Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism

Abstract

Paternal obesity predisposes offspring to metabolic dysfunction, but the underlying mechanisms remain unclear. We investigated whether this metabolic dysfunction is associated with changes in placental vascular development and is fueled by endoplasmic reticulum (ER) stress-mediated changes in fetal hepatic development. We also determined whether paternal obesity indirectly affects the in utero environment by disrupting maternal metabolic adaptations to pregnancy. Male mice fed a standard chow or high fat diet (60%kcal fat) for 8–10 weeks were time-mated with female mice to generate pregnancies and offspring. Glucose tolerance was evaluated in dams at mid-gestation (embryonic day (E) 14.5) and late gestation (E18.5). Hypoxia, angiogenesis, endocrine function, macronutrient transport, and ER stress markers were evaluated in E14.5 and E18.5 placentae and/or fetal livers. Maternal glucose tolerance was assessed at E14.5 and E18.5. Metabolic parameters were assessed in offspring at ~60 days of age. Paternal obesity did not alter maternal glucose tolerance but induced placental hypoxia and altered placental angiogenic markers, with the most pronounced effects in female placentae. Paternal obesity increased ER stress-related protein levels (ATF6 and PERK) in the fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Offspring of obese fathers were glucose intolerant and had impaired whole-body energy metabolism, with more pronounced effects in female offspring. Metabolic deficits in offspring due to paternal obesity may be mediated by sex-specific changes in placental vessel structure and integrity that contribute to placental hypoxia and may lead to poor fetal oxygenation and impairments in fetal metabolic signaling pathways in the liver.

Paternal obesity alters the sperm epigenome and is associated with changes in the placental transcriptome and cellular composition

“…A deconvolution analysis revealed changes in the placental lineage specification comparable with pathological changes observed in placental defects that are associated with adult-onset cardiometabolic diseases (Aliee & Theis, 2021; Chu et al, 2019a; Cuffe et al, 2014; Han et al, 2018). Comparative analysis between placental transcriptomic profiles from our paternal HFD-induced obesity model with that of a hypoxia-induced fetal growth restriction model, revealed common placental defects across the two models (Chu et al, 2019a) consistent with our previous work that sire-obesity induces placental hypoxia (Jazwiec et al, 2022). This study revealed that paternal obesity was linked with transcriptomic and cellular defects in the placenta and may drive developmental origins of cardiometabolic disease in offspring.…”

“…It is therefore likely that the differential expression of imprinted genes detected in female and male placentas as a result of paternal obesity could at least partly explain metabolic phenotypes observed in this mouse model (Jazwiec et al, 2022;Pepin et al, 2022). We identified changes in sperm H3K4me3 associated with paternal obesity, some of which were enriched for transcription factor binding sites.…”

“…This is in line with paternal obesity associated to the developmental origins of neurological, cardiovascular, and metabolic disease in offspring (Andescavage & Limperopoulos, 2021;Binder et al, 2015Binder et al, , 2012Chambers et al, 2016;Cropley et al, 2016;de Castro Barbosa et al, 2016;T. Fullston et al, 2012;Tod Fullston et al, 2013;Grandjean et al, 2015;Huypens et al, 2016;Jazwiec et al, 2022;Mitchell et al, 2011;Ng et al, 2010;Pepin et al, 2022;Perez-Garcia et al, 2018;Terashima et al, 2015;Thornburg et al, 2016;Thornburg & Marshall, 2015;Ueda et al, 2022;Wei et al, 2014). The brain-placenta and heartplacenta axes refer to their developmental linkage to the trophoblast which produces various hormones, neurotransmitters, and growth factors that are central to brain and heart development (Parrettini, Caroli, & Torlone, 2020;Rosenfeld, 2021).…”

“…2.1 High-fat diet-induced obesity alters the sperm epigenome at regions implicated in metabolism, cellular stress and placentation Figure 1 describes the previously phenotypically characterized paternal HFD-induced obesity mouse model used in this study (Jazwiec et al, 2022). Of note, it differs from our previous model (Pepin et al, 2022) by mouse sub-strain (C57BL/6J vs C57BL/6NCrl), research setting, timing of diet exposure (at 6 vs 3 weeks of age), and the control diet (chow vs low-fat diet).…”

“…For example, placental insufficiency occurs in 10 to 15% of pregnancies, and underlying causes include advanced maternal age (Ales, Druzin, & Santini, 1990; Torous & Roberts, 2020; Wu et al, 2019), hypertension (Krielessi et al, 2012), obesity (Delhaes et al, 2018; Lutsiv, Mah, Beyene, & McDonald, 2015; MacInnis, Woolcott, McDonald, & Kuhle, 2016; Mission, Marshall, & Caughey, 2015; Sohlberg, Stephansson, Cnattingius, & Wikström, 2012), cigarette smoking (Pintican, Poienar, Strilciuc, & Mihu, 2019), drug and alcohol use, and medications (Sebastiani et al, 2018). However, emerging studies, indicate that the paternal preconception environment including diet and obesity also play a critical role in placental development and offspring health (Binder et al, 2015; Binder, Hannan, & Gardner, 2012; Jazwiec et al, 2022; Lambrot et al, 2013).…”