The Developmental Origins of Health and Disease (DOHaD)

Objectives

The aim of this study was to relate lifestyle influence from the external as well as the internal environment to genetic modifications and phenotypic alterations beginning with the following:

The term epigenetics was first proposed by Conrad Waddington in the 1940s to describe the interaction of genes with their environment during development. The word itself has developed from the narrative term to an immensely studied field of science in the 21st century. The current meaning of the term epigenetics encompasses conformational changes in DNA and/or chromatin without alterations in the basic genetic code.

To a large degree, the field of epigenetics relates to nutritional deficiencies, biochemistry, and how the external as well as the internal environments influence the cells down to the level of the DNA. The science of epigenetics explains the sum total effect of everything that influences genetic function and dysfunction; research, including anecdotal stories, helps us understand that this influence starts generations before phenotypic and biochemical changes become apparent. The purpose of this article is to report on how both the research and anecdotal stories can influence how health care providers approach patients, especially in relation to lifestyle behaviors. The take home message for both health care providers and the public is that the genes people are born with can be significantly influenced to create either disease or wellness, and much of this influence relates to the lifestyle choices we make every day.

The developmental origins of the health and disease hypothesis (DOHaD) propose a link between periconceptual, fetal, and early infant phases of life and the long-term development of metabolic disorders. Research shows how external factors influence genetic function, resulting in altered longevity and the incidence of cancer and age-related diseases.

According to the DOHaD hypothesis, epigenetic adaptations are made to the fetal/neonatal DNA in response to environmental influences. ¹ The hypothesis further explains that the body responds to the environment and makes genetic changes (predictive adaptations) in anticipation of a presumed future environment. If the predictive adaptations are incorrect, then the metabolic state of the individual is altered to a degree whereby the risk of chronic disease in adulthood is increased; research also shows that the increased risk might be transgenerational. ²

Roth et al ³ explained that the regulation of energy balance is established early in development, and nutritional challenges during pregnancy and/or lactation predispose the offspring to a range of metabolic disorders. Studies also show how developmental plasticity influences the genotype, which then can influence and change the bio-physiology and the phenotype of the organism.

Wattex et al ⁴ discussed how altered early life nutrition connects epigenetic changes within the hypothalamus and alters concentrations of key adipokines such as leptin and adiponectin, both of which regulate energy balance. These alterations have been shown to contribute to long-lasting dysregulation of energy balance and obesity following early adverse life events. ⁵

How Does Lifestyle Affect the Health of a Child From Birth Through Adolescent and Adult Years?

The well-established viewpoint that noncommunicable disease (cardiovascular disease, diabetes mellitus) are the product of the gene-lifestyle interaction in adult life has undergone considerable evolution since the 1990s. It is now recognized that a life course approach to understanding health is more appropriate, and the risk of disease at any stage of life is determined by the interaction of genetics and the cumulative exposures to lifestyle and environmental factors throughout life.

The concept that early life exposures influence the long-term risk of disease is referred to as developmental programming ⁶ ; the environmental factors include maternal nutrition, smoking, infant feeding methods, maternal stress, and infection.

What Impact Does the Health of the Mother Have on the Health of the Child, in Utero and Thereafter?

Whitaker ⁷ found that children of obese mothers were twice as likely to be obese at 2 years of age as compared with normal-weight mothers. Multiple studies^8,9 have reported that infants born to overweight and obese mothers tend to have a higher fat mass at birth and to be at significantly increased risk of developing obesity as well as associated metabolic disorders in childhood and adulthood.

What About the Father?

Radford et al ¹⁰ reported on how undernutrition during prenatal life is able to compromise the male germline (affecting the health of the sperm), which over time contributes to a higher than normal incidence of environmentally induced diseases. This is reported as paternal transgenerational epigenetic inheritance.

Changes to the epigenome brought about by early-life events have been shown to contribute to long-term disease risk. Studies show that intrauterine life is significantly affected by all that influences the mother and the fetus. When birth occurs, it is known that the type of delivery influences the long-term health of the offspring. ¹¹ Vaginal delivery confers added immunological benefits to the child, and conversely, cesarean delivery negatively influences the development of immunity and the normal microbiome in the child. The latter results in a higher risk for development of asthma and allergies. Breast feeding for 6 to 9 months confers positive benefits to the child’s immune system. ¹² Antibiotic use in the first year of life brings negative effects on the immune system and the microbiome.^13,14

How Do Early Lifestyle Behaviors and Nutrition Affect the Risk and Incidence of Diabetes, Obesity, Heart Disease, and Even Cancer?

