Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes

Abstract

Epidemiological studies suggest that a father’s diet can influence offspring health. A proposed mechanism for paternal transmission of environmental information is via the sperm epigenome. The epigenome includes heritable information such as DNA methylation. We hypothesize that the dietary supply of methyl donors will alter epigenetic reprogramming in sperm. Here we feed male mice either a folate-deficient or folate-sufficient diet throughout life. Paternal folate deficiency is associated with increased birth defects in the offspring, which include craniofacial and musculoskeletal malformations. Genome-wide DNA methylation analysis and the subsequent functional analysis identify differential methylation in sperm of genes implicated in development, chronic diseases such as cancer, diabetes, autism and schizophrenia. While >300 genes are differentially expressed in offspring placenta, only two correspond to genes with differential methylation in sperm. This model suggests epigenetic transmission may involve sperm histone H3 methylation or DNA methylation and that adequate paternal dietary folate is essential for offspring health.

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

“…17 A diet poor in folate induced DNA methylation changes in the sperm and alterations of gene expression in the placenta. 47 Using odor-induced fear conditioning in male mice, it was found that offspring also had enhanced sensitivity to the same odor, which was associated with hypomethylation at a specific olfactory receptor gene 48 . Induction of a pre-diabetic state in fathers (feeding a high fat diet in combination with streptozotocin injection) altered pancreatic gene expression pattern in male offspring.…”

Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress

“…Posttranslational histone modifications, DNA methylation patterns, and populations of small noncoding RNAs in sperm have been implicated in the transgenerational transmission of paternal experience, with changes in these epigenetic marks observed following male exposure to such diverse stimuli as stress, malnutrition, and drugs of abuse (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). In particular, the role of sperm RNA as a mechanistic link between paternal experience and its consequences on offspring behavior and physiology has been emphasized by recent studies that characterize offspring phenotypes following in vitro fertilization and/or the experimental manipulation of total sperm RNA content (12,20).…”

“…Rodent models examining paternal transmission have identified epigenetic signatures in mature sperm as possible substrates of transgenerational programming, namely patterns of retained histone modifications, DNA methylation, and/or populations of small noncoding RNAs (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). RNA populations are of primary interest, as they may be altered through intercellular communication via epididymosomes even in transcriptionally inert mature sperm, where DNA condensation impedes other epigenetic change (22)(23)(24).…”

Homage to the ‘H’ in developmental origins of health and disease

“…4,[6][7][8][9][10][11][12][13] It is also increasingly becoming apparent that the environmental state of both the mother and father can underpin later diseases in offspring, even those who appear healthy at birth. [14][15][16][17][18][19][20][21][22][23][24][25][26] Such intrinsic and extrinsic factors in animal models and humans include exposure to endocrine disrupting chemicals, such as bisphenol A, phthalates, heavy metals, stress, obesity, high fat/ high caloric diets, metabolic status and starvation conditions to provide a few examples. It is also clear that in general, males may be at greater risk for later disorders, including those of the cardiovascular and neurological systems, than females.…”