The next generation of disease risk: Are the effects of prenatal nutrition transmitted across generations? Evidence from animal and human studies

Abstract

Suboptimal intrauterine conditions, including poor nutrition, during critical periods of growth may lead to lifelong changes in the body's organs and tissues, thus providing a physiological basis for adult-onset disease. Remarkably, recent evidence suggests that the long-term consequences of adverse conditions during early development may not be limited to one generation, but may lead to poor health in the generations to follow, even if these individuals develop in normal conditions themselves. For example, the diet of a pregnant mother may affect the development and disease risk of her children and even her grandchildren. There is limited evidence for this in humans since studies of multiple generations are difficult to maintain. However, recent animal models have been generated to investigate this phenomenon and will be instrumental in the future for assessing the underlying mechanisms of intergenerational and transgenerational transmission of disease. These mechanisms remain unclear, though environmental, metabolic and epigenetic factors are likely involved. Researchers have begun to address how changes in metabolism and epigenetic regulation of gene expression caused by poor nutrition can be passed from one generation to the next. Ultimately, these findings will shed light on the transmission of diabetes, obesity and cardiovascular disease that are rapidly expanding in Western countries. Public health strategies that focus on improved maternal nutrition may provide a means of promoting cardiovascular and metabolic health. However, the full impact of these strategies may not be apparent for decades.

Introduction

Some diseases that were once thought to arise near the time of their manifestation in adulthood are now acknowledged to originate in pre- and early post-natal life [1]. For example, human studies around the globe have shown that low birth weight babies have increased cardiovascular and metabolic morbidity and mortality in later life [2]. These associations reflect ‘developmental programming,’ a process whereby suboptimal intrauterine or early childhood conditions during critical periods of cellular differentiation and growth. Ultimately, environmental factors (e.g., poor nutrition) have the potential to alter metabolism, hormone production and gene expression, causing lifelong changes in the body's organs and tissues and provide a physiological and metabolic basis for adult-onset disease [3]. Quite remarkably, recent evidence suggests that the long-term consequences of adverse conditions during early development may not be limited to one generation, but may lead to poor health in the generations to follow. This can occur even in the absence of the stressor in the latter generations.

The phenomena whereby the consequences of an environmental insult (e.g., nutrient deficiency, exposure to carcinogens or other environmental factors, etc.) are transmitted between generations are classified as intergenerational programming (also referred to as multigenerational programming by others [4]) or transgenerational epigenetic inheritance, depending on whether or not affected individuals in the latter generations are directly exposed to the stressor [4], [5]. More specifically, intergenerational effects are limited to the generations that are directly exposed to an environmental stressor [4]. For example, when a pregnant mother is undernourished, her fetus (first filial [F₁] generation) and its germ cells (future F₂ generation) are both directly exposed to these adverse conditions in utero. Prenatal under-nutrition during critical periods of organ development, including the placenta, of the F₁ offspring may have detrimental effects on their reproductive outcome, such that the F₂ offspring are developmentally compromised as well [3]. The mechanisms underlying the effects of intergenerational programming are largely unknown and likely involve a complex interplay between environmental, metabolic and epigenetic factors [5]. Alternatively, if the effects of an environmental stressor in one generation are transmitted into further generations that have not been directly exposed as fetus or germ cell (e.g., F₃ or F₄ offspring, etc.), this is referred to as transgenerational programming. Transgenerational effects are thought to largely occur through meiotically-stable changes in DNA methylation patterns, siRNA expression or histone modifications resulting in the epigenetic inheritance of abnormalities [3], [5], [6]. It is experimentally less difficult to determine transgenerational epigenetic inheritance through the paternal lineage since males only contribute their sperm to the next generation and do not have the same physiological interaction with their progeny as a mother [5], [6]. Although altered epigenetic regulation may also arise in the maternal lineage, only embryo transfer experiments will help to elucidate whether the disease is perpetuated through epigenetic inheritance in this case [5].

Human studies of intergenerational programming are observational in nature, and therefore have limited value in determining the mechanisms underlying these phenomena. Studies involving specific animal models whereby the diet of the grandparental generation was modified, have allowed us to assess the outcome of poor nutrition on subsequent generations. These models will eventually help us understand the underlying mechanisms (physiological or epigenetic) behind developmental programming of health and disease.