Biological Mechanisms for Allen's Rule: DNA Methylation as Mediator of the Association Between In Utero Exposure to Environmental Heat and Tibial Growth in Childhood

Abstract

Objectives

Understanding human phenotypic plasticity in response to social, ecosystem, and climate interactions can be an important tool for designing social and public health strategies that increase climate change resilience. Sensitivity of the tibia to environmental perturbations is well established; moreover, Allen's rule predicts relatively longer tibial length in hotter climates. In this study, we hypothesized DNA methylation (DNAm) changes as potential mechanisms for impacts of environmental heat exposure in utero persisting in childhood tibial growth in Kenyan Samburu pastoralist children ages 1.8–9.6 years living in a global climate change vulnerability hotspot.

Methods

DNAm data was measured from whole saliva using the Infinium MethylationEPIC BeadChip array. To test our hypothesis, we tested for differential DNAm and we performed high-dimensional mediation analysis using high-resolution (0.05 × 0.05) land surface temperature variables (LST) for each trimester of gestation and compared this to models using a coarser method (contrasting climate zones).

Results

We found differentially methylated CpG sites in both LST and comparison models, near genes relevant to linear growth, with some overlap between models, as expected. We identified 37 CpG sites mediating the association between LST > 37°C exposure in utero and tibial growth into childhood, and 13 CpG sites as mediators in comparison models.

Conclusions

To our knowledge, these are the first results to identify biological mediators linking environmental heat to lower limb growth in children. The findings contribute evidence of epigenetic mechanisms relevant to Allen's rule and of the tibia as a key biomarker of early life conditions.