Wednesday, December 30, 2009

Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model

Research Article

Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model

Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism, schizophrenia and early-onset bipolar disorder. In order to establish causality, this study used an animal model to investigate the effects of advanced paternal age on behavioural deficits in the offspring.

C57BL/6J offspring (n = 12 per group) were bred from fathers of two different ages, 2 months (young) and 10 months (old), and mothers aged 2 months (n = 6 breeding pairs per group). Social and exploratory behaviors were examined in the offspring.

The offspring of older fathers were found to engage in significantly less social (p = 0.02) and exploratory (p = 0.02) behaviors than the offspring of younger fathers. There were no significant differences in measures of motor activity.

Given the well-controlled nature of this study, this provides the strongest evidence for deleterious effects of advancing paternal age on social and exploratory behavior. De-novo chromosomal changes and/or inherited epigenetic changes are the most plausible explanatory factors.

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Author Contributions
Rebecca G. Smith1#, Rachel L. Kember1#, Jonathan Mill1, Cathy Fernandes2*, Leonard C. Schalkwyk1, Joseph D. Buxbaum3,4, Abraham Reichenberg1,3

1 Medical Research Council Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom, 2 Department of Psychological Medicine and Psychiatry, King's College London, London, United Kingdom, 3 Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America, 4 Laboratory of Molecular Neuropsychiatry, and the Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York, United States of America

Abstract Top
Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism, schizophrenia and early-onset bipolar disorder. In order to establish causality, this study used an animal model to investigate the effects of advanced paternal age on behavioural deficits in the offspring.

C57BL/6J offspring (n = 12 per group) were bred from fathers of two different ages, 2 months (young) and 10 months (old), and mothers aged 2 months (n = 6 breeding pairs per group). Social and exploratory behaviors were examined in the offspring.

Principal Findings
The offspring of older fathers were found to engage in significantly less social (p = 0.02) and exploratory (p = 0.02) behaviors than the offspring of younger fathers. There were no significant differences in measures of motor activity.

Given the well-controlled nature of this study, this provides the strongest evidence for deleterious effects of advancing paternal age on social and exploratory behavior. De-novo chromosomal changes and/or inherited epigenetic changes are the most plausible explanatory factors.

Citation: Smith RG, Kember RL, Mill J, Fernandes C, Schalkwyk LC, et al. (2009) Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model. PLoS ONE 4(12): e8456. doi:10.1371/journal.pone.0008456

Editor: Kenji Hashimoto, Chiba University Center for Forensic Mental Health, Japan

Received: October 28, 2009; Accepted: December 2, 2009; Published: December 30, 2009

Copyright: © 2009 Smith et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by the Beatrice and Samuel A. Seaver Foundation, by a British Medical Association Margaret Temple Award, and National Institute of Health Research (NIHR) Biomedical Research Centre (BRC) for Mental Health at the South London and Maudsley National Health Service (NHS) Foundation Trust and Institute of Psychiatry, King's College London (KCL) Pilot Award to Drs. Jonathan Mill and Abraham (Avi) Reichenberg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail:

# These authors contributed equally to this work.

Introduction Top
Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism [1], schizophrenia [2] and early-onset bipolar disorder [3]. Despite the methodological advantages of epidemiological research, a major limitation is that techniques are limited to observation. In order to establish causality, experimental evidence in the form of randomized-controlled trials or the development of animal models is required [4]. Animal models are particularly important as they allow environmental and genetic confounds to be controlled.

The lack of complete specificity in the association between advancing paternal age and psychiatric disorders may suggest that advancing paternal age is related to phenotypes shared across disorders. One phenotype in-common to schizophrenia, autism and bipolar disorder is abnormalities in social cognition broadly defined severe social deficit [5], [6], [7], [8]. A recent epidemiological study found an association between advancing paternal age and impaired social functioning in male offspring in the general population [9].

In this study we examined the effect of older paternal age on social and non-social behavior in mice. To the best of our knowledge this is the first fully-controlled animal study of the effects of paternal age on these behaviors.

Results Top
Social Behavior
Offspring of old fathers engaged in less social activity than the offspring of young fathers, spending less time socially-interacting with the conspecific mice (t = 2.23, d.f. = 22, p = 0.02, one-tailed test, Figure 1). This result was consistently observed across all measures of social behavior. There were no significant differences in overall locomotor activity.

Figure 1. Results of social behavioral data from male offspring of young fathers (n = 12) and old fathers (n = 12).

* shows a p-value of less than 0.05, † shows p-value of 0.06. A. Mean time (±SEM) displaying all social behaviors toward a conspecific mouse (broken down into components in B, C and D). B. Mean time (±SEM) displaying allogrooming behavior towards a conspecific mouse. C. Mean time (±SEM) displaying anogenital sniffing behavior towards a conspecific mouse. D. Mean time (±SEM) displaying sniffing behavior towards a conspecific mouse.

Exploration in the Holeboard
Offspring of old fathers demonstrated reduced exploration in the holeboard, making fewer nose pokes and spending less time nose poking than offspring of young fathers (t = −2.21, d.f. = 22, p = 0.02; Figure 2A). No significant differences were evident in distance moved or time spent in the centre of the Holeboard arena.

Figure 2. Results of holeboard and open field data from male offspring of young fathers (n = 12) and old fathers (n = 12).

* shows a p-value of less than 0.05. A. Mean number of nose pokes (±SEM) into holes in the holeboard trial. B. Mean time spent in each area of arena (±SEM) in the open field task.

Exploration in the Open Field
Offspring of old fathers were less exploratory in the Open Field, taking longer to enter the central zone of the arena (t = 1.7837, d.f. = 22, p = 0.04). However, there were no significant differences inthe time spent in the middle (t = −0.9548, d.f. = 22, p = 0.1785) or central zones (t = −1.3166, d.f. = 22, p = 0.1056) (Figure 2B) or in overall locomotor activity between offspring of old fathers and offspring of young fathers in the open field.

