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

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.

Male Germline Transmits Fetal Alcohol Adverse Effect on Hypothalamic Proopiomelanocortin Gene Across Generations

“…However, we showed in this study that fetal alcohol-induced hypermethylation of Pomc gene in sperm transferred accross three generations. Recently it has been shown that the non-paring part of the Y-chromosome influences the expression of BEP in the hypothalamus (44). Additionally, the transcription of Mc2R a POMC receptor, is dependent on the Sry gene (45).…”

Male germline transmits fetal alcohol epigenetic marks for multiple generations: a review

“…In the hypothalamus, POMC is regulated in part by the non‐pairing region of the Y chromosome (Y NPAR ) (Botbol et al . ). Additionally, transgenerational changes in the expression of the Pomc gene in rats were detected in sperm (Botbol et al .…”

Alcohol effects on the epigenome in the germline: Role in the inheritance of alcohol-related pathology

“…The reason why methylation patterns on this gene along the male germline can be preserved and escape reprogramming during development is unknown. A possible explanation for this would be, since the phenotype is only passed down along the male germline and Pomc expression is regulated by the non-pairing region of the Y chromosome (Botbol et al, 2011), alcohol exposure leads to epigenetic modifications on the Y chromosome that are spared from reprogramming during development and are then passed down to subsequent generations (Sarkar, 2016). Future studies are needed to address this possibility.…”