McPherson NO, Bell VG, Zander-Fox DL, Fullston T, Wu LL, Robker RL, Lane M. When two obese parents are worse than one! Impacts on embryo and fetal development. Am J Physiol Endocrinol Metab 309: E568 -E581, 2015. First published July 21, 2015; doi:10.1152/ajpendo.00230.2015.-The prevalence of overweight and obesity in reproductive-age adults is increasing worldwide. While the effects of either paternal or maternal obesity on gamete health and subsequent fertility and pregnancy have been reported independently, the combination of having both parents overweight/ obese on fecundity and offspring health has received minimal attention. Using a 2 ϫ 2 study design in rodents we established the relative contributions of paternal and maternal obesity on fetal and embryo development and whether combined paternal and maternal obesity had an additive effect. Here, we show that parental obesity reduces fetal and placental weights without altering pregnancy establishment and is not dependent on an in utero exposure to a high-fat diet. Interestingly combined parental obesity seemed to accumulate both the negative influences of paternal and maternal obesity had alone on embryo and fetal health rather than an amplification, manifested as reduced embryo developmental competency, reduced blastocyst cell numbers, impaired mitochondrial function, and alterations to active and repressive embryonic chromatin marks, resulting in aberrant placental gene expression and reduced fetal liver mtDNA copy numbers. Further understanding both the maternal cytoplasmic and paternal genetic interactions during this early developmental time frame will be vital for understanding how developmental programming is regulated and for the proposition of interventions to mitigate their effects. blastocyst; oocyte; sperm; embryo; fertility; infertility; obesity THE PREVALENCE OF OVERWEIGHT and obesity in reproductive-age adults is increasing worldwide (62). For example, in America it is estimated that 70.9% of males and 61.9% of women are classified as overweight/obese (62). The comorbidities associated with obesity have been well defined; however, until recently the impact on pregnancy and fetal development has been less recognized. Although the effects of either paternal or maternal obesity on gamete health and subsequent fertility and pregnancy have been reported independently, the combination of having both parents overweight/obese on fecundity and offspring health has received minimal attention. This information is essential, as the percentage of couples of reproductive age with both partners overweight/ obese is increasing and is the predominant situation in many countries (62).To date, there have only been three studies that have assessed the combined effects of maternal and paternal obesity on pregnancy and fetal health, two in human-assisted reproductive technology (ART) cohorts and one using a rodent high-fat diet model (41,67,76). These studies found no effect of maternal and paternal obesity on pregnancy establishment (41, 67, 76); however, when ...