimental mutation, they add to our knowledge of the consequences of certain cytostatic treatments.

Paternal age and mental functions of progeny in man.

The effects of maternal age on the quality of offspring are well known. Those due to the father's age are less obvious, apart from the role of increasing paternal age in the onset of many dominant autosomal disorders. But an experimental model has demonstrated that, in rats, increasing paternal age, without any other anomalies, might produce a decreased learning capacity in progeny. The object of the epidemiological investigation presented here was to verify whether this effect might also occur in man. The study involved the distribution of scores obtained in psychometric tests by 18-year-old male subjects, according to their father's age at the time of their birth. This distribution indicated not only that increasing paternal age is accompanied by effects similar to those observed in animals, but also that very young paternal age was also related to these effects. Thus, the curve of such scores produced an inverted U-shape, with maximum scores obtained when the father was about thirty years of age. Maternal age did not appear to play a part in this event. These results pose the problem of identifying genetic and/or psychosocial factors which might have an impact on the quality of the conceptus.

Cyclophosphamide in the male rat: new pattern of anomalies in the third generation.

Several abnormalities, such as postnatal deaths and behavioral impairments, have been previously reported in the progeny of male rats exposed to the cytostatic drug cyclophosphamide 60 days prior to mating. The anomalies were transmitted to the second generation (F2). The present results concern the third generation. Two experimental groups have been studied: a hybrid group, resulting from crosses between control subjects and either experimental F2 males or females, and a nonhybrid group, obtained by mating experimental F2 subjects together. Significant abnormalities were found in all experimental groups, whether the F2 subjects were male or female. F2 females had smaller litters whether they were mated with control or experimental males. Body weight was significantly increased in both hybrid and nonhybrid males. Increased postnatal mortality and learning deficit were also observed in the hybrid group. Such complex phenotypic changes confirm that frequent mutations probably have been inherited from the treated males but also suggest that genetic rearrangements have occurred from one generation to the next.

Antimitotic drugs in the male rat. Behavioral abnormalities in the second generation.

The second generation descended from rats treated either with cyclophosphamide alone or with both cyclophosphamide and vinblastine were investigated. As in the first generation, the offspring were evaluated for mean litter size, sex ratio, frequency of gross external malformations and, within the first 4 months of life, growth and mortality. When they reached adulthood, between 12 and 16 weeks of age, the offspring were also tested for spontaneous activity and learning capacity. At birth, the progeny of the treated grandfathers did not show malformations or any other obvious disorder. However, when compared with the control population, the experimental animals showed significantly decreased success rates in a learning task, whatever the learning performance of their parents. Furthermore, decreased spontaneous activity was observed in the male subjects from unsuccessful parents. The similarities between the anomalies found in the first and the second generations argue for the induction of mutations by antimitotic drugs. This hypothesis and the subtle differences between generations and between sexes are discussed.

Male fertility and positive Chlamydial serology. A study of 61 fertile and 82 subfertile men.

In this study, the frequency and titers of serum antibodies to Chlamydia trachomatis in fertile and subfertile subjects and possible correlations between a positive serology and the values of conventional semen parameters were investigated. The subfertile subjects were divided into those without and those with a history of genitourinary infection. No difference was noted between the proportion of seropositive patients in the fertile group (26.2%) as compared with those in the subfertile group with no history of genitourinary infection (27.7%). The percentage of positive tests was significantly increased only in the subfertile group with past genitourinary infection (53.5%). No difference was found between the antibody titers of the fertile and subfertile groups. Only the fertile group had any semen parameter, namely, the volume of the ejaculate, that was significantly different between the seropositive and seronegative patients. In conclusion, three main points should be stressed; the high frequency of serum antibodies to Chlamydia trachomatis in the control subjects and the apparent absence of effects of a positive serology on their fertility; the significant correlation between a past genitourinary infection and the presence of serum antibodies to Chlamydia trachomatis; and the need for a test to assess Chlamydia in semen.

Antimitotic drugs (cyclophosphamide and vinblastine) in the male rat. Deaths and behavioral abnormalities in the offspring.

The spermatogenesis and the offspring of male rats treated either with cyclophosphamide alone, or with both cyclophosphamide and vinblastine were investigated. The offspring were evaluated for the mean number of pups per litter, sex ratio, the frequency of apparent external malformations and, within the first 4 months of life, growth and mortality. When they reached adulthood and were between 12 and 16 weeks of age, the offspring were also examined for spontaneous activity and learning capacity. Treatment with cyclophosphamide or cyclophosphamide and vinblastine resulted in a decrease in the number of both primary spermatocytes and spermatids; the effect, however, lasted longer for the combined drug regimen. At birth, the animals sired by the treated males did not show any apparent malformations. However, compared with the control population the mortality rate of the offspring was significantly higher within the first 40 days of life; at adult age, the proportion of animals that failed in the learning ability test was significantly increased and those that did succeed showed impaired learning capacity. The difference, however, was significant only in the male offspring. Finally, the offspring's spontaneous activity was significantly decreased. No difference was found in mortality or behavior between the animals born of the cyclophosphamide or cyclophosphamide plus vinblastine-treated males. The behavioral disorders shown in the adult offspring confirm the existence of a long-term risk of paternal origin. This risk, essentially functional and independent of any morphologic pathology, should be taken into account in the context of environmental genotoxicity.