Author:

Abstract:

A number of findings in animals and some in humans support the notion that plasticity of our (epi)genome allows adaptation to environmental changes, resulting in altered genetic programming and phenotypic changes in the offspring. In this regard, we introduced a new paradigm: the Paternal Origins of Health and Disease (POHaD) (1, 2). This theory explains how the paternal germ line may respond to environmental traits, and how this may affect offspring health. We earlier discovered significant associations between urinary levels of metabolites originating from exposures to indoor pollutants, such as flame-retardants or mixtures of endocrine disruptors (EDCs), and alterations in epigenetic patterns at Differentially Methylated Regions (DMRs) of several imprinted genes in sperm of young men (3). In brief, our data suggested that men exposed to mixtures of EDCs acquire DNA methyl molecules at sites that are normally only methylated in the oocyte, but not in sperm cells. This "feminisation" of epigenetic patterns in sperm -due to exposure to EDCs- needs further exploration. Next, we found that sperm cells of obese men or men with an unhealthy life style (such as frequent consumption of fatty foods) have a different epigenetic signature at the level of imprinting control regions, compared to sperm of normal weight men or men with a healthy diet (including whole grain bread, vegetables, etc.) (4). This is consistent with findings in animal experiments. For instance, diet-induced epigenetic changes in rodent sperm have been linked to fertility issues in the exposed fathers or metabolic disturbances in the next generations (5) (6, 7). Although epidemiologic studies indicate that epigenetic signatures from (obese) fathers can be inherited (8, 9), it is currently unclear if these paternally induced effects on gene-regulation are to the extent that children will develop a chronic disorder in later life. Our first studies show that the affected genes (by envionmental exposures) are important in regulation of early growth. Hence, we further explored potential effects of the father on embryo growth, through a prospective IVF study cohort. While studies on influences from extrensic exposures are still ongoing, our first data show that an intrinsic exposure factor, such as ageing, may affect the embryo epigenome and its growth. In our IVF cohort, we measured that older fathers are less likely to produce embryo's with an optimal number of blastomeres (10). This effect was seen regardless of maternal age. It is known that ageing affects the integrity of germ cell DNA, but we hypothesize that the sperm epigenome machinery may also encounter "defects" due to ageing or due to parrallelled effects from chronic exposure to a harmfull environment throughout life. Further research is warranted to better understand our observations. More epidemiologic studies are needed in other populations of men and future fathers. If our POHaD hypothesis can be confirmed; and hence, a man's environment and age play an important role in his fertility and offspring health, it is important to inform clinicians. Patients need to be instructed about potential harm of their life style (or age) to prevent development or worsening of health-related issues. Policy makers should inform the general public, increasing the awareness of potential consequences when delaying fatherhood, for instance. Furthermore, research is needed in the field of occupational epidemiology. It is yet unclear whether some occupational exposures in men before conception affect the sperm epigenome, and subsequently, offspring health. In conclusion, the impact of the environment of future fathers cannot be ignored. Next to current precautions in pregnant women, we believe there is an urgent need to include a male-focused strategy in future research and health policy plans.