Folic acid supplementation reduces multigenerational sperm miRNA perturbation induced by in utero environmental contaminant exposure

P M Herst; M Dalvai; M Lessard; P L Charest; P Navarro; C Joly-Beauparlant; A Droit; J M Trasler; S Kimmins; A J MacFarlane; M-O Benoit-Biancamano; J L Bailey

doi:10.1093/eep/dvz024

Folic acid supplementation reduces multigenerational sperm miRNA perturbation induced by in utero environmental contaminant exposure

Environ Epigenet. 2019 Dec 14;5(4):dvz024. doi: 10.1093/eep/dvz024. eCollection 2019 Oct.

Authors

P M Herst¹, M Dalvai¹, M Lessard¹, P L Charest¹, P Navarro², C Joly-Beauparlant³, A Droit³, J M Trasler⁴, S Kimmins^{5

6}, A J MacFarlane⁷, M-O Benoit-Biancamano⁸, J L Bailey¹

Affiliations

¹ Department of Animal Sciences, Faculty of Agricultural and Food Sciences, Centre de recherche en reproduction, développement et santé intergénérationnelle, Laval University, Quebec City, Canada.
² Department of Nutrition, Faculty of Agricultural and Food Sciences, Institute of Nutrition and Functional Foods, Centre de recherche en reproduction, développement et santé intergénérationnelle, Laval University, Quebec City, Canada.
³ Computational Biology Laboratory Research Centre, Faculty of Medicine, Laval University, Quebec City, Canada.
⁴ Departments of Pediatrics, Human Genetics and Pharmacology & Therapeutics, and The Montreal Children's Hospital and Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
⁵ Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
⁶ Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada.
⁷ Nutrition Research Division, Health Canada, Ottawa, Canada.
⁸ Faculty of Veterinary Medicine, University of Montreal University, Saint-Hyacinthe, Quebec, Canada.

Abstract

Persistent organic pollutants (POPs) can induce epigenetic changes in the paternal germline. Here, we report that folic acid (FA) supplementation mitigates sperm miRNA profiles transgenerationally following in utero paternal exposure to POPs in a rat model. Pregnant founder dams were exposed to an environmentally relevant POPs mixture (or corn oil) ± FA supplementation and subsequent F1-F4 male descendants were not exposed to POPs and were fed the FA control diet. Sperm miRNA profiles of intergenerational (F1, F2) and transgenerational (F3, F4) lineages were investigated using miRNA deep sequencing. Across the F1-F4 generations, sperm miRNA profiles were less perturbed with POPs+FA compared to sperm from descendants of dams treated with POPs alone. POPs exposure consistently led to alteration of three sperm miRNAs across two generations, and similarly one sperm miRNA due to POPs+FA; which was in common with one POPs intergenerationally altered sperm miRNA. The sperm miRNAs that were affected by POPs alone are known to target genes involved in mammary gland and embryonic organ development in F1, sex differentiation and reproductive system development in F2 and cognition and brain development in F3. When the POPs treatment was combined with FA supplementation, however, these same miRNA-targeted gene pathways were perturbed to a lesser extend and only in F1 sperm. These findings suggest that FA partially mitigates the effect of POPs on paternally derived miRNA in a intergenerational manner.

Keywords: folate; microRNA; organochlorine; prenatal exposure; transgenerational epigenetic inheritance.