UC biologists find link between paternal diet and offspring’s health

UC biologists find link between paternal diet and offspring’s health

Doctors long have stressed the importance of good nutrition for expectant mothers.

Now biologists at the University of Cincinnati say the father’s diet could play a similar role in the health of a baby.

UC biology professors Michal Polak and Joshua Benoit manipulated the nutrition of male fruit flies and observed a strong correlation between poor diet and poor survivorship among their offspring. The study was published this week in the journal Proceedings of the Royal Society B.

“We were really surprised,” Polak said. “In many species, the moms do a lot of the care. So we expect there to be an effect from maternal diet on offspring because of that strong link. But it was a real surprise to find a link between paternal diet and offspring.”

UC collaborated on the study with researchers from the University of Western Australia and the University of Sydney’s Charles Perkins Centre.

Everyone knows a father is responsible for half of his offspring’s genes. But the UC study comes at a time when researchers are learning more about other influences fathers have on their offspring’s health that are not necessarily coded within genes, a concept called epigenetics. These influences include direct environmental effects such as exposure to toxins that can be passed from the father to his offspring through his seminal plasma.

Epigenetics is the way by which cells read genes, making some dormant and others active. Environmental cues can turn certain genes on or off. And these epigenetic modifications, too, can be inherited.

For example, an Australian study in 2016 found that male mice that lived on the equivalent of a fast-food diet were more likely to have sons that were diabetic even though daughters remained unaffected. If these traits were coded in the father’s DNA, both sons and daughters would see similar health effects.

“Epigenetic changes are seen in population genetics as less durable than actual mutations to the genetic code or DNA molecule,” Polak said. “If it’s a dominant, deleterious mutation, it could be quickly eliminated out of a gene pool by selection. But if it’s positively selected, then it could sweep the gene pool and increase in frequency until it becomes fixed.”

Research on fruit flies has earned six Nobel Prizes, including this year’s winner in physiology or medicine. The latest Nobel Prize study examined how genes control body clocks or circadian rhythms, which can help explain why some people have chronic trouble sleeping.

“I am very pleased for the field. I am very pleased for the fruit fly,” co-winner Michael Rosbash told The Associated Press.

Fruit flies are found around the world. UC’s Benoit even saw them buzzing around inside a research station in Antarctica, where they probably stowed away on food supplies imported from Chile.

The flies became popular study subjects in the early 1900s when biologists began to unravel how genetic inheritance worked. High school biology textbooks still use the color of fruit fly eyes to illustrate the concept.

Today, scientists regularly study fruit flies because they share 60 percent of our genes and more than 75 percent of our disease genes. Geneticists have mapped their entire genome. More than 150 years of study have made this unassuming little fly a good model system, Polak said.

“It’s almost arbitrary why fruit flies were chosen,” Polak said. “It just became the workhorse in those original labs.”

Benoit said flies are a practical and inexpensive test subject.

“They reproduce quickly. You can rear a few hundred in just one of these little jars. You can have thousands of fruit flies in the same amount of space you could fit six mice,” Benoit said. “It’s a great system to work on. That’s why so many questions have been answered about them.”

For the UC study, Polak isolated females and males of the fruit fly species Drosophila melanogaster, which is famous for its enormous red eyes and high reproductive capacity. A single fly can lay 50 eggs per day or as many as 2,000 eggs in her short two-month lifetime.

UC researchers fed females the same diet. But they fed males 30 different diets of yeast and sugars. The flies could eat all they wanted from the agar mixture in the bottom of their glass beaker homes, but the quality of the food varied dramatically from low to high concentrations of proteins, carbohydrates and calories.

 

After 17 days on the strict diet, the males were mated individually and consecutively with two females, which all received the same diet of yeasted cornmeal. By controlling the diet and age of the mated female, researchers tried to limit variation in maternal conditions for the study.

And by mating the males consecutively, researchers wanted to learn about the effect of male mating order and what role diet played in changing the male’s ejaculate.

After the first mating, the male fly was mated 15 minutes later with a second female. Afterward, the females were placed in isolated breeding vials filled with grape agar suitable for laying eggs. After 24 hours, researchers counted their eggs.

After another 24-hour incubation period, the eggs were examined under a microscope to determine how many hatched or contained viable embryos. Unfertilized eggs were removed from consideration. After the first count, researchers waited another 24 hours to give potentially unviable eggs time to develop or hatch but none did.

