Grandma's Behavior While Pregnant
Affects Her Grandkids' Health
May 13, 2005; Page B1
Although life offers no guarantees, parents-to-be can increase their chances of
having a healthy baby by, among other things, undergoing prenatal testing and
making sure mom has a healthy pregnancy. But almost 2,500 years after Euripides
noticed that "the gods visit the sins of the fathers upon the children,"
scientists are discovering that nature can be even crueler than the ancient
Greek imagined: It can visit the sins of the grandparents on the children.
Such "transgenerational" effects are the latest focus of a growing field called
fetal programming, or the fetal origins of adult diseases. It examines how
conditions in the womb shape physiology in a way that makes people more
vulnerable decades later to cardiovascular disease, diabetes, immune problems
and other illnesses usually blamed on genetics or lifestyle, not on what arrived
via the placenta. If a fetus is poorly nourished, for instance, it can develop a
"thrifty phenotype" that makes it really good at getting the most out of every
meal. After birth, that lets it thrive if food is scarce, but it's a recipe for
Type 2 diabetes in a world of doughnuts and fries. Poor fetal nutrition can lead
to hypertension, too: If it causes the fetus to produce too few kidney cells,
the adult that the fetus will become won't be able to regulate blood pressure
well.
Now, in a finding that seems to put our fate even further outside our control,
researchers are seeing generation-skipping effects.
Last month, scientists reported that a child whose grandmother smoked while
pregnant with the child's mother may have twice the risk of developing asthma as
a child whose grandma didn't flood her fetus with carcinogens. Remarkably, the
risk from grandma's smoking was as great as or greater than from mom's. Kids
whose mothers smoked while pregnant were 1.5 times as likely to develop
childhood asthma as children of nonsmoking moms. Kids whose grandmothers smoked
while pregnant with mom were 2.1 times as likely to develop asthma, scientists
reported in the journal Chest.
The harmful effects of tobacco, it seems, can reach down two generations even
when the intervening generation -- mom -- has no reason to suspect her child may
be at risk.
"Even if the mother didn't smoke, there was an effect on the grandchild," says
Frank Gilliland of the University of Southern California, Los Angeles, who led
the study of 908 children. "If smoking has this transgenerational effect, it's a
lot worse than we realized."
What causes the grandma effect? One suspect is DNA in the fetus's eggs (all the
eggs a girl will ever have are made before birth). Chemicals in smoke might
change the on-off pattern of genes in eggs, including genes of the immune
system, affecting children who develop from those eggs. Men whose mothers smoked
don't seem to pass on such abnormalities, probably because sperm are made after
birth.
Animal data hint at other grandma effects. Last week, scientists reported the
first discovery that obesity and insulin resistance, as in Type 2 diabetes, can
be visited on the grandkids of female rats that ate a protein-poor diet during
pregnancy, lactation or both. Again, this occurred even when those rats'
offspring, the mothers of the affected grandkids, were healthy, Elena Zambrano
of the Institute of Medical Sciences and Nutrition, Mexico City, and colleagues
report in the Journal of Physiology.
The findings, says Peter Nathanielsz of the University of Texas Health Sciences
Center, San Antonio, "stretch the unwanted consequences of poor nutrition across
generations."
In people, the type of "nutritional insult" to the fetus doesn't seem to matter.
Too few calories, too little protein, too few other nutrients can all lead to
diabetes, hypertension and other ills decades later. "That suggests that what
links diet to adult diseases is something quite fundamental," says Simon
Langley-Evans of the University of Nottingham, England. The key suspects:
changes in DNA activity in the fetus or in the balance of hormones reaching it
via the placenta.
