Intergenerational impact of paternal lifetime exposures to both folic acid deficiency and supplementation on reproductive outcomes and imprinted gene methylation

Ly, Lundi; Chan, Donovan; Aarabi, Mahmoud; Landry, Mylène; Behan, Nathalie A.; MacFarlane, Amanda J.; Trasler, Jacquetta M.

doi:10.1093/molehr/gax029

Cited by 95 publications

(123 citation statements)

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“…A total of four studies investigated the associations between folate status and sperm parameters in animals. [ 10–13 ] Furthermore, 13 articles reported on the association between folate status and sperm parameters in human. [ 5–7,12,14–22 ] A total of five studies investigated the association between folate status and sperm epigenetics, of which two were animal studies [ 10,13 ] and three were human studies.…”

Section: Resultsmentioning

confidence: 99%

“…[ 10–13 ] Furthermore, 13 articles reported on the association between folate status and sperm parameters in human. [ 5–7,12,14–22 ] A total of five studies investigated the association between folate status and sperm epigenetics, of which two were animal studies [ 10,13 ] and three were human studies. [ 5,12,23 ] Six studies investigated the associations between folate status and sperm DNA damage and apoptosis, including two animal studies [ 11,13 ] and four human studies ( Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…One study in mice comparing a 20‐fold FA fortified diet (40 mg kg −1 ) with a sevenfold FA deficient diet (0.3 mg kg −1 ), starting during pregnancy through maternal exposure and continued postnatally with a control diet (2 mg kg −1 ), found that both diets resulted in decreased sperm counts. [ 10 ] One study showed that a folate deficient diet (0.3 mg kg −1 ) resulted in decreased sperm counts compared to a control (2 mg kg −1 ) diet (9.3 ± 1.2 × 10 6 vs 13.0 ± 1.1 × 10 6 ). [ 12 ] Furthermore, Swayne et al.…”

Section: Resultsmentioning

confidence: 99%

“…[ 11 ] Furthermore, two other animal studies showed that a low intake of dietary folate resulted in increased as well as decreased sperm DNA‐methylation. [ 10,13 ] Lambrot et al. showed that DNA methylation concentrations in general were both increased and decreased for various genes in the folate deficient group as compared to the control, while histone methylation was primarily downregulated.…”

Section: Resultsmentioning

confidence: 99%

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Paternal Folate Status and Sperm Quality, Pregnancy Outcomes, and Epigenetics: A Systematic Review and Meta‐Analysis

Hoek

Steegers‐Theunissen

Willemsen

et al. 2020

Molecular Nutrition Food Res

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Scope: The effectiveness of maternal folate in reducing the risk of congenital malformations during pregnancy is well established. However, the role of the paternal folate status is scarcely investigated. The aim of this study is to investigate the evidence of associations between the paternal folate status and sperm quality, sperm epigenome, and pregnancy outcomes. Methods and results: Databases are searched up to December 2017 resulting in 3682 articles, of which 23 are retrieved for full-text assessment. Four out of thirteen human and two out of four animal studies show positive associations between folate concentrations and sperm parameters. An additional meta-analysis of four randomized controlled trials in subfertile men shows that the sperm concentration increases (3.54 95% confidence interval (CI) [−1.40 to 8.48]) after 3-6 months of 5 mg folic acid use per day compared to controls. Moreover, two out of two animal and one out of three human studies show significant alterations in the overall methylation of the sperm epigenome. One animal and one human study show associations between low folate intake and an increased risk of congenital malformations. Conclusions: This systematic review and meta-analysis shows evidence of associations between paternal folate status and sperm quality, fertility, congenital malformations, and placental weight.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Paternal Folate Status and Sperm Quality, Pregnancy Outcomes, and Epigenetics: A Systematic Review and Meta‐Analysis

Hoek

Steegers‐Theunissen

Willemsen

et al. 2020

Molecular Nutrition Food Res

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“…Further exploration of mechanisms of effect would also increase understanding and point to potential avenues for intervention. In line with developments in the animal literature, associations between maternal prenatal depression and offspring ASB could in part be explained by paternal programming effects including the impact of sperm quality, seminal plasma and sperm mediated epigenetic mechanisms on the maternal reproductive system [89,90]. For example, seminal plasma has been shown to modify the cell signalling, vascular and nutrient environment of the maternal reproductive tract following conception which impacts on early embryo development [90].…”

