Modulation of Brain β-Endorphin Concentration by the Specific Part of the Y Chromosome in Mice

Michel Botbol,Olivier Bonnot,Michèle Carlier,Séverine Trabado,Pierre L Roubertoux,Sylvie Brailly-Tabard,Guillaume Bronsard,Sylvie Tordjman,Fernando Perez-Diaz

doi:10.1371/journal.pone.0016704

Abstract

BackgroundSeveral studies in animal models suggest a possible effect of the specific part of the Y-chromosome (YNPAR) on brain opioid, and more specifically on brain β-endorphin (BE). In humans, male prevalence is found in autistic disorder in which observation of abnormal peripheral or central BE levels are also reported. This suggests gender differences in BE associated with genetic factors and more precisely with YNPAR.Methodology/Principal FindingsBrain BE levels and plasma testosterone concentrations were measured in two highly inbred strains of mice, NZB/BlNJ (N) and CBA/HGnc (H), and their consomic strains for the YNPAR. An indirect effect of the YNPAR on brain BE level via plasma testosterone was also tested by studying the correlation between brain BE concentration and plasma testosterone concentration in eleven highly inbred strains. There was a significant and major effect (P<0.0001) of the YNPAR in interaction with the genetic background on brain BE levels. Effect size calculated using Cohen's procedure was large (56% of the total variance). The variations of BE levels were not correlated with plasma testosterone which was also dependent of the YNPAR.Conclusions/SignificanceThe contribution of YNPAR on brain BE concentration in interaction with the genetic background is the first demonstration of Y-chromosome mediated control of brain opioid. Given that none of the genes encompassed by the YNPAR encodes for BE or its precursor, our results suggest a contribution of the sex-determining region (Sry, carried by YNPAR) to brain BE concentration. Indeed, the transcription of the Melanocortin 2 receptor gene (Mc2R gene, identified as the proopiomelanocortin receptor gene) depends on the presence of Sry and BE is derived directly from proopiomelanocortin. The results shed light on the sex dependent differences in brain functioning and the role of Sry in the BE system might be related to the higher frequency of autistic disorder in males.

Highlights

The Y chromosome includes the YNPAR and the YPAR
The controls to ensure the isogenicity of the background in each parental strain and its consomic strain rule out a possible contribution of residual autosomal alleles from the donor strain to this effect of the YNPAR in interaction with the genetic background
An indirect effect of the YNPAR in interaction with the genetic background on brain BE levels via plasma testosterone is not supported by our findings

Summary

Introduction

The Y chromosome includes the YNPAR and the YPAR. The YNPAR is called non-pairing or specific region and is transmitted from father to sons exclusively. Intracerebro-ventriculaire injection of BE decreases plasma Luteinizing Hormone concentration and plasma testosterone concentration; this effect involves the m receptors and is blocked by the preliminary administration of Naloxone (an antagonist of the m receptors) [7,8,9,10] Given these previous observations and because YNPAR is involved in plasma testosterone concentration and testicular reactivity to testosterone [11,12], the YNPAR is expected to be associated with brain BE. Male prevalence is found in autistic disorder in which observation of abnormal peripheral or central BE levels are reported This suggests gender differences in BE associated with genetic factors and more precisely with YNPAR

Methods

Results

Conclusion