Environmental Regulation Of “The Love Hormone”: A Comprehensive Overview Of The Literature

The hormone oxytocin is probably best known for its role in establishing and maintaining (romantic) relationships, and is therefore charmingly termed “the love hormone.” While oxytocin has indeed been associated with feelings of bonding, closeness, sexual arousal, and love, it has become increasingly clear that the impact of oxytocin is far more widespread and complex than originally thought.

Surpassing its catchy label, oxytocin seems to regulate a large variety of human behaviors, ranging from reproduction and labor to (social) learning and memory formation. Proper functioning of the oxytocin system is therefore highly desirable, as variabilities in oxytocin and its receptor have repeatedly been linked to several mental disorders.

One such variability entails single nucleotide polymorphisms (SNPs) of the oxytocin gene and, more particularly, of the oxytocin receptor gene (OXTR). These OXTR SNPs have been associated with significant alterations in the brain, which might underlie inter-individual variations in social and emotional behaviors as well as the etiology of various psychopathologies. Although abundant, studies on genetic variations of OXTR in relation to social (dys)functioning are mostly inconclusive. More importantly, the exact functional relevance of these SNPs on OXTR expression and function remains poorly understood.

These impediments have led to a shift of scientific focus from genetic variations to other, non-genetic regulatory mechanisms of gene transcription – in particular to epigenetics (literally meaning “above genetics”). This relatively new field of research has gained an immense increase in interest over the last few years. Epigenetics refers to structural adaptations of chromosomal regions while maintaining the underlying genetic code. One of the most interesting aspects of epigenetics is its dynamic character. Multiple studies indicate that DNA methylation is highly sensitive to environmental influences, ranging from diet and lifestyle to pharmacological treatments and from childhood abuse to air pollution and urbanization. This provides our body with a certain flexibility in response to environmental factors and events.

The most well-known epigenetic process is DNA methylation, which entails the chemical coupling of methyl groups to cytosines mainly located in cytosine-guanine (CpG) sequences. Regions that are enriched in such CpG sequences (CpG islands) are often associated with the transcription site of that particular gene. This enables the regulation of gene expression, traditionally in a negative direction. To simplify matters: DNA methylation allows specific genes to turn “on” and “off.”

Over the last years, the amount of studies investigating the influence of OXTR methylation on social (dys)functioning has extensively expanded. Comprehensive integration of individual results is however lacking, thereby impeding the significance and overall understanding of outcomes. Our goal was therefore to systematically identify and integrate all studies on the association between OXTR methylation and human social behaviors. An initial search of two electronic databases retrieved 123 unique articles. A thorough evaluation of their eligibility resulted in the inclusion of 30 studies, which could be organized into six categories: “social perception and cognition,” “social attachment,” “autism spectrum disorder,” “internalizing disorders,” “externalizing disorders,” and “biological link.” Narrative summaries are presented for all included studies, and comprehensive tables and figures represent the precise locations of all investigated OXTR CpG sites according to the current genetic assembly (GRCh38), thereby facilitating future research by providing an unbiased overview of the literature and enabling direct comparison of results to previous findings.

In general, two main conclusions could be drawn. First, differential DNA methylation patterns of specific OXTR CpG sites can indeed be linked to inter-individual variation in (social) behaviors and the etiology of several mental disorders. Secondly, OXTR methylation may constitute a molecular mechanism by which environmental events can become biologically embedded, thereby altering one’s social sensitivity and susceptibility to psychopathologies. Although insufficiently understood at the moment, the latter may stimulate novel research directions and possible therapeutic interventions. In addition, we dedicated the second part of the review to addressing the current limitations of the field and discussing future directions. In short, we recommend that future studies, 1) integrate both genetic and epigenetic measures to fully understand the genomic influence on socio-behavioral phenotypes, 2) limit potential sources of inter-individual variations (e.g. tissue-specificity, sample characteristics), 3) aim for replication of results in large, heterogeneous samples, and 4) prioritize research into the functional relevance of DNA methylation.

Altogether, the main results from this review confirm our original thought: the involvement of the oxytocin system in human behaviors is indeed far more widespread and complex than its commercial label might suggest. This systematic review may represent a suitable starting point for future research to further unravel the socio-biological consequences of OXTR methylation.

These findings are described in the article entitled Epigenetic variability in the human oxytocin receptor (OXTR) gene: A possible pathway from early life experiences to psychopathologies, recently published in the journal Neuroscience & Biobehavioral Reviews.

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