Polak and Benoit found that embryos from the second mating were more likely to survive as their fathers’ diets improved in nutrition. These effects were less apparent in the first mating. Likewise, embryo mortality was highest for offspring of males that fed on a high-carbohydrate, low-protein diet.

Researchers also found a connection between the male’s body condition and his offspring’s mortality. Males with lower energy reserves (measured in whole-body fatty acids, glucose and protein) were more likely to have fewer surviving offspring.

Females laid roughly the same number of eggs regardless of the male’s diet or mating frequency. But the study suggested that something important in the male’s ejaculate was lost between the first and second pairings.

“The second copulation is where the effects of diet really became stronger,” Polak said. “Emaciated males in poor condition produced embryos with a higher rate of mortality. But only in the second copulation.”

Polak’s study also found a slightly higher incidence of embryo mortality associated with male flies in the first mating that were fed the highest-calorie diet.

“There have been a fair number of studies that suggest male nutrition does affect reproductive capacity,” Benoit said. “But the reduction in viability was a lot smaller than what we saw in the low-quality diet or may have been masked since only a single mating was assessed.”

Polak said the study raises questions about how nutrition might affect successive generations. A 2002 Swedish population study found a correlation between 9-year-old children who had ample access to food and higher rates of diabetes and heart disease among their grandchildren. Meanwhile, children who faced privation from famine at the same age had children and grandchildren with less incidences of heart disease and diabetes.

The study was funded in part by a four-year $882,000 grant from the National Science Foundation.

Now Benoit and Polak are turning their attention to a new study examining the genetic and epigenetic responses of fruit flies that are stressed by parasitic mites.

“The seminal fluid does have a protective role to play for the embryo. You definitely have implications for embryo health and viability. But that’s another chapter,” Polak said.

The researchers also are interested in testing whether parasitic infection could change the quality of male seminal plasma, possibly exerting effects on the embryo as they observed in the diet study.

After spending most of his academic career studying them, Polak has respect for the lowly fruit fly.

“You get a special sort of appreciation for them when you see them in your kitchen courting on a piece of fruit,” he said. “You know a lot about them – and maybe you’re a little less likely to swat them.”

Source:
http://magazine.uc.edu/editors_picks/recent_features/fruitfly.html
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Cancer results from a diseased genome, excited by environmental toxins

Cancer results from a diseased genome. Each tumor contains a collection of genomic aberrations that activate oncogenes and inactivate tumor suppressor genes.

A recent survey of the scientific literature identified 229 oncogenes (or “dominant” cancer genes) and 62 tumor suppressors (“recessive” cancer genes), suggesting that more than 1% of the human genome may contribute directly to carcinogenesis and/or tumor progression (Futreal 2004).

Since many tumor mechanisms likely remain undiscovered, these numbers may underestimate the full spectrum of human cancer genes.

Moreover, the path to cancer may require at least 5–10 genetic mutations (Hahn and Weinberg 2002).

Theoretically, then, the total number of different genetic combinations possible across all human cancers exceeds ten trillion and may even reach 1018.

These estimates imply that a comprehensive genomic approach to cancer therapeutics may be exceedingly difficult to achieve.

Recent insights, however, suggest a more favorable conclusion:

The enormous complexity possible in theory may indeed prove both functionally reducible and therapeutically tractable in practice.

Among these is the recognition that most human cancers derive from perturbations within a finite number of fundamental physiological processes directing cellular proliferation, survival, angiogenesis, and invasion/metastasis (Hanahan and Weinberg 2000).

By itself, this conceptual framework does not completely resolve the challenge of tumor complexity, because many diverse genetic players and mutation chronologies may affect each of these properties.

Nonetheless, the notion that cancer involves definable biological hallmarks suggests that, ultimately, logic and order may be discerned from the immense genomic diversity characteristic of human cancer once the appropriate molecular contexts are more fully understood.

Consistent with this viewpoint is the recognition that cancer genomic aberrations, although complex, do not occur randomly. Instead, a relatively small number of cancer genes tend to undergo alterations at high frequencies.

The fact that cellular pathways involving RAS, p53, and pRb (among others) undergo genetic mutations so commonly (Vogelstein and Kinzler 2004) not only endorses the “hallmarks of cancer” model, but also suggests that cancers tend to employ the same genomic alterations to enact these processes. Thus, despite the inevitable complexity, an increased knowledge of cancer genomic alterations should contribute markedly to the elaboration of essential and broadly applicable tumor mechanisms.