Alarmingly, the list of what can be passed along to the next generation is
growing. If you are undernourished as a first-trimester fetus, you won't pad
your hips and thighs with enough fat tissue. If, as a child or adult, you take
in more calories than you expend, the extras get stored in and around abdominal
organs rather than on the thighs and hips, says Aryeh Stein of Emory University,
Atlanta. One result is a body shaped like an apple (which brings a higher risk
of heart disease). Another is a higher risk of gestational diabetes, in which
blood glucose levels rise during pregnancy and too much glucose reaches the
fetus. Babies born to moms with gestational diabetes have a higher risk of Type
2 diabetes.
When undernourished fetuses grow into adolescents, they don't respond as well to
vaccines as babies who had a healthy gestation, scientists led by Thomas McCune
of Northwestern University, Evanston, Ill., find. One reason may be that the
third trimester is a critical time for development of the thymus, which produces
the immune system's T cells. When immune-compromised girls become pregnant, they
have less chance of having a healthy pregnancy and a healthy baby. Score another
for the grandma effect.
• You can e-mail me at
sciencejournal@wsj.com.
Dad's Hidden Influence
A father's legacy to a child's health may start before conception and last
generations
Tina Hesman Saey
http://www.sciencenews.org/articles/20080329/bob9.asp>http://www.sciencenews.org/articles/20080329/bob9.asp
Pregnant women know the drill. Don't drink. Don't smoke. Don't eat too much
fish. Take vitamins. Mothers have long shouldered the responsibility, and the
blame, for their children's health. Fathers don't usually face the same
scrutiny. How a man lives, where he works, or how old he is when his children
are conceived doesn't affect
their long-term health, scientists used to think. But growing evidence suggests
that a father's age and his exposure to chemicals can leave a medical legacy
that lasts generations. Animal studies demonstrate that drugs, alcohol,
radiation, pesticides, solvents, and other chemicals can lead to effects that
are handed from father to son. Human studies are less clear, but some show that
fathers play a role in fetal development and the health of their children.
Teenage dads face increased risk that their babies will be born prematurely,
have low birth weight, or die at birth or shortly afterward, a new study in
Human Reproduction shows. Babies of firefighters, painters, woodworkers,
janitors, and men exposed to solvents and other chemicals in the workplace are
more likely to be
miscarried, stillborn, or to develop cancer later in life, according to a review
in the February Basic & Clinical Pharmacology & Toxicology. Fathers who smoke or
are exposed at work to chemicals called polycyclic aromatic hydrocarbons put
their children at risk of developing brain tumors. And, older fathers are more
likely to have children with autism, schizophrenia, and Down syndrome and to
have daughters who go on to develop breast cancer.
Though some of these observations are decades old, attitudes lag even further
behind, says Cynthia Daniels, a political scientist at Rutgers University–New
Brunswick in New Jersey. Dads aren't held accountable if something goes wrong
during fetal development.
Matter of math
Since men make new sperm every 74 days, people used to reason, the genetic slate
is wiped clean every couple of months. And even if a man makes defective sperm,
the "all-or-nothing" view of reproduction holds that damaged sperm don't
fertilize eggs. No harm. No foul. So no one bothers to remind men to protect
themselves against environmental toxins. There are no images of "crack dads" and
"crack babies" in the media like those of women who harm developing fetuses with
drug and alcohol use, Daniels said in February at a meeting of the American
Association for the Advancement of Science held in Boston. When someone does
study fathers-to-be, the focus is usually on fertility, not on the consequences
for children's health, she says.
Yet even fertility messages meet resistance from many men. Harry Fisch, director
of the Male Reproductive Center and a urologist at Columbia University Medical
Center, found that out when he suggested that men, like women, have ticking
biological clocks. Men can produce sperm throughout life, but that doesn't
mean their cells are forever young. "Every cell in the body ages," says Fisch.
"Every cell. The older you get, the more chance of an abnormality. The same
thing goes for sperm."
Men younger than 20 and older than 30 make more abnormal sperm than men in their
20s. These damaged sperm could create an unhealthy embryo or pass on damage that
could lead to birth defects or illness in offspring.
It is not a popular message.