To further explore these findings we examined the same set of behaviors in a small group of mice that were the offspring of very old fathers (aged >12 months, n = 9 male offspring generated from 7 breeding pairs). The behavioral results of reduced social behavior and exploration were seen in the offspring of very old fathers, but the numbers are too small to allow for a reliable statistical test (data not shown).

Discussion Top
Using a mouse model we documented deleterious effects of advancing paternal age on offspring behavior. Male offspring of older fathers engaged in less social behavior and exhibited less exploration in a novel environment. These effects were not confounded by differences in overall locomotor activity. Abnormalities in social behavior characterize psychiatric disorders previously linked to advancing paternal age, suggesting a common phenotype affected by paternal age.

There are several advantages for the mouse model used in this study. First, given the tractable nature of animal work, the environment was tightly controlled, minimizing any environmental confounds. Second, the age of all the mothers of the offspring was standard such that differences observed in the offspring cannot be accounted for by maternal age.

Finally, the most common reference inbred strain of mouse was used (C57BL/6J), reducing genetic variation.

In men, it is thought that the spermatogonial stem cell divisions occurring over the life-course of males result in higher mutational rates and cytogenetic abnormalities in the sperm of older men [10], [11]. Numerous neurological and psychiatric disorders have been related to genomic alterations [12]. A number of studies have uncovered an increased prevalence of de-novo copy-number variants (CNVs), and other forms of genomic alterations in autistic and in schizophrenia cases [13], [14].

An alternative explanation is that epigenetic dysfunction underlies some paternal age effects. Epigenetic dysfunction has been associated with several neuropsychiatric disorders, including schizophrenia and bipolar disorder [15]. A study by Flanagan and colleagues [16] reported intra- and inter-individual epigenetic variability in the male germline, and found a number of genes that demonstrated age-related DNA-methylation changes. Epigenetic signals are generally reprogrammed in the germline, although it appears that such reprogramming may not be fully complete across all regions of the genome [17]. In particular, repetitive and transposable elements in the genome, which are generally hypermethylated, are often not efficiently reprogrammed [18]. It is thus plausible that de novo structural mutations, which are often associated with repetitive DNA sequence motifs, may also be subjected to differential epigenetic reprogramming implicating both mutagenic and epigenetic processes in the phenotypic manifestation of increased paternal age.

Despite the advantages of this model, the results of this study should be interpreted in light of some limitations. We only examined one strain of male mice. This was a-priori decided in order to follow common practice in animal research aimed at limiting variation caused by sex differences in behaviors. Hence, findings should not be generalized across sexes. In addition, behavior was assessed at one developmental stage (12 weeks, young adulthood). Thus, the developmental nature of these differences could not be determined.

In conclusion, this study provides the strongest evidence to date for the behavioral effects of advancing paternal age on the offspring. Studies are ongoing to investigate the role of molecular changes in mediating the effects of advancing paternal age on social and exploratory behaviors in offspring, by assessing de-novo CNV events and alterations in DNA methylation.

Methods Top
Breeding Strategy
C57BL/6J mice were bred and maintained in the Biological Services Unit at the Institute of Psychiatry, Kings College London using stocks purchased from Charles River Laboratories. All housing and experimental procedures were performed in accordance with the UK Home Office Animals (Scientific Procedures) Act 1986. Typical breeding age for mice starts at 2 months. Male breeders are generally retired after 7–8 months. Therefore, females aged 2 months were bred with males of two different ages; young males of 2 months (n = 6 breeding pairs), and old males of 10 months (n = 6 breeding pairs). The average litter size within each age group was 7 (male to female ratio 1:1) and total progeny generated was 40 mice in the young fathers group and 44 mice in the old fathers group. Two males were randomly selected from each litter (n = 12 males per group) and weaned aged 4–5 weeks and pair housed with their siblings and then individually housed for two weeks prior to testing. Mice were housed in standard cages measuring 30.5×13×11 cm, with food and water available ad libitum. The housing room was maintained on a standard light/dark cycle with white lights on from 08:00 to 20:00. Ambient temperature in all rooms was maintained at 21±2°C with 45% humidity.

Offspring Behavioral Testing
Offspring were aged 12 weeks at the start of testing and all testing took place during the light phase with a light level <30 lux in the test room. Each apparatus was wiped clean with 1% Trigene® between subjects to avoid olfactory cueing behaviors. Behaviors for all tests were recorded on videotapes for further detailed analysis. Mice were returned to their home cage at the end of each test.

Social Behavior
The social behavior of the test mice towards a juvenile conspecific was assessed in a 5 minute trial [19]. The test mouse is habituated in an arena (36×20×14 cm) for 5 minutes, after which a male juvenile conspecific of the same strain (aged 4 weeks) was introduced for a further 5 minutes. During this trial, social behavior (including social sniffing, anogenital sniffing and allogrooming) by the test mouse towards the conspecific were scored from videotape by an observer blind to the group factor of paternal age.

The holeboard test is used to measure activity and exploration in a novel arena [20]. The Truscan Photo Beam Activity System (Coulbourn Instruments, Whitehall, PA) was used, which consists of an arena (25.4 cm square) and a nose poke floor with 16 holes (4×4 array) with sensor rings to track movement. The beams are spaced 1.52 cm apart providing a 0.76 cm spatial resolution. Animals were placed in the arena and the movement, the number of nose pokes and the time spent nose poking were recorded automatically by beam breaks for 5 minutes using the Truscan program.

