La consommation de cannabis est associée à des modifications généralisées potentiellement héréditaires de la méthylation de l'ADN du gène candidat de l'autisme DLGAP2 dans le sperme

Aperçu: G.M.

La consommation de cannabis par les parents a été associée à des conséquences neurodéveloppementales défavorables chez les enfants, mais la manière dont ces phénotypes sont transmis est en grande partie inconnue. À l'aide du séquençage du bisulfite à représentation réduite (RRBS), nous avons récemment démontré que la consommation de cannabis était associée à des modifications généralisées de la méthylation de l'ADN du sperme chez l'homme et le rat. La protéine DLGAP2 (Discs-Large Associated Protein 2), impliquée dans l'organisation de la synapse, la signalisation neuronale et fortement impliquée dans l'autisme, a présenté une hypométhylation significative (p <0,05) à 17 sites CpG dans le sperme humain. Nous avons validé avec succès la méthylation différentielle présente dans DLGAP2 pour neuf sites CpG situés dans l’intron sept (p <0,05) en utilisant un 'pyrosequencing' quantitatif au bisulfite. La méthylation de l'ADN Intron 7 et l'expression de DLGAP2 dans le tissu cérébral conceptuel humain étaient inversement corrélés (p <0,01). 

Des rats mâles adultes exposés au delta-9-tétrahydrocannabinol (THC) ont présenté une méthylation différentielle de l'ADN à Dlgap2 dans le sperme (p <0,03), de même que le noyau accumbens des rats dont les pères avaient été exposés au THC avant la conception (p <0,05). 

Globalement, ces résultats justifient des recherches supplémentaires sur les effets de la consommation de cannabis avant la conception chez les hommes et sur les effets potentiels sur les générations futures.

Epigenetics. 2019 Aug 26:1-13. doi: 10.1080/15592294.2019.1656158

Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm

Schrott R^1,2, Acharya K³, Itchon-Ramos N⁴, Hawkey AB⁴, Pippen E⁴, Mitchell JT⁴, Kollins SH⁴, Levin ED⁴, Murphy SK^1,2.

Author information

1

Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Duke University Medical Center , Durham , NC , USA.

2

Integrated Toxicology and Environmental Health Program, Nicholas School of the Environment, Duke University , Durham , NC , USA.

3

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Duke University Medical Center , Durham , NC , USA.

4

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center , Durham , NC , USA.

Abstract

Parental cannabis use has been associated with adverse neurodevelopmental outcomes in offspring, but how such phenotypes are transmitted is largely unknown. Using reduced representation bisulphite sequencing (RRBS), we recently demonstrated that cannabis use is associated with widespread DNA methylation changes in human and rat sperm. Discs-Large Associated Protein 2 (DLGAP2), involved in synapse organization, neuronal signaling, and strongly implicated in autism, exhibited significant hypomethylation (p < 0.05) at 17 CpG sites in human sperm. We successfully validated the differential methylation present in DLGAP2 for nine CpG sites located in intron seven (p < 0.05) using quantitative bisulphite pyrosequencing. Intron 7 DNA methylation and DLGAP2 expression in human conceptal brain tissue were inversely correlated (p < 0.01). Adult male rats exposed to delta-9-tetrahydrocannabinol (THC) showed differential DNA methylation at Dlgap2 in sperm (p < 0.03), as did the nucleus accumbens of rats whose fathers were exposed to THC prior to conception (p < 0.05). Altogether, these results warrant further investigation into the effects of preconception cannabis use in males and the potential effects on subsequent generations.

PMID:31451081

DOI:10.1080/15592294.2019.1656158

Paternité retardé

Traduction: G.M.

J Fam Plann Reprod Health Care. 2014 Oct;40(4):283-288. doi: 10.1136/jfprhc-2013-100866. Epub 2014 Jun 23.

Delayed fatherhood

Lawson G¹, Fletcher R².

Author information

• ¹Former Consultant Obstetrician and Gynaecologist, John Hunter Hospital, Newcastle, New South Wales, Australia.
• ²Senior Lecturer, Faculty of Health and Medicine, Family Action Centre, University of Newcastle, Newcastle, New South Wales, Australia.

