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Genome Science reveals how one generation’s experience can affect the next


Genome Science reveals how one generation’s experience can affect the next

Today, a number of studies document a link between ancestral environmental conditions and changes in offspring behavior or metabolism, potentially validating some of the thinking of both seminal evolutionary theorists on this topic. It is now becoming clear that the environments of both the mother and the father can influence offspring phenotype.

Mama knows best
One of the earliest connections between environmental conditions affecting human parents and disease rates in their offspring was made in the late 1980s by British epidemiologist David Barker, who noticed that babies with low birth weights were significantly more likely to suffer from diabetes and coronary heart disease later in life.4 He proposed what is now known as the “thrifty phenotype” hypothesis: in response to inadequate nutrition during fetal growth, a person will exhibit a long-lasting physiological response of aggressively storing calories. This thrifty phenotype then wreaks havoc when and if times of plenty return, leading to obesity and other diseases related to caloric excess.

It is now becoming clear that the environments of both the mother and the father can influence offspring phenotype.

The general concept of the thrifty phenotype is supported by studies in multiple human populations, the most famous being the Dutch survivors of the “Hunger Winter” of World War II. In response to a strike by railway workers meant to aid the Allied forces, the Nazis occupying the Netherlands imposed an embargo on food shipments to the western part of the country. The result was a reduction in government rations to roughly 700 calories per day per person, and a severe famine that lasted from October 1944 until early 1945. Many people resorted to measures such as eating tulip bulbs to survive, and at least 18,000 people died of malnutrition. Children of pregnant women exposed to this famine are more susceptible to obesity, diabetes, cardiovascular disease, and even schizophrenia than are people who were born just before or conceived after the famine.5

These human studies have been supplemented by hundreds of experimental investigations using a variety of mammalian models. In such studies, pregnant female animals are either subjected to a significant caloric restriction or are surgically treated to restrict the main blood supply to the uterus. In both scenarios fetal growth is inhibited as a consequence of poor access to nutrients. As seen in human cohorts, rodents and other animals subjected to in utero growth restriction exhibit a multitude of changes in metabolism, including poor insulin release and insulin resistance—two factors relevant to type 2 diabetes in humans. Importantly, even though animals starved during gestation are then provided with sufficient access to food for the remainder of their lives, the early conditions somehow establish lifelong metabolic changes. A large field is dedicated to understanding how animals “remember” conditions present transiently early in their lives.

But the fact that environmental conditions affecting a mother can influence the phenotype of her offspring is not in itself greatly surprising, as the womb is a baby’s first environment. Mothers who drink heavily during pregnancy are exposing their babies to a toxin and may give birth to children with fetal alcohol syndrome. Much more curious than maternal effects on children are cases where the lifestyle or history of the father has been implicated in disease risk of his children.

Daddy issues

To determine whether a father’s experiences are passed down to his offspring via his sperm or some other mechanism, researchers can breed mice via in vitro fertilization (IVF), which uses purified sperm to fertilize an egg. If the effect is still apparent, this points to an epigenetic mechanism within the sperm itself. If the effect disappears, this suggests that the relevant information may be located outside of the sperm, such as in the seminal fluid.

Male mice exposed to different odorants paired with foot shocks sire offspring with greater sensitivity to those odorants. Odor sensitivity is affected in offspring generated via IVF, and the effect is transmitted to those mice’s offspring as wellsubjected to social defeat spend less time in exposed areas and exhibit other anxiety-related behaviors. When the sperm of these socially defeated fathers is used to sire offspring via IVF technology, however, the offspring are normal.

Offspring of male mice subjected to social defeat spend less time in exposed areas and exhibit other anxiety-related behaviors. When the sperm of these socially defeated fathers is used to sire offspring via IVF technology, however, the offspring are normal.