ONCOGENE ADDICTION AND TUMOR DEPENDENCY

Another pivotal insight pertaining to deconvolution of cancer genomic complexity derives from the recent observation that some tumors require continued activity of a single activated oncogene for survival (Weinstein 2002).

Termed “oncogene addiction,” this phenomenon was first demonstrated in transgenic mouse models that enabled conditional overexpression of oncogenes such as myc, ras, and bcr-abl (Chin et al. 1999; Felsher and Bishop 1999; Huettner et al. 2000; Jain et al. 2002; Pelengaris et al. 2002). In these models, induction of the relevant oncogene triggered cancer formation; however, subsequent loss of oncogene expression resulted in regression and apoptosis of tumor cells. The presence of oncogene addiction in human malignancies was first demonstrated in chronic myelogenous leukemia (CML), which harbors the BCR-ABL translocation; and in gastrointestinal stromal tumors (GIST), which contain oncogenic mutations in the c-kit gene. Targeting the tyrosine kinase activity of these oncogenes with the small-molecule inhibitor imatinib was sufficient to induce complete remissions in the great majority of patients (Druker et al. 2001; Demetri et al. 2002; Kantarjian et al. 2002). More recently, oncogene addiction was also demonstrated in a subset of lung cancers that contain base mutations or small deletions in the epidermal growth factor receptor (EGFR) gene; these alterations confer sensitivity to EGFR inhibitors such as gefitinib or erlotinib (Lynch et al. 2004; Paez et al. 2004). Thus, a single oncogenic lesion may play a decisive role in tumor maintenance, even when many additional genetic alterations have also accrued (Kaelin 2004).

A synthesis of the oncogene addiction involves a massive apparent genetic complexity may be underpinned by a much smaller collection of critical “dependencies” operant in human tumors. By this view, the predicted tumor promoting effects of many genomic perturbations may converge onto a finite number of physiological processes, which in turn exhibit an even smaller set of limiting “nodes” or “bottlenecks” within key cellular pathways directing carcinogenesis.

MITF Gene

This gene encodes a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. It regulates the differentiation and development of melanocytes retinal pigment epithelium and is also responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008])

Tumors arise from the pigment cells (melanocytes)

GeneCards Summary for MITF Gene

MITF (Microphthalmia-Associated Transcription Factor) is a Protein Coding gene. Diseases associated with MITF include tietz albinism-deafness syndrome and waardenburg syndrome, type 2a. Among its related pathways are IL6-mediated signaling events and Transport to the Golgi and subsequent modification. GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding and RNA polymerase II core promoter proximal region sequence-specific DNA binding. An important paralog of this gene is TFE3.

UniProtKB/Swiss-Prot for MITF Gene

MITF_HUMAN,O75030

Transcription factor that regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. Binds to symmetrical DNA sequences (E-boxes) (5-CACGTG-3) found in the promoters of target genes, such as BCL2 and tyrosinase (TYR). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium.

Source: Cold Spring Harbor Symposia on Quantitative Biology, Volume LXX. © 2005 Cold Spring Harbor Laboratory Press 0-87969-773-3.


On chemicals and cancer, an eminent German oncologist says that cancer is caused by environmental toxins. Others agree. While there are obviously other issues, fungus, viruses, genetics, etc., the major change in the world that could have lead to the explosion of cancer over the last 100 years has been the introduction of tens of thousands of chemicals into the environment. Chemicals that we had never been exposed to before. Ones that our bodies don’t know how to handle. The link between toxic Chemicals and Cancer becomes clearer the longer we are surrounded by them.

Dr Tuttle: Most of the time we don’t know what causes a specific patient’s thyroid cancer. The only well-accepted risk factor for the common types of thyroid cancer — papillary and follicular thyroid cancers — is exposure to ionizing radiation that occurs after exposure to fallout from nuclear reactors (like that following the Chernobyl accident), atomic bombs or therapeutic uses of radiation during young childhood.  However, since the incidence of thyroid cancer has dramatically increased over the last 20 years, both in the United States and abroad, many investigators are re-examining the possibility that some environmental factor may be linked to the rise in thyroid cancer. But as of now, no specific chemical or environmental factor has been demonstrated to commonly cause thyroid cancer in humans.

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