Exposure to environmental contaminants and folic acid supplementation intergenerationally impact fetal skeleton development through the paternal lineage in a rat model

Phanie L Charest; Emmanuel Tessougue; Maryse Lessard; Pauline M Herst; Pauline Navarro; Sarah Kimmins; Jacquetta M Trasler; Amanda J MacFarlane; Marie-Odile Benoit-Biancamano; Janice L Bailey; Mathieu Dalvai

doi:10.3389/ftox.2022.881622

Exposure to environmental contaminants and folic acid supplementation intergenerationally impact fetal skeleton development through the paternal lineage in a rat model

Front Toxicol. 2022 Sep 27:4:881622. doi: 10.3389/ftox.2022.881622. eCollection 2022.

Authors

Phanie L Charest^{1

2}, Emmanuel Tessougue^{1

2}, Maryse Lessard^{1

2}, Pauline M Herst^{1

2}, Pauline Navarro³, Sarah Kimmins^{4

5}, Jacquetta M Trasler⁶, Amanda J MacFarlane⁷, Marie-Odile Benoit-Biancamano^{2

8}, Janice L Bailey^{1

2}, Mathieu Dalvai^{1

2}

Affiliations

¹ Department of Animal Sciences, Faculty of Agricultural and Food Sciences, Université Laval, Quebec City, QC, Canada.
² Centre de Recherche en Reproduction Développement et Santé Intergénérationnelle (CRDSI), Université Laval, Quebec City, QC, Canada.
³ Department of Nutrition, Faculty of Agricultural and Food Sciences, Institute of Nutrition and Functional Foods, Université Laval, Quebec City, QC, Canada.
⁴ Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada.
⁵ Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC, Canada.
⁶ Departments of Pediatrics, Human Genetics and Pharmacology and Therapeutics, Research Institute-McGill University Health Center, McGill University, Montreal, QC, Canada.
⁷ Nutrition Research Division, Health Canada, Ottawa, ON, Canada.
⁸ Groupe de Recherche En Pharmacologie Animale du Québec (GREPAQ), Department of Pathology and Microbiology, Faculty of Veterinary Medicine, Université de Montréal, Sainte Hyacinthe, QC, Canada.

Abstract

Persistent organic pollutants (POPs) are ubiquitous in the environment, which is of concern since they are broadly toxic for wildlife and human health. It is generally accepted that maternal prenatal folic acid supplementation (FA) may beneficially impact offspring development, but it has been recently shown that the father's exposures also influence the health of his offspring. Bone is an endocrine organ essential for whole-body homeostasis and is susceptible to toxicants. Herein, we tested the hypotheses that prenatal paternal exposure to POPs induces developmental bone disorders in fetuses across multiple generations and that FA supplementation attenuates these disorders. We used a four-generation rat model, in which F0 founder females were divided into four treatment groups. F0 females were gavaged with corn oil or an environmentally-relevant POPs mixture and fed either a control diet (2 mg FA/kg), or FA supplemented diet (6 mg FA/kg) before mating and until parturition (four treatments in total). After the birth of the F1 litters, all F0 females and subsequent generations received the FA control diet. Staining with alcian blue and alizarin red S of male and female fetal skeletons was performed at Gestational Day 19.5. Paternal direct and ancestral exposure to POPs delayed bone ossification and decreased the length of long limb bones in fetuses. Maternal FA supplementation did not counteract the POPs-associated delayed fetal ossification and reduced long bone length. In conclusion, prenatal paternal POPs exposure causes developmental bone abnormalities over multiple generations, which were not corrected by maternal FA supplementation.

Keywords: DOHaD (development origins of health and disease); POPs; development; fetus; folic acid; persistent organic pollutants; prenatal exposure; skeleton.