Transgenerational Latent Early-Life Associated Regulation Unites Environment and Genetics Across Generations

Abstract

The origin of idiopathic diseases is still poorly understood. The latent early-life associated regulation (LEARn) model unites environmental exposures and gene expression while providing a mechanistic underpinning for later-occurring disorders. We propose that this process can occur across generations via transgenerational LEARn (tLEARn). In tLEARn, each person is a 'unit' accumulating preclinical or subclinical 'hits' as in the original LEARn model. These changes can then be epigenomically passed along to offspring. Transgenerational accumulation of 'hits' determines a sporadic disease state. Few significant transgenerational hits would accompany conception or gestation of most people, but these may suffice to 'prime' someone to respond to later-life hits. Hits need not produce symptoms or microphenotypes to have a transgenerational effect. Testing tLEARn requires longitudinal approaches. A recently proposed longitudinal epigenome/envirome-wide association study would unite genetic sequence, epigenomic markers, environmental exposures, patient personal history taken at multiple time points and family history.

Prenatal epigenetics diets play protective roles against environmental pollution

“…The F3 generation (the offspring of the F2 generation) is the first generation that exhibits transgenerational inheritance as both the F1 (the offspring of the parent generation) embryo and the F2 (the offspring of the F1 generation) germline involve direct exposure when an F0 (the parent generation) gestating female is exposed to an environmental factor [241–244]. Of great concern is that prenatal environmental exposure-induced epigenetic modifications may pass across subsequent generations through the germ line, leading to predisposition to diseases or disorders in the offspring [1, 30, 245]. Guerrero-Bosagna et al proposed plausible molecular mechanisms/conditions for environment-induced epigenetic transgenerational inheritance including stepwise processes: first, exposure during gametogenesis; second, epigenetic insults in PGCs; third, imprinting-like programming in the germ line, especially in the male germ line, escaping reprogramming during early embryonic development; fourth, altered epigenome in the germ line transmitted to subsequent generations in cells and tissues; and finally, increased susceptibility to related diseases in postnatal life [124].…”

Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5′-untranslated region: Implications in Alzheimer’s disease

“…Although autosomally dominant inherited (familial) forms of AD exist, they constitute no more than 5% of AD cases [2]. AD (familial and sporadic) is influenced by multiple genetic and environmental factors, and these factors are considered particularly influential in sporadic AD [3, 4], which requires the study of multiple molecular targets, mechanisms, pathways, and therapeutic strategies [5–8]. Significant evidence supports an Aβ-centric view of AD, e.g., carriers of a protective Aβ precursor protein (APP) polymorphism, APP A673T (Icelandic) [9], have reduced: incidence of AD, of Aβ levels throughout their lives, and of Aβ aggregation.…”

Non-genetic risk and protective factors and biomarkers for neurological disorders: a meta-umbrella systematic review of umbrella reviews

“…Similarly, intermediate risk factors (as defined in [ 169 ]), such as birth weight, or other increasingly recognized factors, such as social networks, the impact of which on health outcomes is being steadily better understood [ 170 ], could have been neglected by umbrella reviews. Another major example is that studies on early life risk factors, including in utero exposure, seem absent in umbrella reviews, even though the early life-related factors (and even those evoked in a transgenerational manner by progenies, e.g., through epigenetic regulations [ 171 – 173 ], or those described in the capacity-load model [ 174 ]) play crucial roles in the development of adult diseases [ 56 , 57 , 175 ]. Interpreting these studies with caution is essential as, at least in theory, several early life factors may influence the intercept of adult disease manifestations, whereas other factors may exercise an influence later in the disease course.…”