Key points

Social determinants of child health

The health consequences of material deficiency (eg, extreme malnutrition or lack of water or inadequate clothing and shelter) have been long known. However, recently, a new, more broadly applicable research agenda emphasizing social factors and health has emerged. The term social determinant of health often refers to any nonmedical factor directly influencing health, including values, attitudes, knowledge, and behaviors. However, it can also refer to more external sources of influence such as family, neighborhood, and social network context. A large and convincing literature over the last several decades shows that health across the life span is strongly linked to social disadvantage.

For example, neighborhoods can influence health through their physical and geographic characteristics, such as air and water quality, lead paint exposure, proximity to both health-promoting and health-suppressing features (ie, hospitals and nutritious food stores vs toxic factories and fast food), access to green space, and so on. Additionally, more social aspects of neighborhoods such as strong cohesion are associated with far better health and safety.

Recent evidence demonstrates that the chronic stress of social disadvantage, socioeconomic inequality, and racial discrimination act through a variety of biological pathways to influence health, including neuroendocrine, developmental, immunologic, and vascular mechanisms. In response to stressful events, cortisol, cytokines, and other intermediates are released, and if there is long-term, repetitive or chronic exposure, these substances may damage key physiologic systems. It is thought that this mechanism of physiologic strain accelerates the onset or progression of chronic illnesses.

One of the largest and most consistently replicated areas of research demonstrates the negative effects of social disadvantage in childhood on later child and adult health, socio-emotional wellbeing, and cognitive ability. This body of work indicates that childhood social disadvantage operates through a variety of complex mechanisms to result in dramatically different developmental outcomes, which are often apparent even in childhood, but which are typically more fully manifest in adulthood. Indeed, there is evidence that early childhood disadvantage appears to leave a biological residue, which in turn has effects on development, health, and wellbeing.

Social determinants of child health

The health consequences of material deficiency (eg, extreme malnutrition or lack of water or inadequate clothing and shelter) have been long known. However, recently, a new, more broadly applicable research agenda emphasizing social factors and health has emerged. The term social determinant of health often refers to any nonmedical factor directly influencing health, including values, attitudes, knowledge, and behaviors. However, it can also refer to more external sources of influence such as family, neighborhood, and social network context. A large and convincing literature over the last several decades shows that health across the life span is strongly linked to social disadvantage.

For example, neighborhoods can influence health through their physical and geographic characteristics, such as air and water quality, lead paint exposure, proximity to both health-promoting and health-suppressing features (ie, hospitals and nutritious food stores vs toxic factories and fast food), access to green space, and so on. Additionally, more social aspects of neighborhoods such as strong cohesion are associated with far better health and safety.

Recent evidence demonstrates that the chronic stress of social disadvantage, socioeconomic inequality, and racial discrimination act through a variety of biological pathways to influence health, including neuroendocrine, developmental, immunologic, and vascular mechanisms. In response to stressful events, cortisol, cytokines, and other intermediates are released, and if there is long-term, repetitive or chronic exposure, these substances may damage key physiologic systems. It is thought that this mechanism of physiologic strain accelerates the onset or progression of chronic illnesses.

One of the largest and most consistently replicated areas of research demonstrates the negative effects of social disadvantage in childhood on later child and adult health, socio-emotional wellbeing, and cognitive ability. This body of work indicates that childhood social disadvantage operates through a variety of complex mechanisms to result in dramatically different developmental outcomes, which are often apparent even in childhood, but which are typically more fully manifest in adulthood. Indeed, there is evidence that early childhood disadvantage appears to leave a biological residue, which in turn has effects on development, health, and wellbeing.

Biological underpinnings of social determinants

Early life experience gets under the skin in ways that affect the health, wellbeing, and child development. Although the most extensive research shows strong biological effects of physical and emotional abuse (and other similarly extreme childhood events) on health and developmental consequences, more recent research shows that less obvious but more regular adversities of early childhood also have a lasting influence on later health and development. Recent work has begun to focus on epigenetics as a key biological mechanism linking early life experience and health.

Description of epigenetics

Despite having the same DNA, different cell types have distinct gene expression patterns in order to perform different functions. One mechanism of this differential gene expression is through epigenetic changes, which some have argued may also explain some of the variation in behavioral phenotypes of people. One key aspect of the epigenome is that, unlike the DNA sequence, it may be modified by environmental or pharmaceutical interventions. This provides the potential for reversing the effect of adverse life events on later health and wellbeing. Epigenetic changes, or marks, refer to alterations in DNA or histone structure that do not affect the sequence of DNA but may affect gene expression and therefore cellular function. The effect on cellular function may be sustained, and under many circumstances, it can be transmitted to subsequent generations of cells.

Recall that DNA is organized as a linear molecule, in which the 4 nucleotides (adenine, A; thymine, T; guanine, G; cytosine, C) form the core of the DNA molecule, and sugar phosphates form the backbone of the DNA ( Fig. 1 ). In people, nuclear DNA is organized into 46 chromosomes: 22 autosomes and 1 sex chromosome from each parent. The flow of information in a cell has been termed the central dogma ( Fig. 2 ), in which information flows from DNA to messenger RNA (mRNA), to protein. Genes are arrayed along the chromosomes, and a gene can be viewed as consisting of the arrangement of base sequences that specifies a complementary mRNA, and, therefore, a specific protein, together with those nearby DNA sequences that determine when and to what extent the gene is transcribed into RNA.

