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

Abstract

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.

Keywords: developmental origins of health and disease (DOHaD); environment; epigenetics; imprinted genes; offspring; paternal exposures; spermatogenesis; transgenerational effects.

Figure 1

Susceptibility windows for environmentally induced epigenetic changes through the paternal germ line. Hypothetical pedigree chart of children with altered epigenetic profiles that may increase risk for disease. Changes in epigenetic profiles may have different causes that vary by timing (lightning bolts) and type of exposure, including – but not limited to – environmental toxins, pollutants, endocrine disruptors, ionizing radiation, smoking, nutrition, etc. Windows of heritable epigenetic damage include: 1. during migration of primordial germ cells (PGCs) to the genital ridge (before week 6 of development of the future father in the grandmother), when genome-wide epigenetic erasure occurs; 2. before puberty, from PGC (or gonocyte) to spermatogonia, during which methylation profiles are largely established; 3. during each reproductive cycle, from spermatogonium (SG) to spermatocyte (SC) and finally the spermatozoon (SZ), when DNA methylation should be fully established; and 4. in the zygote, when the acquired methylation marks need to withstand post-zygotic epigenetic reprogramming at specific regions (e.g. imprinted genes).