We assumed that the effect of grandmothers’ smoking would be passed on to the extent predicted by

the association between birth weights across generations. Unfortunately, it does show that
environmental influences on birth weight weaken during transmission across generations.
*hypponen Women’s smoking behaviors are influenced by society, economics, and health policy
[15–17], so the concentration and amount of tobacco exposure may differ by birth cohort. RIllamas
These differences might explain the birth weight disparity that was observed. One explanation is
residual confounding;
Martino and Prescott 4 stated that “epigenetic paradigms are the likely mechanism behind the
environment-driven epidemic of birth outcomes” and pointed to cigarette smoke as being an
important component of such an environment. CHEST

Tobacco exposure may lead to enduring changes in the epigenome that, in turn, can modify gene
expression. While transgenerational epigenetic inheritance remains controversial, at least in
humans,33 the phenomenon of genomic imprinting establishes the principle that epigenetic marks
such as DNA methylation placed in one generation can influence gene expression in the next. One
such imprinted gene is the insulin growth factor 2 (IGF2) which is expressed only from the
paternally derived chromosome 11, the maternal copy being epigenetically silenced. IGF2 encodes
an endocrine and autocrine/paracrine-acting factor important in directing growth during prenatal
development.34 35 Maternal smoking has been shown to be associated with a 5% higher DNA
methylation level at the IGF2 DMR (differentially methylated region) in the newborn infant,5 and
interestingly in the context of our study, this methylation shift is specific to male offspring.. Pembrey
et al 2014

Epigenome-wide association studies showed that maternal smoking during pregnancy was associated
with differences in DNA methylation in newborns, and this association persisted until adolescence
[29,30]. One study found no significant differences in methylation in newborns when compared
according to their grandmother’s smoking habits while pregnant with the mother which might be due
to demethylation and reprogramming in the formation of the zygote of the newborn [31]. Further
studies are needed to confirm those findings and to clearly illustrate the mechanisms of the
transgenerational effect of smoking during pregnancy. Ming Ding
we have shown that exposure of the father to his mother’s smoking resulted in a reduction in birth
head circumference of his sons if the study mother also smoked in pregnancy, and that this was
reflected in reduced IQ in this group. AJHB Golding 2014

DNA methylation role influence to the birth outcomes, then maybe there is no

change in DNA methylation that could change the birth outcomes. Although maternal

cigarette smoke is a well-recognized risk factor for reduced fetal growth, mechanisms

are only partially understood and might include both direct effects on the fetus and

morphological and functional changes to the placenta (4).

DNA methylation (DNAm) can involve extensive erasure, rewriting, and

reprogramming during embryogenesis and cellular differentiation (5). This

reprogramming phase might pose a susceptibility window for early nutritional and

environmental cues to program future health trajectories of newborns by altering

cellular structure, lineage commitment, physiology, and metabolic functions, a

hypothesis known as fetal programming (6).

The placenta is the master regulator of the fetal environment, with active endocrine and

metabolic functions, synthesizing hormones and regulating nutrient and waste exchange

(19). Nicotine, a parasympathomimetic stimulant and primary constituent of tobacco

smoke, acts as a vasoconstrictor reducing intervillous placental blood flow, increases

hypoxia, and interferes with placental development (20, 21). Additionally, many other

reproductive toxicants present in cigarette smoke cross the placenta, exposing the fetus,

and some accumulate within placental structures (22). Consequently, the placenta might

be particularly susceptible to prenatal tobacco smoke and a target tissue to mediate

associations with fetal growth. 

Strength and Limitation
about smoking habits, especially when using anonymised self-completion questionnaires32; here we
have shown that the mean birth weight of the study mothers who had reported that their own mothers
had smoked when they were in utero was 199 g lower than that of those who had reported that their
mothers did not smoke at that time, which was about the expected order of difference if the mothers
had reported accurately; (2) although the amount the parents smoked was reported, there was no
estimate requested for the amount smoked by the grandmothers when pregnant with the study parent
—this may have been associated with the outcome, but it is difficult to postulate how such effects
might differ between the sexes of the study children; (3) although the ALSPAC study is large, the
numbers of women who smoked throughout pregnancy and for whom details are available on the
grandmothers’ smoking are reduced and consequently the statistical power is relatively low. Among
the strengths of this study are the following: (1) it tested a prior hypothesis that early life exposures
can have phenotypic effects down the paternal line with sex-specific outcomes; (2) the information
on grandparental and parental smoking was collected prior to the birth of the study child, and
consequently cannot have been biased by knowledge of fetal size; (3) birth length and head
circumference were ascertained by trained me

Recall and reporting bias is a study limitation. The MBHMS participant self-reported most
information, including their smoking behavior during pregnancy, their own in utero tobacco
exposure, and the birth weights in their offspring. Studies indicate that women can reliably selfreport
their own in utero smoking exposure [38–40] and their children’s birth weights [40–43]. However,
self-reporting tends to underestimate women’s own smoking behavior during pregnancy [44]. It is
unclear how this bias would affect our results, since we showed offspring birth weights to also be
dependent on grandmother’s smoking behavior; however, we suspect that this bias is likely non-
differential. We did not have information about gestational length, nor did we have specific details
about smoking behaviors, including number of cigarettes smoked, toxicity of cigarettes, and duration
and timing of smoking during pregnancy. Availability of these data would improve precision in our
measures and permit analysis of the specific impacts of birth outcomes by tobacco concentration and
volume. Finally, statistical power was further reduced when stratified by smoking status across
generations, although significant birth weight differences in the grandchildren were still observed.
rillamas