A paternal environmental legacy: Evidence for epigenetic inheritance through the male germ line

Literature on maternal exposures and the risk of epigenetic changes or diseases in the offspring is growing. Paternal contributions are often not considered. However, some animal and epidemiologic studies on various contaminants, nutrition, and lifestyle‐related conditions suggest a paternal influence on the offspring's future health. The phenotypic outcomes may have been attributed to DNA damage or mutations, but increasing evidence shows that the inheritance of environmentally induced functional changes of the genome, and related disorders, are (also) driven by epigenetic components. In this essay we suggest the existence of epigenetic windows of susceptibility to environmental insults during sperm development. Changes in DNA methylation, histone modification, and non‐coding RNAs are viable mechanistic candidates for a non‐genetic transfer of paternal environmental information, from maturing germ cell to zygote. Inclusion of paternal factors in future research will ultimately improve the understanding of transgenerational epigenetic plasticity and health‐related effects in future generations.     

Homonucleotide stretches in chromosomal DNA of Campylobacter jejuni display high frequency polymorphism as detected by direct PCR analysis

Homopolymeric nucleotide tracts have been previously identified in the genome sequence of Campylobacter jejuni 11168 [Parkhill et al., Nature 403 (2000) 665-668]. These tracts are believed to regulate contingency genes but as yet no phenotypic variation has been identified associated with many of these genes. To investigate homopolymeric tracts for genes for which there is no observable phenotype, a method was designed to visualise profiles of the various tract lengths directly at the genomic level by means of PCR and denatured polyacrylamide gel electrophoresis. Six of the seven contingency genes investigated displayed variation in the length of the respective homonucleotide tracts. Surprisingly, each contingency gene gave a typical peak profile that represented a conserved size distribution of polymorphic forms. For each gene studied, peak profiles were conserved between strains of C. jejuni. Duplicated genes, containing homonucleotide stretches, displayed locus-specific peak distributions for each gene copy. Contingency genes were polymorphic within single colonies, and the observed complex peak profiles suggested a frequency of slippage several orders of magnitude higher than reported for other organisms. No G7 (or C7) stretch was ever observed, and their absence from the complete genome suggests strong selection against their presence. In view of the predictable outcome of the process leading to these polymorphisms, it is hypothesised that the formation and/or selection of these tracts is not a random process, but is driven by as yet unknown mechanism(s). High-frequency polymorphism of these genes may be a mechanism by which C. jejuni survives selection bottlenecks between opportunities for growth within a host.     

Pharmacology of DB844, an Orally Active aza Analogue of Pafuramidine, in a Monkey Model of Second Stage Human African Trypanosomiasis

Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-yl]-nicotinamide (DB820), exhibiting plasma C(max) values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible.     

Hpz1 modulates the g1-s transition in fission yeast

Here we characterize a novel protein in S. pombe. It has a high degree of homology with the Zn-finger domain of the human Poly(ADP-ribose) polymerase (PARP). Surprisingly, the gene for this protein is, in many fungi, fused with and in the same reading frame as that encoding Rad3, the homologue of the human ATR checkpoint protein. We name the protein Hpz1 (Homologue of PARP-type Zn-finger). Hpz1 does not possess PARP activity, but is important for resistance to ultraviolet light in the G1 phase and to treatment with hydroxyurea, a drug that arrests DNA replication forks in the S phase. However, we find no evidence of a checkpoint function of Hpz1. Furthermore, absence of Hpz1 results in an advancement of S-phase entry after a G1 arrest as well as earlier recovery from a hydroxyurea block. The hpz1 gene is expressed mainly in the G1 phase and Hpz1 is localized to the nucleus. We conclude that Hpz1 regulates the initiation of the S phase and may cooperate with Rad3 in this function.     

Spermatogenesis in Atlantic cod (Gadus morhua): a novel model of cystic germ cell development

Precocious male puberty significantly compromises sustainability aspects of aquaculture in a number of finfish species. As part of a program aiming to understand and eventually control testis maturation in farmed Atlantic cod, we studied the first reproductive cycle. The gonadosomatic index shows a 41-fold increase from immature (August) to mature (March) stages, reaching almost 10% of the total body weight. The paired cod testes are composed of several lobes arranged around a central collecting duct. In each individual lobe, spermatogenesis occurs in a marked gradient of development, with undifferentiated spermatogonia in the periphery of the lobe and the most advanced germ cells in the vicinity of the collecting duct, suggesting a tight spatiotemporal organization of spermatogenesis in the testis lobes of this species. Spermatogonial proliferation starts in August and continues for about 6 mo. Meiosis and spermiogenesis are first observed in October and are completed in all cysts by February, when a 2-mo-long spawning season starts. Spermatogonia go through 11 mitotic divisions before differentiating to primary spermatocytes. Apoptosis is rare, but when observed it occurs mainly during the last spermatogonial generations. Our observations suggest a model in which a maturational wave progresses through each growing lobe that is first driven by appositional growth from the lobe's periphery, reflecting spermatogonial proliferation and cyst formation which, when ceasing, is terminated by completing spermiogenesis and spermiation that progress toward the lobe's periphery.