Résumé

Les données sur la natalité dans les pays développés indique que l'âge paternel moyen augmente. Alors que la tendance à la paternité plus tardive est établie, des préoccupations ont été soulevées selon lesquelles cela pourrait être lié à des effets indésirables, tels que les complications de la grossesse, des anomalies congénitales, et les implications pour la santé à long terme de l'enfant. Puisque le sperme des pères plus âgés peut être compromis en raison des effets généraux du vieillissement, leur progéniture peut être à risque en raison des défauts dans la qualité du sperme à la conception. Une recherche de littérature a été effectuée pour identifier les complications de la grossesse, des anomalies fœtales et des problèmes de santé de l'enfant lorsque le père est dans une tranche d'âge plus avancée. La preuve de la dépréciation du sperme et du matériel génétique de pères plus âgés a été examinée. Avec un père âgé, il existe des preuves d'une augmentation de la mortinatalité et un risque légèrement accru d'autisme, de trouble bipolaire et de schizophrénie chez les enfants plus tard dans la vie. Le risque accru d'achondroplasie est reconnu depuis longtemps. Pour la mère, il y a une augmentation du taux de césarienne. Les enquêtes sur les autres effets indésirables possibles ont produit des résultats mitigés. Des études plus robustes et longitudinales sont nécessaires pour clarifier ces questions.

Abstract

Birth data from developed countries indicates that the average paternal age is increasing. As the trend to older fatherhood has become established, concerns have been raised that this may be linked to adverse outcomes, such as pregnancy complications, congenital anomalies, and long-term health implications for the child. Since the sperm of older fathers may be impaired due to the general effects of ageing, their offspring may be at risk due to defects in sperm quality at conception. A literature search was performed to identify pregnancy complications, fetal anomalies and health issues for the child when the father is in an older age bracket. Evidence for impairment in the sperm and genetic material of older fathers was reviewed. With an older father, there is evidence of an increase in stillbirths and a slightly increased risk of autism, bipolar disorder and schizophrenia in the offspring later in life. The increased risk of achondroplasia has long been recognised. For the mother, there is an increased rate of Caesarean section. Investigations of other possible adverse outcomes have produced mixed findings. Further robust and longitudinal studies are needed to clarify these issues.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PMID: 24958072

Sperm Mutation Linked To Autism

Science Daily — University of Iowa researchers have learned more about a genetic mutation that contributes to autism. The mutation occurred in sperm cells of a father, who does not have autism, but passed the condition on to two of his children.

The investigators now know more about how the mutation causes problems with a specific gene and are testing for additional mutations of the same gene in other people with autism. Thomas Wassink, M.D., associate professor of psychiatry in the UI Carver College of Medicine, presented the findings May 3 at the annual International Meeting for Autism Research in Seattle.

Earlier this year, UI researchers and collaborators were part of an international team that identified, among other findings, deletions in a gene called neurexin 1, which caused the two cases of autism in one family. The UI researchers and collaborators were Wassink; Val Sheffield, M.D., Ph.D., UI professor of pediatrics and a Howard Hughes Medical Investigator; Kacie Meyer, a graduate student in Wassink's laboratory; and former UI investigator Joseph Piven, M.D., now professor of psychiatry at the University of North Carolina (UNC) and director of the UNC Neurodevelopmental Disorders Research Center,

"Genes with the most compelling evidence of causing autism appear to be components of a specific kind of neuronal connection, or synapse, called the glutamate synapse. The gene neurexin 1 was the fourth of these genes to be identified, and it is a scientifically interesting mutation because it wasn't found in either of the parents, who do not have autism," Wassink said.

Instead, the mutation is a germline mosaic -- meaning the deletion occurred only in the father's sperm cells when he himself was in gestation. As result, the father did not have autism, but his two children, both daughters, inherited from him a chromosome that was missing a small piece of DNA that contained neurexin 1. The daughters now have autism.

Because of this missing DNA, certain proteins cannot form that normally contribute to glutamate synapses and, by extension, normal development.

"Now, using this information, we can look in a very detailed way at this gene in other families and begin to understand what happens when this protein that is normally active in the brain is missing," Wassink said.

Knowing more about how the deletions function could eventually lead to the development of diagnostic and therapeutic tools.

About Autism: Autism is a complex brain disorder that inhibits a person's ability to communicate and develop social relationships, and it is often accompanied by extreme behavioral challenges. Autism spectrum disorders are diagnosed in one in 166 children in the United States, affecting four times as many boys as girls.

Note: This story has been adapted from a news release issued by University of Iowa.