Section: Research Recommendationsmentioning

confidence: 99%

Longitudinal studies examining the impact of prenatal and subsequent episodes of maternal depression on offspring antisocial behaviour

Morgan

Channon

Penny

et al. 2019

Eur Child Adolesc Psychiatry

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Maternal depression is associated with adverse child outcomes including antisocial behaviour (ASB). Prospective longitudinal studies have focused on the timing and cumulative exposure to maternal depression to further delineate the association and mechanisms of effect. The objective of this systematic review was to synthesise and evaluate the findings of longitudinal studies of maternal depression and offspring antisocial behaviour. Three databases were searched (Psychinfo, Web of Science, and Medline). Twenty of 5936 studies met inclusion criteria. Study quality was assessed using the Critical Appraisal Skills Programme criteria [Critical Appraisal Skills Programme (2017) CASP (cohort observation checklist). https ://casp-uk. net/wpcon tent/uploa ds/2018/01/CASP-Cohor t-Study -Check list.pdf]. Results of individual studies were highly varied, using diverse analytical approaches and not all studies explored the independent effects of different episodes. Only three studies examined hypothesised mechanisms. Prenatal, postnatal, and later episodes of depression were all predictive of antisocial outcomes. One particular time period of depression exposure did not emerge as more predictive of offspring ASB than another. However, measures of maternal depression after the perinatal period were limited and typically included a one-off assessment of mothers' depressive symptoms that was concurrent to the assessment of offspring ASB. When cumulative exposure to maternal depression and specific timing effects were measured within the same study it was cumulative exposure that conferred the greatest risk for offspring ASB-particularly when this exposure began during the perinatal period. Findings are discussed in terms of limitations in the literature and highlight the need for future research to examine the biological and environmental mechanisms that underpin associations between maternal depression and offspring antisocial behaviour during different stages of development.

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Teratogenesis and the epigenetic programming of congenital defects: Why paternal exposures matter

Golding

2023

Birth Defects Research

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Until recently, clinicians and researchers did not realize paternal exposures could impact child developmental outcomes. Indeed, although there is growing recognition that sperm carry a large amount of non‐genomic information and that paternal stressors influence the health of the next generation, toxicologists are only now beginning to explore the role paternal exposures have in dysgenesis and the incidence of congenital malformations. In this commentary, I will briefly summarize the few studies describing congenital malformations resulting from preconception paternal stressors, argue for the theoretical expansion of teratogenic perspectives into the male preconception period, and discuss some of the challenges in this newly emerging branch of toxicology. I argue that we must consider gametes the same as any other malleable precursor cell type and recognize that environmentally‐induced epigenetic changes acquired during the formation of the sperm and oocyte hold equal teratogenic potential as exposures during early development. Here, I propose the term epiteratogen to reference agents acting outside of pregnancy that, through epigenetic mechanisms, induce congenital malformations. Understanding the interactions between the environment, the essential epigenetic processes intrinsic to spermatogenesis, and their cumulative influences on embryo patterning is essential to addressing a significant blind spot in the field of developmental toxicology.

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Intergenerational impact of paternal lifetime exposures to both folic acid deficiency and supplementation on reproductive outcomes and imprinted gene methylation

Abstract: This study was supported by a grant to J.M.T. from the Canadian Institutes of Health Research (CIHR #89944). The authors declare they have no conflicts of interest.

Cited by 95 publications

References 56 publications

Paternal Folate Status and Sperm Quality, Pregnancy Outcomes, and Epigenetics: A Systematic Review and Meta‐Analysis

Paternal Folate Status and Sperm Quality, Pregnancy Outcomes, and Epigenetics: A Systematic Review and Meta‐Analysis

Longitudinal studies examining the impact of prenatal and subsequent episodes of maternal depression on offspring antisocial behaviour

Teratogenesis and the epigenetic programming of congenital defects: Why paternal exposures matter

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