Open Field
The open field [21] used a square white acrylic box with dimensions 72×72×33 cm. The animal was placed in the outer part of the arena facing an outer wall and allowed to freely explore the arena for 5 minutes. A video camera placed above the arena allowed movement to be tracked using an automated tracking system (Ethovision, Noldus Information Technologies). The number of faecal boli and urination were recorded at the end of the test. A square of equal distance from the periphery (36×36 cm) was defined in Ethovision as the ‘outer’, ‘middle’ and ‘central’ zones in order to determine the number of entries into, and time spent in, these zones in the arena. In addition, the latency to enter the inner zones as well as locomotor activity in all three zones of the arena were measured by the tracking system.

Statistical Analysis
Behavioral performances of offspring of young fathers and offspring of old fathers in the social interaction task, holeboard and open field were compared using unpaired, one-tailed Students t-tests. Significance level was set at 0.05.

Author Contributions Top
Conceived and designed the experiments: JM CF LCS AR. Performed the experiments: RGS RLK. Analyzed the data: RGS RLK CF. Contributed reagents/materials/analysis tools: JDB. Wrote the paper: RGS RLK JM CF LCS AR.

References Top
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Torrey EF, Buka S, Cannon TD, Goldstein JM, Seidman LJ, et al. (2009) Paternal age as a risk factor for schizophrenia: how important is it? Schizophr Res 114: 1–5. Find this article online
Frans EM, Sandin S, Reichenberg A, Lichtenstein P, Langstrom N, et al. (2008) Advancing paternal age and bipolar disorder. Arch Gen Psychiatry 65: 1034–1040. Find this article online
Rothman KJ, Greenland S (1997) Modern Epidemiology: Lippincott Williams and Wilkins.
Geschwind DH (2009) Advances in autism. Annu Rev Med 60: 367–380. Find this article online
Green MF, Penn DL, Bentall R, Carpenter WT, Gaebel W, et al. (2008) Social cognition in schizophrenia: an NIMH workshop on definitions, assessment, and research opportunities. Schizophr Bull 34: 1211–1220. Find this article online
Green MF (2006) Cognitive impairment and functional outcome in schizophrenia and bipolar disorder. J Clin Psychiatry 67: e12. Find this article online
Brotman MA, Skup M, Rich BA, Blair KS, Pine DS, et al. (2008) Risk for bipolar disorder is associated with face-processing deficits across emotions. J Am Acad Child Adolesc Psychiatry 47: 1455–1461. Find this article online
Weiser M, Reichenberg A, Werbeloff N, Kleinhaus K, Lubin G, et al. (2008) Advanced parental age at birth is associated with poorer social functioning in adolescent males: shedding light on a core symptom of schizophrenia and autism. Schizophr Bull 34: 1042–1046. Find this article online
Crow JF (2000) The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet 1: 40–47. Find this article online
Buwe A, Guttenbach M, Schmid M (2005) Effect of paternal age on the frequency of cytogenetic abnormalities in human spermatozoa. Cytogenet Genome Res 111: 213–228. Find this article online
Reichenberg A, Mill J, MacCabe J (In Press) Epigenetics, Genomic Mutations and Cognitive Function. Cognitive Neuropsychitry. Find this article online
Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, et al. (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82: 477–488. Find this article online
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Flanagan JM, Popendikyte V, Pozdniakovaite N, Sobolev M, Assadzadeh A, et al. (2006) Intra- and interindividual epigenetic variation in human germ cells. Am J Hum Genet 79: 67–84. Find this article online
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Saturday, December 26, 2009

Older fathers appear to raise risks of genetic disorder

Older fathers appear to raise risks of genetic disorder - Print Version - International Herald Tribune 19/09/07 20.04 Page 1 of 2
Older fathers appear to raise risks of genetic disorders
By Roni Rabin
Wednesday, February 28, 2007
When it comes to fertility and the prospect of having normal babies, it has always been assumed
that men have no biological clock — that unlike women, they can have it all, at any age.
But mounting evidence is raising questions about that assumption, suggesting that as men get
older, they face an increased risk of fathering children with abnormalities. Several recent studies
are starting to persuade many doctors that men should not be too cavalier about postponing
marriage and children.
Until now, the problems known to occur more often with advanced paternal age were so rare they
received scant public attention. The newer studies were alarming because they found higher rates
of more common conditions — including autism and schizophrenia — in offspring born to men in
their middle and late 40s. A number of studies also suggest that male fertility may diminish with
"Obviously there is a difference between men and women; women simply can't have children after
a certain age," said Dr. Harry Fisch, director of the Male Reproductive Center at New York-
Presbyterian Hospital/Columbia University Medical Center and the author of "The Male Biological
"But not every man can be guaranteed that everything's going to be fine," Fisch said. "Fertility will
drop for some men, others will maintain their fertility but not to the same degree, and there is an
increased risk of genetic abnormalities."
It's a touchy subject. "Advanced maternal age" is formally defined: women who are 35 or older
when they deliver their baby may have "AMA" stamped on their medical files to call attention to
the higher risks they face. But the concept of "advanced paternal age" is murky. Many experts are
skeptical about the latest findings, and doctors appear to be in no rush to set age guidelines or
safety perimeters for would-be fathers, content instead to issue vague sooner-rather-than- later
"The problem is that the data is very sparse right now," said Dr. Larry Lipschultz, a specialist in
the field of male infertility and a past president of the American Society for Reproductive Medicine.
"I don't think there's a consensus of what patients should be warned about."
And many men maintain their fertility, said Dr. Rebecca Sokol, president of the Society of Male
Reproduction and Urology. "If you look at males over 50 or 40, yes, there is a decline in the
number of sperm being produced, and there may be a decline in the amount of testosterone,"
Sokol said. But by and large, she added, "the sperm can still do their job."
Some advocates, however, welcome the attention being paid to the issue of male fertility, saying it
is long overdue.
"The message to men is: 'Wake up,'" said Pamela Madsen, executive director of the American
Fertility Association, a U.S. education and advocacy group. "It's not just about women anymore,
it's about you, too."
Analyses of sperm samples from healthy men have found changes as men age, including
increased fragmentation of DNA, and some studies outside the United States have noted
increased rates of some cancers in children of older fathers.
Geneticists have been aware for decades that the risk of certain rare birth defects increases with
the father's age. One of the most studied of these conditions is a form of dwarfism called
achondroplasia, but the list also includes neurofibromatosis, the connective tissues disorder Marfan
syndrome, skull and facial abnormalities like Apert syndrome, and many other diseases and
Some studies suggest that the risk of sporadic single-gene mutations may be four to five times
higher for fathers who are 45 and older, compared with fathers in their 20s, said Dr. Joe Leigh
Simpson, president-elect of the American College of Medical Genetics. Overall, having an older
father is estimated to increase the risk of a birth defect by 1 percent, against a background 3
percent risk for a birth defect, he said.
Even grandchildren may be at greater risk for some conditions that are not expressed in the
daughter of an older father, according to the American College of Medical Genetics. These include
Duchenne muscular dystrophy, some types of hemophilia and fragile-X syndrome.
A recent study on autism attracted attention because of its striking findings. Researchers analyzed
a large Israeli military database to determine whether there was a correlation between paternal
age and the incidence of autism and related disorders. It found that children of men who became
a father at 40 or older were 5.75 times as likely to have an autism disorder as those whose fathers
were younger than 30.
"Until now, the dominant view has been, 'Blame it on the mother,'" said Dr. Avi Reichenberg, the
lead author of the study, published in September in The Archives of General Psychiatry. "But we
Older fathers appear to raise risks of genetic disorders - Print Version - International Herald Tribune 19/09/07 20.04


