Impact of excessive hypercholesterolemia in pregnancy on the placentas of the male and female offspring.

Excessive hypercholesterolemia (eHC) in pregnancy reduces placental efficiency in both fetal sexes, but the mechanisms are not known. In this study, Sprague Dawley rats received a control or high cholesterol diet (to model eHC) during pregnancy, after which various markers of placental function were assessed. Lipid levels, but not reactive oxygen species levels, were increased in both the male and female eHC placentas vs. controls. However, compared to control placentas, eHC reduced cholesterol receptors, increased cholesterol transporters, lowered fetal cholesterol levels, and altered the unfolded protein response in a sex-specific manner. Moreover, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) levels were increased in only the male eHC placentas, and associated with reduced interleukin 1β levels, likely due to its rapid secretion into the circulation. The levels of caspase 8, but not caspase 1, were increased in only the male eHC placentas vs. controls, suggesting that the processing of interleukin 1β may have happened via a non-canonical pathway. In conclusion, eHC in pregnancy impacts the placentas of both the male and female offspring, but the activation of the NLRP3 inflammasome in only the male placentas suggests that the male offspring may be more susceptible to excessive increases in maternal cholesterol levels.