"Men do not want to hear this," Fisch says. "When my book came out, I got
e-mails. I got faxes saying, 'How dare you say this? How can you say this? We
know that there are men in their 70s having healthy children.'" Despite these
anecdotal accounts of elderly dads, studies demonstrate that older men are at
increased risk of passing on genetic abnormalities. It's a matter of math. Women
are born with all the eggs they will produce in their lifetime. The cells that
give rise to eggs divide 24 times, all before birth. But the cells that
produce sperm continue to divide throughout a man's lifetime. Each year after
puberty, a man's sperm-producing cells replicate about 23 times. Every time the
cells divide is another chance for error. As a result, the sperm produced by a
40-year-old man have gone through about 610 rounds of replication. That's 610
chances of introducing a mutation in the DNA, or improperly divvying up genetic
material.
Parents over age 40 are six times more likely to have children with Down
syndrome than 25-year-old parents, Fisch and colleagues showed in a 2003 study
in the Journal of Urology. An extra copy of chromosome 21 causes Down syndrome.
This extra chromosome is just as likely to come from dad as mom in the older
couples.
Older dads also have a higher risk of fathering children with rare mutations
that cause dwarfism or a premature aging disease called Hutchinson-Gilford
progeria syndrome. But sometimes aging fathers pass along traits that can't be
traced to only a single mutation. Fathers 40 and older have an increased chance
that their children will develop complex disorders such as autism or
schizophrenia. There is growing evidence that those disorders are caused by
defects in many genes and the way genes are turned off and on. Scientists don't
yet understand the changes that age induces in sperm-making germ cells, and
environmental exposure presents an even bigger mystery. People come in contact
with a plethora of chemicals every day. But it is no easy task to sort out
exactly which ones, or which combinations, cause heritable problems. The effects
chemicals and radiation may have on offspring don't always follow predictable
patterns either.
And when researchers do find a clear link between a father's lifestyle and his
children's health, it's not always clear what the data mean. "What we can say is
that we identified a group of fathers with adverse outcomes for their fetuses,
but we don't have an idea of the mechanism," says Shi Wu Wen of the University
of Ottawa in Canada and one of the lead authors of the study showing that babies
of teenage fathers have a greater risk of birth problems. Wen and his colleagues
examined birth records for more than 2.6 million babies born between 1995 and
2000 to married, first-time, 20-something mothers in the United States. Looking
at the husbands' ages, the team found that babies of teenage fathers, but not
middle-age men, had an elevated risk of still birth, low birth weight, and other
birth problems.
The study was
<http://dx.doi.org/10.1093/humrep/dem403>published
online Feb. 6 in <http://dx.doi.org/10.1093/humrep/dem403>Human Reproduction.
'Preposterous' inheritance
Some animal studies showing paternal effects emerged years ago but were
roundly dismissed, says Gladys Friedler, professor emeritus at Boston
University.
a9437_233.jpg
OLDER AGE, HIGHER RISK. As men age, they stand a greater chance of fathering
children who will develop schizophrenia by age 34. Paternal age is only one of
many factors linked to schizophrenia. E. Roell, (Source: D. Malaspina, et al.,
Arch. of Gen. Psychiatry, 2001)
Four decades ago, Friedler was studying tolerance to narcotics, one of the first
steps of addiction. To find out if a mother rat could pass tolerance on to her
offspring along with antibodies and other immune factors, as some scientists
theorized, Friedler exposed female rats to morphine before pregnancy. Babies of
exposed mothers were born much smaller than average. And those babies also went
on to give birth to tiny babies, even though the offspring had never encountered
the drug. Friedler also gave male rats morphine before they bred. "To my total
disbelief and bewilderment, paternal exposure also affected progeny," Friedler
said at the AAAS meeting.
