In species exhibiting paternal care (including humans), perhaps the most obvious way that fathers can influence offspring phenotype directly is through a direct effect on the offspring postnatal environment
. This will be affected by multiple factors, including the father’s frequency and style of parenting, their socioeconomic and cultural circumstances and their own health behaviours [
25‐
27]. In some cases, epigenetic mediation might be involved in the biological manifestation of these effects [
28]. There is also growing evidence that direct non-genetic paternal effects can be transmitted prenatally. The most commonly postulated mechanism is transmission of epigenetic factors in sperm, such as DNA methylation, chromatin modifications and non-coding RNAs [
29]. We consider a broad definition of the term ‘epigenetics’ as heritable molecular changes that affect gene expression but do not involve changes to the underlying sequence of DNA [
30]. DNA methylation is the most widely studied epigenetic mechanism in humans in this context. In mammals, DNA methylation undergoes two rounds of ‘reprogramming’ between generations, which involves waves of demethylation and remethylation. The first round occurs shortly after fertilisation, during embryogenesis, and the second occurs in the primordial germ cells (PGCs) of the developing fetus during gametogenesis. For DNA methylation patterns to be passed between generations to influence gene expression and phenotype, some loci must escape this reprogramming. The number of reprogramming waves that must be overcome depends crucially on whether the inheritance is ‘intergenerational’ or ‘transgenerational’ [
31] (see Text box). There is evidence that methylation at some loci of the sperm epigenome can escape epigenetic reprogramming at embryogenesis. Although the majority of the sperm genome is packaged in protamines, the small fraction (5–10%) that remains attached to histones may be protected from demethylation [
32]. This fraction includes paternally derived imprinted loci [
32,
33] . Proposed windows of susceptibility [
34] when the gamete epigenome of a father-to-be might be particularly susceptible to environmental exposures are: (1) during PGC reprogramming in utero; (2) before puberty, as methylation is re-established; and (3) during each reproductive cycle, as methylation profiles become fully established in mature spermatozoa [
34]. It has also been suggested that methylation at imprinted genes (because only one allele is active) might be particularly vulnerable to environmental perturbation [
35]. Aside from DNA methylation, there is increasing evidence that sperm RNAs and histone modifications are compelling candidates for epigenetic inheritance, but understanding of these mechanisms is in its infancy [
32].
In addition to epigenetic factors, sperm can also transmit cytoplasmic factors to offspring at fertilisation. These include activation factor, centrosomes, messenger RNA and microRNAs, which could modify post-fertilisation events and offspring embryonic development [
17,
23]. Components of the non-sperm fraction of the ejaculate (e.g. seminal fluid proteins, peptides, lipids, salts, etc.) have also been shown to vary with paternal environment [
36] and there is some evidence from animals that, in addition to an effect on sperm function, success and selection, they can also have a direct effect on offspring phenotype [
37], although the mechanisms are unclear.