But we now know that sperm carry epigenetic information in addition to their haploid genomic payload. Moreover, during mating, a male provides his partner with a bolus of seminal fluid, which carries proteins and other molecules that might have signaling roles. Fathers may also contribute microbes to their partner and offspring by direct contact or in feces. There is even evidence that in some species a mother’s investment in offspring is modulated by her judgment of the prospective father’s adequacy, so the impression a male makes on his mate has the potential to alter his offspring’s future. Given these contributions, we and others have used lab models to ask how paternal exposure history may influence offspring behavior, metabolism, or disease risk.6

Already, a large number of studies in rodents have shown that altering a father’s diet can influence a number of metabolic traits in his offspring. The typical experimental paradigm used for such studies involved separating male siblings from one another and providing one brother a control diet and the other an altered diet, low in protein or with excess fat. At sexual maturity, each brother was mated with a female who had been fed a control diet. Researchers then examined the offspring for various phenotypes, most commonly, metabolic features or behavioral traits such as anxiety-related activities. In multiple studies of this sort, paternal diet was shown to affect glucose control, cholesterol metabolism, blood pressure, and other cardiovascular measures in offspring. In addition to studies focused on paternal diet, several studies have shown that males subjected to undernutrition in utero—the male offspring of mothers subjected to starvation during pregnancy—can sire offspring with altered glucose and lipid metabolism.7 These rodent studies are complemented by research in other mammals such as pigs, as well as by human epidemiological studies. This body of work suggests a link between access to food and metabolic phenotypes in one’s offspring, and possibly in future generations as well.

But its father’s diet is not the only environmental factor that can affect the biology of a rodent: stress experienced by fathers can also negatively impact future offspring. A number of studies from Tracy Bale’s lab at the University of Pennsylvania have shown that prospective mouse fathers subjected to stressful environments, such as separation from their mothers at a young age, have offspring that exhibit altered cortisol release in response to stress.8 Similarly, Mount Sinai neurobiologist Eric Nestler and his colleagues have shown that male mice subjected to social defeat sire offspring with altered anxiety- and depression-related behaviors, such as decreased time spent in exposed areas.9

Studies of stress, diet, and additional environmental stimuli such as toxin exposure all strongly support the idea that a father’s environment can influence the phenotype of his offspring. How exactly is this information transferred across the generations? In principle, huge amounts of information could be transmitted to offspring in sperm, as millions of genomic cytosines can each potentially transmit a “bit” of information in the form of an attached methyl group. Researchers have recently discovered that the vast majority of cytosine methylation on the paternal genome is erased at fertilization, but proteins and RNAs in the seminal fluid or in the sperm may also carry information, as could sperm chromatin packaging. How much detail about a father’s lifestyle sperm really passes on to his offspring remains unclear, however.

One recent study provides support for the “high bandwidth” hypothesis, in which a very detailed account of a father’s experiences is transmitted in his sperm, as opposed to a more general quality-of-life summary. Neurobiologists Brian Dias and Kerry Ressler of Emory University exposed male mice to different odorants while stressing them with foot shocks, conditioning the mice to startle when they merely smelled the shock-associated odor. Offspring of these mice showed greater sensitivity to just the specific odorant that had been paired with the foot shock for their fathers. Smell is mediated by binding of odorants to a large family of olfactory receptors. Dias and Ressler found that the offspring of the fear-conditioned males had more neurons expressing the olfactory receptor specific for the shock-paired odor.10 This finding raises the exciting and surprising possibility that sperm can transmit thousands of bits of information to offspring. If odorants can induce specific responses in offspring, why not other factors such as hormones, and so forth? It will be very exciting to see whether other labs have similar results with effects on offspring of paternal exposure to odorants and other small molecules.

Although epigenetic marks on sperm DNA seem the likeliest carrier of paternal information, fathers transmit much more to mothers and children than sperm. One way to experimentally probe the question of how a father transmits information to his offspring is to breed rodents using assisted reproductive technologies, such as artificial insemination or in vitro fertilization (IVF), that use purified sperm to fertilize ova. In the case of Nestler’s social-defeat paradigm, IVF experiments using sperm from control or defeated male mice did not reproduce the effect in offspring, indicating either that the relevant paternal information is located outside of sperm (perhaps in the seminal fluid), or that the disruptive process of IVF and embryo culture might somehow prevent accurate transmission of sperm information to progeny. In contrast, in Diaz and Ressler’s study pairing odorants with foot shocks, odor sensitivity was also affected in offspring generated via IVF using sperm from exposed versus unexposed male mice.


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