Her adviser dismissed the result. Morphine doesn't cause mutations, so the idea
that males could hand down a trait without passing along a mutation seemed
preposterous. The whole thing smacked of Lamarckism, the long-rejected idea that
environmental influences can change an animal or plant's structure and offspring
can inherit that change. But in recent decades, scientists have discovered that
chemical modifications to DNA and proteins can change the way genes are packaged
and regulated without changing the genes themselves. Such modifications are
known as epigenetic changes. "What was Lamarckian is now epigenetic," Friedler
says. Epigenetic modifications act as a molecular scrapbook, preserving memories
of events in parents' lives and handing them down to the next generation and
beyond.
"There's a chromosomal memory," says Anne Ferguson-Smith, a developmental
geneticist at Cambridge University in England. "The chromosomes remember whether
they came from the mother or the father." That memory is established in the form
of a chemical mark called methylation. Methylation usually turns a gene off. At
least 100 genes in humans are turned off only on the chromosome contributed by
the mother or only on the chromosome that came from the father. Such genes
are called imprinted genes because of the indelible impression parents leave on
their offspring's DNA. Several imprinted genes help build the placenta or encode
growth factors that need to be tightly controlled so an embryo will develop
correctly. "There's a contribution from both parents that is essential,"
Ferguson-Smith says. "One can't do without the other. They must work together to
have a healthy offspring."
Imprints and other methylation marks are not encoded in the DNA. Instead the
epigenetic modifications decorate chromosomes like ornaments on a Christmas
tree. But these ornaments are heirlooms of a different type. It's as if a
seedling grows straight from the ground already gussied up with tinsel and
lights in the same places its parents were decorated. If a chemical or aging
alters the epigenetic pattern on a man's chromosomes, his heirs could bequeath
mismarked DNA to their children, too. Some mistakes may be as benign as
exchanging a red bulb for a blue one. Other alterations, akin to placing the
star on the lowest branch instead of the treetop, are likely to have more
profound consequences. Male mice exposed to cocaine, for example, pass memory
problems on to their pups, a 2006 study in Neurotoxicology and Teratology shows.
The male mice inhaled cocaine in long daily sessions akin to crack binges. When
they mated with females never given coke, they had pups that had trouble
learning and remembering where to find food in simple mazes. The problem was
especially severe for female offspring. The researchers couldn't find any
obvious DNA damage in coke-smoking males' sperm, but did find altered levels of
two enzymes involved in the methylation of DNA in sperm-producing tissue in the
father mice. The result suggests that epigenetic changes may be responsible for
the offspring's behavior problems.
Fungicide legacy
Matthew Anway doesn't know whether the rats in his lab at the University
of Idaho in Moscow have methylation problems. Some studies suggest they do, but
Anway doesn't yet have definitive proof. He can prove that male rats exposed to
a fungicide in the womb can pass tumors and diseases of the prostate and kidney
down for at least three generations. The rats could provide the first model for
how prostate disease is inherited, he says. Male babies born to mothers that had
been injected with fungicide had prostate problems that mimic those seen during
human aging. The second-generation rats also had more tumors, kidney defects,
and higher rates of abscesses, cysts, and other infections than unexposed
control rats. Germ cells in the testes of exposed rats also died more quickly
than those in the control rats.
Subsequent generations of male rats also had the prostate and testes defects,
and both male and female offspring developed kidney problems and tumors. But
only male rats could pass along the defects. The exposed rats bequeathed their
fungicide legacy to their sons, grandsons, and great-grandsons even though none
of the later generations were exposed to the chemical.
Exposed animals decrease production of enzymes that methylate DNA, Anway
says. But he hasn't yet found consistent changes in the methylation patterns in
exposed rats. It's not clear whether Anway's results have any implication for
human health. The rats were exposed to extremely high doses of fungicide through
the completely unnatural route of injection. What's important is that the male
shares experiences with descendants for years to come. Further research could
give new insights, Anway says, into how alterations in early development could
lead to adult disease in humans.