'Effect of advanced paternal age on fertility and pregnancy'

Medline ® Abstracts for References 7-11
of 'Effect of advanced paternal age on fertility and pregnancy'


TI Changes with age in the level and duration of fertility in the menstrual cycle.
AU Dunson DB; Colombo B; Baird DD
SO Hum Reprod 2002 May;17(5):1399-403.

BACKGROUND: Most analyses of age-related changes in fertility cannot separate effects due to reduced frequency of sexual intercourse from effects directly related to ageing. Information on intercourse collected daily through each menstrual cycle provides the data for estimating day-specific probabilities of pregnancy for specific days relative to ovulation, and these estimates allow unconfounded analysis of ageing effects. METHODS: A total of 782 healthy couples using natural family planning methods contributed prospective data on 5860 menstrual cycles. Day of ovulation was based on basal body temperature measurements. Estimates of day-specific probabilities of pregnancy and the length of the fertile window were compared across age groups. RESULTS: Nearly all pregnancies occurred within a 6 day fertile window. There was no evidence for a shorter fertile window in older men or women. On average, the day-specific probabilities of pregnancy declined with age for women from the late 20s onward, with probabilities of pregnancy twice as high for women aged 19-26 years compared with women aged 35-39 years. Controlling for age of the woman, fertility was significantly reduced for men aged>35 years. CONCLUSIONS: Women's fertility begins to decline in the late 20s with substantial decreases by the late 30s. Fertility for men is less affected by age, but shows significant decline by the late 30s.

AD Biostatistics Branch, MD A3-03, National Institute of Environmental Health Sciences, National Institutes of Health, P.O.Box 12233, Research Triangle Park, NC 27709, USA.


Friday, December 18, 2009

And the real kicker? Men over 35 are twice as likely to be infertile as those under 25.


Wednesday, December 16, 2009

Age is a factor in autism

Age is a factor in autism
December 15, 9:41 PMDouglas County Special Needs Kids Examiner

Gina St. Aubin

(Photo By: Ghutchis / Flickr)We've know for some time that the parent's age at conception and birth plays a large role in the possibility of birth defects for a child. For a woman, researchers indicate that as she reaches her late 30's and 40's the risk of infertility and miscarriage significantly increase. In the United States alone, approximately 1 in 12 first-time births are to women over 35; even while more studies have shown that infertility rates increase by 3% for each year beyond 35.

Now, a recent study from American Journal of Epidemiology indicates that age has more of a factor for birth defects than previously thought. In a study of 7.5 million births in California between 1989 and 2002, researchers identified 23,311 children who received state-sponsored services for autism. Further, through this research, the state's health department found that a child's risk of developing autism increased along with the age of the parents. For each 10-year increase in a mother's age between the ages of 20 and 40, the risk of her child developing autism climbed by 38 percent. Similarly, each 10-year increase in a father's age between the ages of 20 and 60 was associated with a 22-percent increase in autism risk.

Although past studies have indicated that the older age of parents may increase a child's risk of autism, or that it has no impact at all, these latest findings suggest (not prove) that an older age in parents may be an additional risk factor. With studies showing that the number of autism diagnosis' has skyrocketed over the past two decades, along with this new information, it may possible that the concomitant trend toward delaying childbirth could have contributed to that rise." But even if older parental age is a factor, she said, it would be a "relatively minor one."

So what do couples contemplating starting or continuing a family do with this information? What do women and men do as individuals mapping out their life's plan where beginning a family earlier in life is not possible or desired? At this point, with autism and it's research essentially still very young, is it not possible to take this information along with you as you have the previous information? Take it with you, in consideration, but not an end-all as the previous knowledge that increased age can increase the overall risk for birth defects? Could it not be added to the number of issues "listed" as those your possible future child is at risk for?

Or would couples begin their families sooner, beyond the consideration of education, finances and stability, all in the hopes of dodging the chance that their child, too, will be effected by autism?


