| Summary: | Animal experiments demonstrate ways in which an exposure in one generation can be reflected in a variety of outcomes in later generations. In parallel human observational studies have shown associations between grandparental and parental exposures to cigarette smoking and/or nutrition and growth and survival of the grandchild. These studies have controlled for just a few confounders selected ad hoc. Here we use an exposome approach (using all available measures of exposure) to determine trans/inter-generational factors that may be important in studying environmental factors associated with fat mass in young human adults. The study takes advantage of the rich data available in the Avon Longitudinal Study of Parents and Children (ALSPAC). We test associations with features of grandparents (G0) and the childhood of the parents (G1) of 24-year olds (G2). We hypothesized that intergenerational associations would be revealed, particularly with exposure to cigarette smoke, and that these would vary with the sexes of all three generations. The study exposome analyzed 172 exposures to the maternal line and 182 to the paternal line. A series of stepwise regression analyses reduced the initial 40 unadjusted factors (P < 0.05) to eight independent features on the maternal line, and of 26 on the paternal line to five. We found strong associations between the father starting to smoke cigarettes regularly before age 11 and increased fat mass in his adult children (unadjusted = +7.82 [95% CI +2.75, +12.90] Kg; adjusted = +11.22 [+5.23, +17.22] Kg); this association was stronger in male offspring. In addition, when the paternal grandmother had smoked in pregnancy her adult granddaughters, but not grandsons had elevated mean fat mass (interaction with sex after adjustment, P = 0.001). The exposome technique identified other factors that were independently associated with fat mass in young adults. These may be useful in identifying appropriate confounders in other more proximal analyses, but also may identify features that may be on epigenetic pathways leading to increased fat mass in subsequent generations. We acknowledge that the results need to be replicated in other cohorts and encourage further linkage of outcomes with previous generational exposures, particularly along the paternal line.
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