----------
References:
Anway, M.D., et al. 2005. Epigenetic transgenerational actions of endocrine
disruptors and male fertility. Science 308(June 3):1466-1469.
Anway, M.D., S.S. Rekow, and M.K. Skinner. 2008.Transgenerational epigenetic
programming of the embryonic testis transcriptome. Genomics 91(January):30-40.
Anway, M.D., and M.K. Skinner. 2008. Transgenerational effects of the endocrine
disruptor vinclozolin on the prostate transcriptome and adult onset disease. The
Prostate 68(April 1):517-529.
Chen, X.K., S.W. Wen, et al. In press. Paternal age and adverse birth outcomes:
Teenager or 40+, who is at risk? Human Reproduction.Available at
<http://dx.doi.org/10.1093/humrep/dem403>http://dx.doi.org/10.1093/humrep/dem403.
Choi, J.-Y., et al. 2005. Association of paternal age at birth and the risk of
breast cancer in offspring: A case control study. BMC Cancer 5(Oct. 31):143.
Cordier, S. 2008. Evidence for a role of paternal exposures in developmental
toxicity. Basic & Clinical Pharmacology & Toxicology 102(February):176-181.
Cordier, S., et al. 2004. Parental exposure to polycyclic aromatic hydrocarbons
and the risk of childhood brain tumors. American Journal of Epidemiology
159(June 15):1109-1116.
Croen, L.A., et al. 2007. Maternal and paternal age and risk of autism spectrum
disorders. Archives of Pediatric and Adolescent Medicine 161(April):334-340.
El-Saadi, O., et al. 2004. Paternal and maternal age as risk factors for
psychosis: Findings from Denmark, Sweden and Australia. Schizophrenia Research
67(April 1):227-236.
Fisch, H., et al. 2003. The influence of paternal age on Down syndrome. Journal
of Urology 169(June):2275–2278.He, F., I.A. Lidow, and M.S. Lidow. 2006.
Consequences of paternal cocaine exposure in mice. Neurotoxicology and
Teratology 28(Feb. 3):198–209.
Lewis, B.H., M. Legato, and H. Fisch. 2006. Medical implications of the male
biological clock. Journal of the American Medical Association 296(Nov.
15):2369-2371.
Thacker, P.D. 2004. Biological clock ticks for men, too. Journal of the American
Medical Association 291(April 14):1683-1685.
Further Readings:
Skinner, M.K. 2008. What is an epigenetic transgenerational phenotype? F3 or F2.
Reproductive Toxicology 25(January):2–6.
Frequently asked questions from the Epigenome Network of Excellence can be found
at
<http://www.epigenome-noe.net/consulting/webconsulting.php>http://www.epigenome-noe.net/consulting/webconsulting.php.
Sources:
Matthew Anway
University of Idaho
Department of Biological Sciences
Gibb Hall 239
P.O. Box 443051
Moscow, ID 83844-3051
Sylvaine Cordier
INSERM U625,
GERHM, IFR140,
University of Rennes I,
Campus de Beaulieu
Rennes cedex F-35042
France
Cynthia Daniels
Department of Political Science
Rutgers, the State University of New Jersey
Hickman Hall
89 George Street
Douglass College
New Brunswick, NJ 08901
Anne C. Ferguson-Smith
Department of Physiology, Development and Neuroscience
University of Cambridge
Physiology Building, G-floor Downing Street
Cambridge CB2 3EG
United Kingdom
Harry Fisch
Columbia University
College of Physicians and Surgeons
Department of Urology
944 Park Avenue
New York, NY 10028
Gladys Friedler
4 Newport Road #4
Cambridge, MA 02140
Shi Wu Wen
OMNI Research Group
Department of Obstetrics and Gynecology
University of Ottowa
501 Smyth Road, Box 241
Ottowa, Ontario K1H 8L6
Canada
>From Science News, Vol. 173, No. 13, March 29, 2008, p. 200.
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