Sources of Genetic Variability

This article will not deal with major gene effects on HPA axis activity as seen in endocrine diseases induced by corticosteroid receptor or enzymatic defects. Traits such as circulating cortisol levels are normally distributed in genetically heterogeneous populations, suggesting that several genes may influence the phenotype, each gene with a small effect, and with complex gene x gene and gene x environment interactions. Several sources of genetic variability have been identified in farm animals.

Adrenal Sensitivity to ACTH. In the 1980s, D. P. Hennessy (Victoria, Australia) demonstrated in pigs that the increase of plasma cortisol after ACTH injection was variable among individuals but stable across time for a given animal. Similar differences in cortisol secretion were shown in response to corticotropin-releasing hormone (CRH), physical exercise, or insulin-induced hypoglycemia, although the release of ACTH was not different among individuals. Furthermore, the metabolic clearance of cortisol bears no relationship with the response to ACTH.

Altogether, these data demonstrate that the key index of individual differences in HPA axis activity is the adrenal sensitivity to ACTH that was shown to be heritable in pigs. Several experimental results confirm genetic influences on the sensitivity of adrenal glands to ACTH. For instance, Meishan pigs (high cortisol levels) have a higher response to ACTH than Large Whites (low cortisol).

In poultry, divergent lines could be selected on this trait. In quails, selection for high corticosterone to immobilization increased the steroidogenic response of adrenocortical cells to ACTH, and in turkeys, selection for a high corticosterone response to cold stress also increased the sensitivity of the adrenal gland to ACTH.

In trout, the divergent cortisol response to confinement stress mostly results from the selection of animals with divergent interrenal gland response to ACTH, together with a large difference in the expression level of genes involved in corticosteroid hormone synthesis. Taken together, these data show that the adrenal sensitivity to ACTH is an important mechanism by which genetic factors influence HPA axis response to stress.

Hormone Bioavailability. Quantitative trait locus (QTL) analysis is a strategy to search for gene polymorphisms influencing a quantitative trait. It is based on the linkage between phenotypic value and genetic polymorphisms in a segregating population, usually an F2 intercross or a backcross.

A QTL analysis run on an F2 intercross between the Large White and Meishan breeds revealed the large influence of a locus located at the end of the q arm of chromosome 7 on basal and post-stress (novel environment exposure) levels of cortisol, explaining, respectively, 7.7% and 20.7% of the phenotypic variance, with the Meishan alleles increasing cortisol levels.

Other loci on chromosome 1 and 17 were shown to influence poststress ACTH levels. The comparison of genetic maps from different species shows that the end of the long arm of chromosome 7 is homologous to the telomeric end of the long arm of human chromosome 14. In this region corticosteroid-binding globulin (CBG), a glycoprotein specifically carrying cortisol in blood plasma, has been mapped.

CBG is an important factor influencing bioavailability of the hormone, as it has been shown in humans that differences in CBG levels are a major determinant of differences in plasma cortisol levels. Therefore, the Cbg gene is an interesting positional and functional candidate gene to explain QTL influences on plasma cortisol levels. Indeed, comparison of gene sequences in Large White and Meishan pigs revealed several polymorphisms influencing CBG levels and function.

Corticosteroid Hormone Receptors. Two receptors (mineralocorticoid receptor [MR] and glucocorticoid receptor [GR]) mediate the biological effects of corticosteroid hormones. They act as transcription factors to increase or decrease the expression of target genes. The efficiency of corticosteroid hormone receptors is a major site of genetic variation, but few data are available in farm animals.