Increased Bipolar Risk Linked to Father's Age

Psychiatric News November 7, 2008
Volume 43 Number 21 Page 18
© American Psychiatric Association
Clinical & Research News
Increased Bipolar Risk Linked to Father's Age
Joan Arehart-Treichel
Next Section
Older men are more likely than younger men to father children with autism, schizophrenia, or early-onset bipolar disorder.

Previous Section
Fathering a child later in life seems to increase its risk of having autism or schizophrenia, research has shown. And now it seems to increase a child's risk of having bipolar disorder as well, a new study suggests.

The study was headed by Emma Frans, a doctoral student in epidemiology at the Karolinska Institute in Stockholm. Results were published in the September Archives of General Psychiatry.

Sweden's Multigeneration Register, as well as Sweden's National Hospital Discharge Register, made this new investigation possible. The former, which has been in existence since 1947, gives demographic information about all people living in Sweden as well as about their parents. The latter, which has been in existence since 1973, lists all people living in Sweden who have been hospitalized for various conditions.

Using the hospital discharge register, the researchers identified more than 13,000 persons who had been hospitalized for bipolar disorder at least twice since 1973 when the hospital discharge register was started. Using the Multigeneration Register, the researchers picked out five healthy individuals who matched each of the 13,000 persons on gender and date of birth. In other words, some 13,000 persons with bipolar disorder served as subjects, and 67,000 other individuals served as controls.

The researchers then used the Multigeneration Register to determine the age of each subject's father and of each control's father at the time of the subject's or control's birth. Finally, the researchers used this data to determine whether there was any link between paternal age at the time of birth and an offspring's chances of having bipolar disorder.

A link was found. Even when some possibly confounding factors such as socioeconomic status, family history of mental disorders, or maternal age at time of birth were considered, the offspring of men aged 55 or older were significantly more likely—1.37 times more likely—to have bipolar disorder than were the offspring of men aged 20 to 24. And for early-onset bipolar disorder (defined as occurring before age 20), the impact of paternal age was even more pronounced: the offspring of men aged 50 or older were 2.63 times more likely to have bipolar disorder than were the offspring of men aged 20 to 24.

Thus, paternal age seems to be “an independent risk factor for bipolar disorder,” Frans and her colleagues concluded in their study report. “Furthermore, our results indicate that the paternal age effect might be most evident in patients with an early onset of the disorder.”

Why older men are more at risk of fathering children with bipolar disorder, or autism or schizophrenia, than younger men are is not known. However, Frans and her team suspect that it is genetic, especially since they found a strong link between older paternal age and early-onset bipolar disorder, which has shown greater heritability than bipolar disorder that occurs later in life.

Furthermore, Frans and her group speculated in their report, older men's genetic proneness to father children with bipolar disorder may be due to the fact that “spermatogonial cells replicate every 16th day, resulting in approximately 200 divisions by the age of 20 years and 660 divisions by the age of 40 years [and even more divisions as a man grows older. Thus] disorders associated with advancing paternal age could partially result from de novo mutations.”

Women, in contrast, they explained, “are born with their full supply of eggs that have gone through only 23 replications, a number that does not change as they age. Therefore DNA copy errors should not increase in number with maternal age.”

The study had no outside funding.

An abstract of “Advancing Paternal Age and Bipolar Disorder” is posted at.▪

American Psychiatric Association


Wednesday, December 09, 2009

Egg and sperm donation rules to be reviewed

Egg and sperm donation rules to be reviewed

By John von Radowitz, Press Association

Wednesday, 9 December 2009

A major review of the rules regarding sperm, egg and embryo donation will take place over the course of next year.

The most controversial area to be discussed concerns expenses payments made to donors.

Also on the agenda will be age limits for male and female donors, and restrictions on how many families a man can donate his sperm to.

Currently in the UK payments for sperm and egg donations can only be made to reimburse travel costs and loss of earnings.

Some other European countries interpret the rules more liberally to include compensation for "inconvenience".

Under EU law donors cannot be paid directly for their eggs and sperm, as happens in the US where people earn large sums of money helping infertile couples. An EU directive limits compensation to "making good expenses and inconveniences related to the donation".

In the UK expenses payments for donors are broadly in line with those given to jurors. There is an overall limit of £250 for each course of sperm or egg donation.

Four years ago the Human Fertilisation and Embryology Authority (HFEA), which regulates fertility services and research, decided not to allow compensation for "inconvenience". It was felt that paying "inconvenience" money might encourage people to make donations without thinking enough of the consequences.

Since then there have been calls for more flexibility to better reflect the sacrifices made by many donors.

Members of the HFEA agreed to hold the review at a meeting today.

Professor Lisa Jardine, who chairs the authority, said: "The authority had a rewarding and well informed debate across a wide range of important issues and arrived at some significant decisions. I welcome the fact that we are now beyond the implementation of the new legislation and can address issues which have implications for all of our stakeholders.

"There was a general view that the HFEA's policy with regard to reimbursement for donors, which has now been in place for two years since the introduction of the European Tissue and Cell Directive, was one that could usefully be revisited in light of what we have learned over those two years. We will not prejudge the outcome of the review that will now take place."

Other issues to be addressed include whether to change the current lower age limit for egg donation, which currently stands at 18, to take account of potential health risks.

The authority will also look at whether its upper age limit of sperm donors should be brought in line with professional guidelines. The official age limit is now 45, while the professional guidance recommends 40 or younger.

Also under discussion is the 10-family limit for sperm donors. This prevents a man donating his sperm to more than 10 families, irrespective of the number of babies that result.

Egg sharing, donations between family members, and the possibility of allowing people only to donate to certain patient groups will also be considered.


Sunday, December 06, 2009

Paternal age as a risk factor for schizophrenia: How important is it?

