Disentangling prenatal and inherited influences in humans with an experimental design

Abstract

Exposure to adversity in utero at a sensitive period of development can bring about physiological, structural, and metabolic changes in the fetus that affect later development and behavior. However, the link between prenatal environment and offspring outcomes could also arise and confound because of the relation between maternal and offspring genomes. As human studies cannot randomly assign offspring to prenatal conditions, it is difficult to test whether in utero events have true causal effects on offspring outcomes. We used an unusual approach to overcome this difficulty whereby pregnant mothers are either biologically unrelated or related to their child as a result of in vitro fertilization (IVF). In this sample, prenatal smoking reduces offspring birth weight in both unrelated and related offspring, consistent with effects arising through prenatal mechanisms independent of the relation between the maternal and offspring genomes. In contrast, the association between prenatal smoking and offspring antisocial behavior depended on inherited factors because association was only present in related mothers and offspring. The results demonstrate that this unusual prenatal cross-fostering design is feasible and informative for disentangling inherited and prenatal effects on human health and behavior. Disentangling these different effects is invaluable for pinpointing markers of prenatal adversity that have a causal effect on offspring outcomes. The origins of behavior and many common complex disorders may begin in early life, therefore this experimental design could pave the way for identifying prenatal factors that affect behavior in future generations.child ͉ psychopathology ͉ genetic ͉ antisocial behavior ͉ birth weight

Maternal Pre-Pregnancy Body Mass Index and Internalizing and Externalizing Problems in Offspring

“…Further control of genetic or familial risk could be provided by the use of within-family studies comparing siblings born to the same woman (particularly before and after significant weight loss), by Mendelian randomization, 57 and (or) the examination of the offspring of women who conceived using certain assisted reproductive technologies. 58 While such observational data will be helpful in further establishing this link, a clear demonstration of causal effects requires the use of experimental approaches. While it is challenging to effect lasting weight loss, experimental studies done in humans and aimed at examining strategies to reduce pre-pregnancy obesity could potentially be used to assess the cognitive, emotional, and behavioural outcomes of the offspring of these gestations and compare them to control groups.…”

Prenatal Smoking Exposure and the Risk of Behavioral Problems and Substance Use in Adolescence: the TRAILS Study

“…Roza et al [40] demonstrated that the relationship between MSP and child behavior problems was fully accounted for by family socioeconomic status and parental psychopathology. Convincing evidence for the role of inheritable pathways was reported by Rice et al [41] , comparing the association between MSP and antisocial behavior in the offspring of mothers who were either biologically related or unrelated to their child as a result of in vitro fertilization. The authors concluded that the relationship was entirely explained by inherited pathways, as the offspring of mothers who smoked during pregnancy and were biologically related to their child were at higher risk for conduct problems, while such an effect was not found in the offspring of mothers who smoked during pregnancy but were biologically unrelated to their child [41] .…”

“…Convincing evidence for the role of inheritable pathways was reported by Rice et al [41] , comparing the association between MSP and antisocial behavior in the offspring of mothers who were either biologically related or unrelated to their child as a result of in vitro fertilization. The authors concluded that the relationship was entirely explained by inherited pathways, as the offspring of mothers who smoked during pregnancy and were biologically related to their child were at higher risk for conduct problems, while such an effect was not found in the offspring of mothers who smoked during pregnancy but were biologically unrelated to their child [41] . Based on a longitudinal twin study, it was concluded that around half of the observed association between MSP and young children's conduct problems was attributable to correlated genetic effects [42] .…”

Em busca das origens desenvolvimentais dos transtornos mentais

“…Um estudo recentemente publicado exemplifi ca a necessidade de compreendermos o mecanismo através do qual um fator supostamente ambiental atua 23 . Existe uma longa e ainda não resolvida discussão na literatura em relação ao mecanismo através do qual a exposição intraútero ao tabaco levaria à psicopatologia nas crianças.…”

“…Há evidências que apontam que tal mecanismo se daria através de ação sobre o ambiente intraútero, enquanto outros estudos indicam que fumar durante a gestação é um marcador de psicopatologia materna associada a fatores genéticos que, por sua vez, são herdados pelas crianças, levando então à psicopatologia 24 . Rice et al 23 23 . O peso de nascimento foi menor no grupo de crianças expostas ao tabaco intraútero, independentemente de serem geneticamente relacionadas ou não às suas mães.…”