Genetic susceptibility to beryllium: a case-referent study of men and women of working age with sarcoidosis or other chronic lung disease.

Objective: The study was designed to investigate whether beryllium exposure was related to illness diagnosed as sarcoidosis. Chronic beryllium disease (CBD) and sarcoidosis are clinically and pathologically indistinguishable, with only the presence of beryllium-specific T-lymphocytes identifying CBD. Testing for such cells is not feasible in community studies of sarcoidosis but a second characteristic of CBD, its much greater incidence in those with a glutamic acid residue at position 69 of the HLA-DPB1 gene (Glu69), provides an alternative approach to answering this question.

Role of DNA damage and epigenetic DNA methylation changes in radiation-induced genomic instability and bystander effects in germline in vivo.

Ionizing radiation (IR) is a curative treatment for many human malignancies, an important diagnostic modality, and a pivotal preparative regimen for bone marrow transplantation. On the other hand, IR is a potent damaging agent that can affect a variety of processes in directly exposed cells, in their descendents, and in neighboring un-irradiated naïve 'bystander' cells. Accumulation of DNA damage caused by IR in conjunction with disrupted cellular regulation processes can lead to genome instability in the germline, and therefore to transgenerational genome instability in offspring of exposed males.

Hypomethylation and genome instability in the germline of exposed parents and their progeny is associated with altered miRNA expression.

Recent studies suggest that transgenerational genome instability may be epigenetic in nature and mediated via altered DNA methylation and microRNAome. Here, we investigated the nature and mechanisms underlying the disruption of DNA methylation and microRNA expression status in the germline and progeny of exposed parents. We have found that paternal irradiation leads to upregulation of the miR-29 family in the exposed male germline, which causes decreased expression of de novo methyltransferase, DNA methyltransferase 3a, and profound hypomethylation of long interspersed nuclear elements 1 (LINE1) and short interspersed nuclear elements B2 (SINE B2).

DNA damage-induced upregulation of miR-709 in the germline downregulates BORIS to counteract aberrant DNA hypomethylation.

MicroRNAs as potent regulators of gene expression are involved in spermatogenesis, yet their role in response of germline to genotoxic stress is obscure. We studied the microRNAome profile of X-ray irradiated mouse testes using the microarray technique. We found that radiation exposure significantly affected microRNA expression in testes.

Paternal cranial irradiation induces distant bystander DNA damage in the germline and leads to epigenetic alterations in the offspring.

It is now well accepted that parental whole body irradiation causes transgenerational genome and epigenome instability in the offspring. The majority of human exposures to radiation, such as therapeutic and diagnostic irradiation, are localized and focused. The potential of localized body-part exposures to affect the germline and thus induce deleterious changes in the progeny has not been studied.