Paternal age as a risk factor for schizophrenia: How important is it?
Auteur(s) / Author(s)
FULLER TORREY E. (1) ; BUKA Stephen (2) ; CANNON Tyrone D. (3) ; GOLDSTEIN Jill M. (4) ; SEIDMAN Larry J. (5 6) ; TIANLI LIU (2) ; HADLEY Trevor (7) ; ROSSO Isabelle M. (8) ; BEARDEN Carrie (3) ; YOLLCEN Robert H. (9) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) The Stanley Medical Research Institute, 8401 Connecticut Ave., Suite 200, Chevy Chase, MD 20815, ETATS-UNIS
(2) Department of Community Health, Brown University, 121 South Main Street, Providence, RI 02806, ETATS-UNIS
(3) Departments of Psychology and Psychiatry, 1285 Franz Hall, University of California, Los Angeles, Los Angeles, CA 90095, ETATS-UNIS
(4) Departments of Psychiatry and Medicine, Harvard Medical School at Brigham and Women's Hospital, One Brigham Circle, Division of Women's Health, 3rd floor, 1620 Tremont St., Boston, MA 02120, ETATS-UNIS
(5) Harvard Medical School, Department of Psychiatry, Massachusetts Mental Health Center Public Psychiatry Division, Beth Israel Deaconess Medical Center, Boston, MA 02115, ETATS-UNIS
(6) Harvard Medical School, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, ETATS-UNIS
(7) Department of Psychiatry, University of Pennsylvania, 3535 Market Street, Philadelphia PA 19104, ETATS-UNIS
(8) McLean Hospital and Harvard Medical School, 115 Mill Street, Belmont, MA 02478, ETATS-UNIS
(9) The Stanley Division of Developmental Neurovirology, Johns Hopkins University, 600 N. Wolfe Street, Blalock 1105, Baltimore, MD 21287-4933, ETATS-UNIS

Résumé / Abstract
Advanced paternal age has been widely cited as a risk factor for schizophrenia among offspring and even claimed to account for one-quarter of all cases. We carried out a new study on 25,025 offspring from the Collaborative Perinatal Project (CPP), including 168 diagnosed with psychosis and 88 with narrowly defined schizophrenia. We also conducted a meta-analysis of this and nine other studies for which comparable age-cohort data were available. The mean paternal age for the CPP cases was slightly, but not significantly, higher than the matched controls (p=0.28). Meta-analyses including these new results were conducted to determine the relative risk associated with alternative definitions of advanced paternal age (35, 45 or 55 years and older). These yielded pooled odds ratios and 95% confidence intervals of 1.28 (1.10, 1.48),1.38 (0.95, 2.01) and 2.22 (1.46, 3.37), respectively. Thus, increased paternal age appears to be a risk factor for schizophrenia primarily among offspring of fathers ages 55 and over. In these 10 studies, such fathers accounted for only 0.6% of all births. Compared with other known risk factors for schizophrenia, advanced paternal age appears to be intermediate in magnitude. Advanced paternal age is also known to be a risk factor for some chromosomal and neoplastic diseases in the offspring where the cause is thought to be chromosomal aberrations and mutations of the aging germline. Similar mechanisms may account for the relationship between advanced paternal age and schizophrenia risk.
Revue / Journal Title
Schizophrenia research ISSN 0920-9964
Source / Source
2009, vol. 114, no1-3, pp. 1-5 [5 page(s) (article)] (3/4 p


Friday, December 04, 2009

Men's biological clocks are ticking, too

Evidence is piling up that men, or at least our reproductive parts, have a "best before" date. Not only is it harder to create a pregnancy after the age of 35 or 40, researchers are finding that our sperm quality decreases with age. This can result in a higher-than-normal incidence of offspring with schizophrenia, autism and low IQ, as well as an increased chance of miscarriage.

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Tuesday, December 01, 2009

Scientists Believe Your Cell Phone Is a Death Trap

Scientists Believe Your Cell Phone Is a Death Trap
Articles Home » Scientists Believe Your Cell Phone Is a Death Trap

Dr. Mercola

December 01 2009

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In the video above, founder Camilla Rees presents an overview of an emerging public health issue -- excessive exposures to microwave radiation from wireless technologies.

Illness linked to electromagnetic radiation exposure inclufiede many cancers, neurological conditions, ADD, sleep disorders, depression, autism, cognitive problems, cardiovascular irregularities, hormone disruption, immune system disorders, metabolism changes, stress, fertility impairment, increased blood brain barrier permeability, mineral disruption, DNA damage and much, much more.

Learn how to sensibly protect yourself in high EMF environments, and why it is important you join others in advocating for stricter safety standards for wireless technologies.

The Web site also offers ten free audio interviews with some of the world’s leading experts in the field of EMF.

Click the source link below to hear some of the fascinating information and insights they offer!


Electromagnetic Health

Dr. Mercola's Comments
The video above is a great, broad summary of what we now know about the dangers inherent with our wireless revolution. There’s no doubt in my mind that if our society keeps ignoring this issue, we will pay a very steep price in declining health over the coming generations.

However there are a large number of other excellent video interviews on their site,, which is a tremendous resource of EMF knowledge. There is even one from my mentor Dr. Dietrich Klinghardt. If you were to attend a conference that had all these presentations, I am sure you would spend hundreds of dollars, but now you can access them all for free.

Personally, I believe this issue is so important, I’ve created an entire web site dedicated to EMF education and information. Feel free to bookmark, and check back on occasion for the latest news and updates.

Unfortunately, while some countries are taking measures to reduce public radiation, the United States is not one of them. Instead, the US is heading in the exact opposite direction with the introduction of Wi-Max, short for Worldwide Interoperability for Microwave Access.

As infatuating as this type of technology can be to technological geeks and business people alike (myself included), the health ramifications cannot be ignored. We are already seeing increasing numbers of people suffering the very real effects of electrohypersensitivity.

The problem has gotten bad enough that France, for example, has created “EMF refugee zones,” where those who are hypersensitive now live in trailers, doing everything they can to protect themselves in order to be able to function normally.