A study in the town of Hertfordshire in the United Kingdom ¹⁵ with men in the United Kingdom born in the 1920s who weighed <2.5 kg found a strong association between low birth weight and the risk and incidence of coronary death, type 2 diabetes, and metabolic syndrome. There was a similar study of people born in Scotland in the 1950s, with similar results.

The Dutch Hunger Winter study describes the German occupation of The Netherlands in 1944, which resulted in the population eating only 400 to 800 calories per day.^16,17 When this famine affected pregnant women, early gestation food restriction resulted in elevated rates of adult obesity, hyperlipidemia, and cardiovascular disease. Calorie restriction during midgestation and late gestation resulted in reduced birth weight of the offspring, who also suffered from lower adult weight and stature. Exposure to famine during any stage of gestation was associated with glucose intolerance. ¹⁸

What About the Effects of Certain Types of Protein?

Chavarro et al ¹⁹ reported on the relative risk of infertility depending on the type of protein consumed. They found that mothers who ate more animal protein had a 39% higher risk of infertility as compared with those eating more vegetable protein, who had a 22% less risk. Substituting just 5% of the total energy intake as vegetable protein lowered the risk of infertility by 50%.

Goh et al ²⁰ found that micronutrients have a positive epigenetic effect on fertility, conferring a 41% lower risk of infertility and resulting in fewer miscarriages, fewer birth defects, less pediatric cancer and less autism.

Environmental Toxins Also Appear to Play a Role in Epigenetics and the Development of Chronic Illness

The EARTH study (the Environment and Reproductive Health) enrolled 155 men and found that those exposed to more pesticides (residue on fruits and vegetables) had a 49% lower total sperm count and 32% more abnormal sperm overall. ²¹

How Does Inheritance of Gene Mutations Influence the Developing Health and How Does Science Explain Transgenerational Inheritance?

The explanation of transgenerational inheritance is seen in mice surviving on a very-low-calorie diet, who then had underweight offspring prone to diabetes. The males in this litter fathered another generation of offspring who also developed diabetes even though they consumed a normal diet.

Does the Inheritance of Bad Genes Always Translate Into the Development of Disease and What Lifestyle Interventions Decrease the Risk and Incidence of Disease?

Research conducted by Ornish et al ²² showed that intensive lifestyle intervention influences 500 genes in males with early prostate cancer. Similar results were seen in individuals with heart disease. Nutrition focusing on whole plant foods revealed that many nutritional compounds in food influence enzymatic activity and modulate gene expression: for example, epigallocatechin gallate (ECGC) in green tea, resveratrol in red grapes, genistein in soya, curcumin or turmeric, and isothiocyanates in cruciferous vegetables.

Paternal transgenerational epigenetic inheritance describes how epigenetics affects the male DNA. Radford et al ¹⁰ reported on how undernutrition during prenatal life is able to compromise the male germline (affecting the health of the sperm), which over time contributes to a higher than normal incidence of environmentally induced diseases. Jensen et al ²³ found that the male diet also affects fertility. He studied Danish recruits who ate the most saturated fat and found that they had 38% lower sperm concentrations and sperm counts that were decreased by 41%.

Factors that affect the genes include micro and macro nutrients, fasting/calorie restriction, exercise, chronic stress, sleep deprivation, mental health, how individuals respond to life experiences, toxins, medications, heavy metals, pesticides, tobacco, hormones, radioactivity, antibiotics, viruses, bacteria, and more. Substances are not the only source of epigenetic changes. It is known that high-quality maternal care results in better health of the offspring. Scientists at Duke University ²⁴ analyzed DNA first from 5-year-old children and then again when these children were 10 years of age. The children who experience physical or emotional abuse or other life stressors between 5 and 10 years of age had shorter telomeres, showing that life experiences have a direct influence on the expression of genes.

The study of epigenetics might be described as follows: what we thought we knew to be correct and much of what we thought factual was actually in error. We know from history that there have been numerous times in medicine where dogma turned out not to be true or what was thought to be understood was incomplete, and as such, epigenetics might be an example of the same. There are many examples of what the medical establishment in the 16th and 17th centuries thought they knew but found out that was not the case, possibly similar to what we in the 21st century believe to be true about the function of the genes and the destiny of the DNA. ²⁵

In summary, the science of epigenetics is quickly growing with the understanding that the environment and individual lifestyle directly interact with the genome to influence epigenetic changes. Human epidemiological studies have provided evidence that prenatal and postnatal environmental factors influence the adult risk of developing various chronic illnesses and behavioral disorders. This research is making it apparent that epigenetic effects occur not only in the womb but over the full course of a human life span and that epigenetic changes can be reversed by controlling lifestyle choices and environmental exposures. Therefore, we see that there is a lot that can be done to affect the health of the DNA, showing us that genes are not always our destiny!