Human Growth and Development: Developmental Origins of Health & Disease (DOHaD)

DOHAD Premise

• In utero environmental interaction with genomic factors influences health and the risk of disease later in life.

Learning Objectives

• Describe the key principles of the DOHaD hypothesis.
• Appreciate the history and evolution of the field.
• Describe the underlying mechanisms associated with DOHaD.
• Discuss interventions to minimize the impact of DOHaD.

Introduction

• Human health is often defined as the absence of disease, influenced by various factors.
• Nutrition in utero and during critical development periods plays a significant role in health in adulthood.
• The Fetal Origins Hypothesis (formerly Fetal Programming) was renamed to Developmental Origins of Health and Disease (DOHaD).

DOHaD Hypothesis

• Exposure to specific environmental influences during critical developmental periods can significantly affect an individual's health.
• Associated non-communicable diseases (NCDs): heart disease, diabetes, hypertension, etc.

Impacts on Developing Foetus

• Foetus exposed to a hostile uterine environment adapts for immediate viability and survival to similar environments encountered later.

Adaptations

• Short-term adaptations may include:
  • Down-regulation of endocrine and metabolic functions.
  • Changes to organ functions.
  • Slowing growth rates.
• Long-term adaptations can result in:
  • Irreversible changes in development, structure, and organ functions.
  • Disruption in gene expression, cell differentiation, and proliferation.

Evidence and Risk Factors

• Evidence from animal models and observational studies support DOHaD principles.
• Critical periods from conception to early childhood significantly affect future health outcomes.
• Example of undernutrition (protein/calorie restriction) leading to lifelong changes:
  • Growth restrictions.
  • Links to Type 2 diabetes mellitus (T2DM), cardiovascular (CVD) disease, kidney disease, obesity, hypertension, etc.

Historical Origins of DOHaD

• 1800s: Early views on generation viewed maternal and paternal contributions as influential. The concept of "Maternal Impressions": anything a mother experienced could influence the offspring.
• August Weismann: Introduced the idea of heredity affecting future generations regardless of somatic cell experiences.
• William Ogilvy Kermack (1934): Proposed early-life exposures significantly influence later disease outcomes based on cohort studies.
• World War II: Wartime famine studies showed links between severe undernutrition in pregnancy and adverse health outcomes for offspring.

Barker Hypothesis

• Formulated by David Barker, examining health correlations between birth weight and adult diseases:
  • Suggested that fetuses divert nutrients primarily to the brain when resources are scarce, leading to weaker hearts in adults.
  • A significant correlation was drawn between inadequate prenatal nourishment and future health risks such as heart disease.

Thrifty Phenotype Hypothesis

• Proposed by Barker & Hales in 1992, suggesting fetuses under deprived conditions grow slowly and are influenced by environmental factors contributing to T2DM risks in later life.

Mismatch and Predictive Adaptive Response (PAR)

• Proposed by Gluckman & Hanson (2005), highlighting that mismatched environments may lead to increased susceptibility to non-communicable diseases.
• The concept of PAR suggests adaptations in anticipation of future environments based on early nutrient availability.

Underlying Mechanisms

• Mechanisms include:
  • Excessive glucocorticoid exposure.
  • Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis.
  • Irreversible organ structure changes.
  • Alterations in gene expression (epigenetics).

Excessive Exposure to Glucocorticoids

• Example: Cortisol’s role in blood pressure regulation and glucose metabolism; excessive levels during fetal development may lower birth weight and contribute to adult health risks.

Dysregulation of the HPA Axis

• The HPA axis plays a critical role in stress response and regulation of various bodily functions.

Irreversible Organ Structure Changes

• Undernutrition and hypoxia can lead to:
  • Decreased nephron counts, increasing risks for hypertension and renal disease.
  • Fewer pancreatic beta cells, potentially leading to glucose control issues in older ages.

Epigenetics

• Epigenetic mechanisms (e.g. DNA methylation, histone modifications, microRNA regulation) significantly impact gene expression without altering DNA sequences, driving long-term effects.
• DNA Methylation:
  • Important for controlling gene activity with implications for developmental origins of health and disease.
• MicroRNAs:
  • Play roles in regulating gene expression linked to low-birth weights and long-term health consequences.

Maternal Effects

• Maternal obesity/diabetes are crucial factors influencing DOHaD, leading to:
  • Increased risks of T2DM, hypertension, and cardiovascular disease.
• Gestational Diabetes Mellitus (GDM) implications include:
  • Maternal and fetal growth complications and increased risks for post-pregnancy metabolic disorders.

Suggested Interventions

• Reducing poverty to improve living conditions.
• Investing in nutrition and health education focusing on diet, physical activity.
• Promoting breastfeeding and proper feeding practices for infants and young children.
• Enhancing access to clean water and sanitation.
• Supporting public health strategies to reduce tobacco and alcohol use.