Do You Experience Electromagnetic Hypersensitivity Symptoms?
The graph below, created by Prof. Magda Havas, PhD, illustrates the frequency of electromagnetic hypersensitivity symptoms based on your distance to a cell phone base station (cell phone tower). It is based on a Spanish study published in 2001 in the journal La Presse Medicale, which clearly showed that the closer you are to the base station, the greater your chances of exhibiting a number of health related symptoms such as fatigue, sleep disturbances, visual and auditory disturbances, and cardiovascular effects, just to name a few.

It’s worth noting that these symptoms are just for ONE type of exposure, at a distance. It does not include the effects of other technologies that are emitting radiofrequency radiation as well, such as cell phones, cordless home phones, and wi-fi networks in your office.

Now we’re even blasted with WiFi on airplanes. Last week I actually used WiFi in the sky to get some work done on a four hour trip to LA. Soon WiFi internet will be on EVERY aircraft.

When you add all sources of exposure together, the potential effects become quite staggering.

The Biological Effects of EMF
There is a significant amount of studies showing the biological effects of electromagnetic fields and radiofrequencies within the microwave range. However, the crux of the issue is that industry claims that since these technologies do not have a thermal (heating) effect on your body, they will not cause biological problems.

There are literally thousands of studies showing that this logic is incorrect. EMF’s DO cause biological harm, even without thermal effects, including:

The truth is that industry, and our regulating agencies, are simply choosing not to look at any of this research…

Scientists across the globe are starting to pay attention to this issue, and they’re seeing the problems. Professor Franz Adelkofer, coordinator of the REFLEX report, has stated:

“This is real evidence that hyperfrequency electromagnetic fields can have geno-toxic effects. And this damaged DNA is always the cause of cancer.

We’ve found these damaging effects on the genes at levels well below the safety limits. That’s why we think it’s urgent to base our safety limits on the biological effects, not the thermic ones.

They should be based on biology, not on physics.”

Two great sources of research into the biological effects of EMF’s and other types of radiation include the BioInitiative Report, which was published in August 2007 (available on, and the 2009 special EMF issue of the Journal of Pathophysiology.

I also recommend the book Public Health SOS: The Shadow Side of the Wireless Revolution, written by Camilla Rees and Magda Havas, PhD.

The Real Reason Why US Government is So Slow to Protect You
Most people do not realize this, but the US government has significant conflicts of interest on this issue.

For example, the top 20 telecom companies have spent $2.3 billion in political lobbying over the past 10 years to influence government officials, both in the US and in other countries. The US also receives significant federal revenue from individual usage taxes, in addition to the revenue collected directly from the telecom industry.

Last but not least, companies bought spectrum rights with little money down in the late 1990s, with the agreement to pay these loans back with user fees over time. Essentially, the FCC is a mortgage holder for the mobile phone industry!

As is the case any time you’re dealing with conflicts of interest of this magnitude, it will take Herculean efforts to break through the walls of greed to protect human health. But it must be done, and it will require people like you and me to keep pushing for change.

Says Olle Johanson, PhD, from the Karolinska Institute in Sweden:

“It is evident that various biological alterations, including immune system modulation, are present in electrohypersensitive persons.

There must be an end to the pervasive nonchalance, indifference and lack of heartfelt respect for the plight of these persons. It is clear something serious has happened and is happening. Every aspect of electrohypersensitive people’s lives, including the ability to work productively in society, have healthy relations and find safe, permanent housing, is at stake.

The basics of life are becoming increasingly inaccessible to a growing percentage of the world’s population. I strongly advise all governments to take the issue of electromagnetic health hazards seriously and to take action while there is still time. There is too great a risk that the ever increasing RF-based communications technologies represent a real danger to humans.

Governments should act decisively to protect public health by changing the exposure standards to be biologically-based, communicating the results of the independent science on this topic and aggressively researching links with a multitude of associated medical conditions.”

Factors that Influence Your Susceptibility to EMF Damage
Researchers have found that there are a number of factors that influence the degree to which you may be affected by EMF’s and other types of radiowaves. For example, according to the research by Dr. Dietrich Klinghardt, your physical body, such as your body weight, body-mass index, bone density, and water and electrolyte levels can alter the conductivity and biological reactivity to EMFs.

Heavy metals in your brain also act as micro-antennas, concentrating and increasing reception of EMF radiation. Likewise, any kind of metal implants and/or amalgam tooth fillings will significantly increase reception of microwaves, and the mircrocurrents from cell phones and other ambient fields.

This is yet another major reason for having your mercury fillings removed by a trained biological dentist.

Your genes can also play a part, as certain genes regulate metal detoxifying enzymes. So depending on your genetic makeup, you may be more or less predisposed to electromagnetic hypersensitivity.

People who suffer from diseases that causes myelin loss, such as muscular sclerosis, Lyme disease, and other autoimmune diseases are also at greater risk of electro-sensitivity.

Unfortunately, EMFs have been found to cause microorganisms to release higher amounts of potent toxins, which can exacerbate infections and autoimmune diseases.

Your overall risk is also dependent on other sources of EMF, such as the synergistic effect from geopathic earth radiation, metallic objects and furnishings in your home or office, electronic appliances, and household wiring.

Mechanism of Action
According to Dr. Andrew Goldsworthy retired from the Imperial College of London, acute electrohypersensitivity symptoms and diseases stemming from excessive non-thermal radiation exposure could potentially be explained by the effects on the cell wall.

Because as your body absorbs radiation, currents are created that weaken your cells’ walls by removing calcium and other divalent ions.

This creates permeability, or “leakage” in your body, and this is known to happen even in non-thermal fields, and, interestingly, only in certain “amplitude windows.” Low frequencies can be worse than high frequencies, and pulsed waves are worse than sine waves.