( A ) A schematic representation of the double helical structure of DNA. A, adenosine; C, cytosine; G, guanine; T, thymidine. The strips represent the helical structure formed by the phosphodiester bonds (the double helix), and the horizontal bars represent paired bases. ( B ) A space-filling model of the DNA double helix. The color-coded atoms are shown at the top of the figure.

( From Hardin J, Bertoni G, Kleinsmith LJ. Becker’s World of the cell. 8th edition. San Francisco (CA): Benjamin Cummings; 2006. ©2012. Reprinted by permission of Pearson Education, Inc., New York, New York.)

The central dogma of molecular biology, modified to include reverse transcription.

Fig. 3 provides a schematic of a typical gene as it appears in DNA. Bases that code specific amino acids are organized in blocks termed, exons. Between the exons are the introns, which are composed of bases that do not specify specific amino acids but may contain control regions. Because of the orientation of the DNA strands, 1 side of the gene is termed the 5′ end, and the other, the 3′ end. At the 5′ end of the gene is a sequence of bases termed the promoter/enhancer, which is enriched for cytosine and guanine bases. Binding of the promotor by a series of transcription factors activates transcription, the process by which RNA polymerase syntheses a complementary strand of mRNA. Soon after the new primary RNA copy of the gene is synthesized, the introns are removed, and the exons are stitched together. After several more steps, the mRNA is used by the ribosome as a template for synthesis of a polypeptide chain, the basic structure of all proteins.

Schematic of a typical human gene. The 5′ end of the gene contains a promoter/enhancer region that is enriched for CpG sequence. The promoter also contains a special sequence, TATTAAA, which is a target for the transcription factors to bind. Several other sequences may intervene between the CpG island and the TATTAAA. Introns are shown in blue, and exons in orange. During transcription and splicing, an RNA copy of the gene is made, and the introns are excised. A 5′ cap and a 3′ tails are added to the final mRNA copy of the gene.

This arrangement provides for several points at which gene regulation can adjust the synthesis of proteins to meet the needs of the cell. Transcriptional control is a key form of regulation, through which the amount of mRNA synthesized from a particular gene is increased or decreased as necessary.

Upon receipt of an appropriate signal, the cell can deploy or withdraw specific transcription factors within minutes, thereby rapidly modulating the transcription of specific genes. This type of signaling response is rapid, and easily reversible. On the other hand, epigenetic changes to DNA generally take days to years to occur, and as mentioned, they tend to be stable.

DNA methylation

The promotor regions of genes are enriched for sequences containing cytosine alternating with guanine (5′-CG-3′ abbreviated CpG). Areas in which the proportion of CpG is greater than statistically predicted are termed CpG islands. Wherever a CpG occurs, the C is susceptible to being modified by the enzyme DNA methyltranferase through the addition of a methyl (CH ₃ ) group (forming 5-methylcytosine) ( Fig. 4 ). A promoter containing a group of CpG sequences that have been methylated is less able to bind relevant transcription factors, and this attenuates or halts transcription. Because the addition of a methyl group to cytosine is a covalent reaction, it may be an enduring change; furthermore, the DNA replication apparatus has mechanisms for ensuring that the corresponding CpG is methylated in newly synthesized DNA.

5-methylcytosine is formed by the addition of a methyl (–CH ₃ ) group to cytosine.

( From Alberts B, Johnson A, Lewis J, et al. Molecular biology of the cell. 5th edition. New York: Garland Science; 2008; with permission.)

Clusters of CpG residues are not only found in promoters, but also interspersed within genes, and along intergenic regions. The role played in cellular physiology by methylation of these other CpG sites is the subject of considerable research, and may be more important in controlling transcription than the CpG islands.

The methylation of DNA is just 1 way in which a cell can create an epigenetic mark. DNA is tightly coiled around highly basic proteins called histones. One effect of this winding is to greatly compress the DNA, allowing it to be packaged into a cell nucleus. Fully extended, the DNA of a chromosome would extend about 75 mm, but in its coiled state, it is about 5 μm (compression of about 15,000 fold). Often, when DNA is tightly wound on a nucleosome, the DNA regulatory sites (such as the promoter) become inaccessible to transcription signals, and the affected genes become silent. Histone proteins have several sites at which they can be covalently modified, principally by methylation or acetylation. The effect of these covalent changes may be to slightly relax the DNA, thereby freeing regulatory sites for interactions with various transcriptional activator proteins. These histone changes are also termed epigenetic marks. As is the case with DNA methylation, the cell is able to duplicate the histone marks on newly synthesized histones that are destined for daughter cells. Thus, histone-based epigenetic marks are heritable, even though they are not coded in the DNA.

It is important to note that although epigenetic marks are heritable from parent cell to daughter cell, this is often misunderstood to mean that in multicellular organisms, such as people, epigenetic marks are transferred directly from parent to child. Rather, during the process of gamete formation, most epigenetic marks are cleared, and each generation develops a new set of epigenetic marks. However, under appropriate circumstances environmental signals (including those supplied through maternal behavior) may result in patterns of epigenetic marks in the offspring that reflect those also found in the parent.

At the biochemical level, epigenetics affects transcription and ultimately the protein repertoire of a cell. The epigenetic mechanism serves 4 essential cellular roles: (1) X-chromosome inactivation, (2) differentiation, (3) imprinting, and (4) medium- and long-term transcriptional control. This article focuses on how social and environmental signals shape DNA methylation and thereby transcription. Aberrations in DNA methylation are frequently associated with cancer, but this phenomenon is not within the scope of this article.