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Welcome to The Visible Embryo, a comprehensive educational resource on human development from conception to birth.

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The National Institutes of Child Health and Human Development awarded Phase I and Phase II Small Business Innovative Research Grants to develop The Visible Embryo. Initally designed to evaluate the internet as a teaching tool for first year medical students, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than one million visitors each month.

Today, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than 1 million visitors each month. The field of early embryology has grown to include the identification of the stem cell as not only critical to organogenesis in the embryo, but equally critical to organ function and repair in the adult human. The identification and understanding of genetic malfunction, inflammatory responses, and the progression in chronic disease, begins with a grounding in primary cellular and systemic functions manifested in the study of the early embryo.

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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
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Home | Pregnancy Timeline | News Alerts |News Archive Dec 18, 2014

The key to the test's sensitivity is the way it uses untamed house mice - rather than docile,
inbred laboratory strains - and subjects them to a relentless, Darwinian competition
for food, shelter and mates much like they would face in the wild.

 






s

 

 

Paxil — antidepressant has a hidden toxicity

Because of undetected toxicity, about a third of prescription drugs approved in the U.S. are withdrawn from the market or require added warning labels upon reaching the market. A new test aims to detect dangerous side effects much earlier.

An exceptionally sensitive toxicity test invented at the University of Utah could make it possible to uncover more dangerous side effects early in pharmaceutical development so fewer patients get unsafe drugs.

To prove this, researchers ran their new test using Paxil, an antidepressant that thousands of pregnant women took before it was linked to increased risk of birth defects. Today the U.S. Food and Drug Administration requires a warning against Paxil use in the first trimester of pregnancy.

In the Paxil study, researchers gave food laced with Paxil to 20 breeding pairs of mice for several weeks, until all had produced up to four litters. Doses were equivalent to about 1.8 times the level typically prescribed for people. Litter offspring also ate Paxil-laced chow until they reached breeding age.

The exposed offspring were released into the competitive arena with the offspring of a control group of mice never exposed to Paxil. Groups consisted of eight males and 14 to 16 females, at population densities comparable to those in the wild. Researchers created five such populations and kept them going for six months.


In the University of Utah study, males exposed to Paxil were about half as likely to control a territory. They also lagged behind control males in body weight throughout the competition and were more likely to die. Exposed males produced 44 percent fewer offspring. Exposed females showed no significant weight or mortality differences, but they produced half as many offspring as control females and those offspring were underweight. Their fecundity rebounded at later points in time.


The mouse doses of Paxil approximated those prescribed for people. In animal testing reported by Paxil though, no reproductive side effects were seen until rodents took doses many times higher than those given to humans.

University of Utah biology professor Wayne K. Potts, the study's senior author, says that detecting toxicity problems early in preclinical testing would not only protect patients, but also help pharmaceutical companies avoid wasting billions of dollars bringing drugs to market too early. "If we can find these health problems early on in preclinical testing, it has the potential of saving them a lot of money," Potts added.


The key to the test is that it uses untamed house mice - rather than docile, inbred laboratory mouse strains - and subjects them to a relentless, Darwinian competition for food, shelter and mates much like they would face in the wild.


Mice jostle and race for a place in a roughly 300-square-foot pen divided into six territories by wire fencing. Individuals must climb the fencing to invade - or flee - neighboring turf. Four of the territories are prime real estate with multiple hidden nesting sites and direct access to feeders. Two territories are poor, offering only open nesting sites and indirect feeder access. The test is called OPA the organismal performance assay.

Potts' first idea was to explore the impact of inbreeding — and his work revealed the harmful effects of cousin-level inbreeding gone unnoticed for decades in the genes of lab mice.  During that project, he observed that laboratory mice that are slightly less healthy may go unnoticed when fed ample food and given a living space. But he realized that a defect in any physiological system is more likely to stand out during intense competition. Potts: "When they really have to compete directly, males are constantly testing each other and fighting over territories. If they don't win a territory, females won't consider them when it comes time to choose a mate."

The new test can provide an early warning of possible toxic effects, but it does not identify cause. In the case of Paxil, this test might have alerted the drug's developers to the risk of birth defects when taken during pregnancy at prescribed doses, not just at the high levels used in conventional safety testing. Other selective serotonin reuptake inhibitors, or SSRIs, don't appear to pose the same level of risk as Paxil, but their safety for use during pregnancy remains unclear.

Study lead author Shannon M. Gaukler: "It's unknown how Paxil causes birth defects and why Paxil has a stronger correlation with birth defects than other SSRIs. We believe most results were driven by endocrine disruption."

Potts says the performance assay may be even more important for identifying the toxic effects of agricultural chemicals, industrial pollutants, and other manufactured chemicals released into the environment.


"We don't really have a sensitive, broad toxicity assessment system.That's why these things slip through the cracks and we often don't discover harmful effects until after 10 or 20 years of epidemiology studies using the public as the experimental guinea pigs."

Wayne K. Potts PhD, professor, Department of Biology, University of Utah.


In a study published last year, the performance assay revealed that doses of sugar people regularly consume - and deemed safe by regulators - may be toxic. When mice ate a diet of 25 percent extra sugar (the mouse equivalent of drinking three cans of soda daily) females died at twice the normal rate and males were a quarter less likely to hold territory and reproduce.

The study will be published in the January-February issue of Neurotoxicology and Teratology, which has posted a preprint online.

Abstract
Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is currently available on the market and is suspected of causing congenital malformations in babies born to mothers who take the drug during the first trimester of pregnancy. We utilized organismal performance assays (OPAs), a novel toxicity assessment method, to assess the safety of paroxetine during pregnancy in a rodent model. OPAs utilize genetically diverse wild mice (Mus musculus) to evaluate competitive performance between experimental and control animals as they compete among each other for limited resources in semi-natural enclosures. Performance measures included reproductive success, male competitive ability and survivorship. Paroxetine-exposed males weighed 13% less, had 44% fewer offspring, dominated 53% fewer territories and experienced a 2.5-fold increased trend in mortality, when compared with controls. Paroxetine-exposed females had 65% fewer offspring early in the study, but rebounded at later time points, presumably, because they were no longer exposed to paroxetine. In cages, paroxetine-exposed breeders took 2.3 times longer to produce their first litter and pups of both sexes experienced reduced weight when compared with controls. Low-dose paroxetine-induced health declines detected in this study that were undetected in preclinical trials with doses 2.5–8 times higher than human therapeutic doses. These data indicate that OPAs detect phenotypic adversity and provide unique information that could be useful towards safety testing during pharmaceutical development.

Gaukler and Potts conducted the study with James Ruff, Tessa Galland, Kirstie A. Kandaris, Tristan K. Underwood, Nicole M. Liu, Elizabeth L. Young, Linda C. Morrison and Garold S. Yost. The project was funded primarily by the University of Utah's Technology Commercialization Program.

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