One of the most noticeable effects of this permeability in your body is the effect it can have on your brain function. As explained in the video, programmed flow of calcium ions through your cell membranes is a prerequisite for release of neurotransmitters. “Unscheduled” leakage of calcium ions increases background calcium which makes membranes hypersensitive and more likely to transmit random signals.

The end result can be clouded mental activity. It can also activate random thoughts, which naturally makes it more difficult to concentrate.

Much of this effect is characteristic of ADHD…

Also, leakage of digestive enzymes from lysosomes can account for damage to DNA, and may offer yet another explanation for cancer rates and the rise in infertility. The resulting DNA fragmentation may also create genetic mutations that could appear in future generations.

Interestingly, and quite believably, the rise in microwave radiation and EMF exposure may be a significant contributing factor to the skyrocketing increase in autism, as electromagnetically induced membrane leakage leads to brain hyperactivity. A summary of a study conducted by Dr. Dietrich Klinghardt, MD, on the EMF level in the bedrooms of pregnant women whose children were autistic, versus EMF levels of mothers who had healthy children, can be found in the "Media Story Leads" section of Body voltage levels in that location were also measured in the study.

The results suggest an urgent need for further research in the autism-EMF area, especially given the official number of children with autism was recently announced to be 1 in 91, compared to 1 in 150 in 2002.

More research is also needed on the mechanisms of action in general. A summary of all currently known mechanisms of action is expected to be published in 2010.

For example, in addition to Dr. Goldsworthy's theories discussed above, other possible mechanisms of action leading to symptoms and diseases include: increased free radical production, and impact on serotonin and melatonin.

In Defending Itself, Your Body Wears Itself Out…
The good news is that your body can, to a degree, defend itself from these types of radiation damage. It does so by pumping surplus calcium out of your cells, and by activating certain enzymes that protect your DNA, and by making heat shock proteins to protect enzymes.

The bad news is that in doing so, your body becomes fatigued, and the more it has to defend itself, the worse your health will fare. Eventually, it can start interfering with your metabolism; impair your immune system; and lower your resistance to disease and cancer.

Last but not least, EMF exposures have a sensitizing effect, so you will become more and more sensitive over time.

How You Can Help Yourself
Fortunately, you are not completely helpless. There are strategies that can help reduce your exposure and protect your health against the constant onslaught of radiation.

First and foremost, you’ll want to reduce your exposure to as many sources as you can.

For my latest list of safety tips and guidelines on how to reduce your exposure, please see this previous article.

In addition to my recommendations, Camilla Rees mentions a few more in her video above, including:

Intestinal care – mainly by making sure you’re getting plenty of healthy probiotics. The Paracelsus Clinic in Switzerland discovered that symptoms of electrosensitivity can be reduced by providing gut barrier support. For more information, listen to the interview with Dr. Rau, medical director of the Paracelsus Clinic, available at this link.
Regular detoxification programs – Reducing your toxic burden has become far more important than it ever was before. Not only are you dealing with increasing amounts of toxic chemicals in your environment, your body is full of microorganisms that respond to EMFs by generating increased levels of their own toxins, according to a course for physicians on this subject, taught by Dr. Dietrich Klinghardt, MD.
Beware of mold – Mold, just like other microorganisms, can also react in high EMF environments. One study showed 600 times more neurotoxins generated from mold in a high EMF environment. According to Rees, there are also mold legal cases being reviewed, assessing if problems in buildings infested with mold may have actually been related to nearby antenna infrastructure.
Last but not least, please do help spread awareness about this ever increasing problem.

For more information, please see for the latest news and updates.

It’s unfortunate, but the government is not likely to step up and do the right thing to protect your health, and the health of your children and grandchildren. We need you to get involved, at any level you can, to help increase the pressure on industry and industry regulators, to ensure a safer future for everyone, everywhere.

Related Links:

A Cell Phone on Your Hip Weakens Your Bones

Top 'Safe' Cell Phones That Aren't Safe

Secret Link Between Cigarettes and Cell Phones


Differences in maternal and paternal age between Schizophrenia and other psychiatric disorders.

Schizophr Res. 2009 Nov 27. [Epub ahead of print]

Differences in maternal and paternal age between Schizophrenia and other psychiatric disorders.
Lopez-Castroman J, Gómez DD, Belloso JJ, Fernandez-Navarro P, Perez-Rodriguez MM, Villamor IB, Navarrete FF, Ginestar CM, Currier D, Torres MR, Navio-Acosta M, Saiz-Ruiz J, Jimenez-Arriero MA, Baca-Garcia E.

Department of Psychiatry at Fundacion Jimenez Diaz Hospital and Autonoma University, CIBERSAM, Madrid, Spain.

Advanced parental age has been shown to increase offspring risk for a number of neuropsychiatric disorders including schizophrenia and Down's syndrome. Other psychiatric disorders have been less studied with respect to the effect of parental age on offspring risk. In this study we examine if advanced parental age increased risk for ICD-10 diagnoses. We hypothesized that advanced parental age would increase risk for offspring psychotic disorders and mental retardation but not other ICD-10 diagnoses. We examined follow-up data for 30,965 subjects treated in outpatient psychiatric facilities between 1980 and 2007. Subjects were younger than 18years of age at their first outpatient visit. A comparison group was obtained from data on registered births in Spain from 1975. We compared parental age (maternal, paternal, combined) across diagnostic categories using ANOVA and logistic regression was used to estimate the risk of psychopathology in the offspring with advanced parental age (maternal, paternal, combined). Maternal and paternal ages were higher for subjects diagnosed with mental retardation. Risk for psychotic disorders showed a significant linear increase only with advancing maternal age, and not paternal age as is more often reported.

PMID: 19945257 [PubMed - as supplied by publisher]