Paternal developmental toxicant exposure is associated with epigenetic modulation of sperm and placentalPgrandIgf2in a mouse model†

Abstract

Preterm birth (PTB), parturition prior to 37 weeks' gestation, is the leading cause of neonatal mortality. The causes of spontaneous PTB are poorly understood; however, recent studies suggest that this condition may arise as a consequence of the parental fetal environment. Specifically, we previously demonstrated that developmental exposure of male mice (F1 animals) to the environmental endocrine disruptor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was associated with reduced sperm quantity/quality in adulthood and control female partners frequently delivered preterm. Reproductive defects persisted in the F2 and F3 descendants, and spontaneous PTB was common. Reproductive changes in the F3 males, the first generation without direct TCDD exposure, suggest the occurrence of epigenetic alterations in the sperm, which have the potential to impact placental development. Herein, we conducted an epigenetic microarray analysis of control and F1 male-derived placentae, which identified 2171 differentially methylated regions, including the progesterone receptor (Pgr) and insulin-like growth factor (Igf2). To assess if Pgr and Igf2 DNA methylation changes were present in sperm and persist in future generations, we assessed methylation and expression of these genes in F1/F3 sperm and F3-derived placentae. Although alterations in methylation and gene expression were observed, in most tissues, only Pgr reached statistical significance. Despite the modest gene expression changes in Igf2, offspring of F1 and F3 males consistently exhibited IUGR. Taken together, our data indicate that paternal developmental TCDD exposure is associated with transgenerational placental dysfunction, suggesting epigenetic modifications within the sperm have occurred. An evaluation of additional genes and alternative epigenetic mechanisms is warranted.

Transgenerational epigenetic effects from male exposure to endocrine-disrupting compounds: a systematic review on research in mammals

“…Nevertheless, after further investigation of placental samples for Pgr and Igf2 genes products, such as mRNAs and protein expression, reduced profiles were detected in F1 and F3 male-derived samples, compared to control placentae. This was in line with a significant increase of Dnmt1 mRNA in placentae, normally suppressed by progesterone and estradiol [50]. The study of Ding et al focused on genes involved in preterm birth and placental dysfunction.…”

“…This gene is known to modulate progesterone receptor (Pgr) and insulin-like growth factor (Igf2) gene expression. Validation of methylation status and expression of Pgr and Igf2 in F1/F3 sperm and F3-derived placentae showed consistent findings, although results did not always reach statistical significance [50]. It should be noted that the limited transgenerational effects measured could be due to selection, given that the most severely impacted F1 mice exhibited complete infertility.…”

“…Hence, intermediate epigenetic effects remain unknown. Ding et al conducted a global methylation analysis of late pregnancy mice placentae (E18.5) after TCDD exposure in the F0 generation [50]. They examined multiple placentae per litter, using at least five litters per group.…”

Minor DNA methylation changes are observed in spermatozoa prepared using different protocols

“…Furthermore, alterations in IGF2 methylation were associated with sperm concentration, 47 but it was also suggested that alterations in IGF2 methylation are caused by ART and can be detected in fetuses 48 . The transgenerational impact of rearranged IGF2 methylation was studied in animal models after paternal exposure to different environmental pollutants, and it was suggested that endocrine disruptor (TCDD) exposure can cause changes in sperm IGF2 methylation, which are detected even in offspring, 49 while benzo[a]pyrene exposure did not cause such effects 50 . Two genes, which are predicted to be imprinted according to the Imprinted Gene Database and showed differential methylation, have diverse roles in development.…”

Environmental Impact on Male (In)Fertility via Epigenetic Route

“…Developmental exposure to TCDD has been associated to reduced sperm quality/quantity and the occurrence of reproductive defects also in F3 males suggest that sperm conveys the father’s entire contribution to pregnancy, thereby contributing to placental dysfunction in his control partner [ 235 ].…”