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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development


Stronger muscles for newborn babies

Glucocorticoids effects on the fetus must be considered when treating expectant mothers or newborn babies with steroids. Ongoing research is determining whether these negative effects can be minimized or eliminated by medical intervention after birth.

A frequent and significant problem in neonates is poor growth following premature birth. "A condition for which causes, optimal management and long-term consequences are still not completely understood," says Marta Fiorotto PhD, associate professor of pediatrics-nutrition and of molecular physiology and biophysics at the USDA/ Children's Nutrition Research Center at Baylor College of Medicine and Texas Children's Hospital.

"It is important to know how muscles are affected in the fetus because we need muscles to breathe, to eat and swallow and to move," Fiorotto adds. "If those muscles are compromised in any way during fetal development, those functions are also likely to be compromised in the newborn baby and affect his or her growth." Her paper is published in the Journal of Endocrinology.

Scientists propose malnutrition and stress as two major environmental factors affecting fetal growth.

Interestingly, these two factors expose the fetus to high levels of cortisol, an endogenous glucocorticoid which is part of a class of steroid stress hormones.

"Lack of proper nutrition, a form of stress, in an expectant woman raises the levels of cortisol in her blood," says Fiorotto, also director of the Mouse Metabolic Research Unit at the USDA/ARS Children's Nutrition Research Center at Baylor and Texas Children's Hospital. But is it the lack of proper nutrition during pregnancy itself or the exposure to increased levels of glucocorticoids that affect fetal growth?

Dr. Ganga Gokulakrishnan, a neonatologist at Texas Children's Hospital and assistant professor at Baylor College of Medicine working with Dr. Fiorotto, investigates how glucocorticoids affect the growth of fetal muscles in the rat.

"You can think of a muscle as a bundle of uncooked spaghetti; each spaghetti is a fiber - a single muscular cell - with many nuclei in a matrix of protein," Gokulakrishnan explains. "The number of fibers is already determined by birth and does not increase during postnatal life. So, postnatally, muscles grow by adding both more protein and more nuclei to the fibers. Nuclei are added by muscle stem cells — also called satellite cells — that divide and fuse with the fibers. These muscle stem cells drive muscle growth during fetal development. After puberty, however, the muscles stop accumulating nuclei and grow by adding only protein to the fibers."

Previous studies in rats show exposure of fetuses to glucocorticoids impairs muscle growth. This is partly due to reduced proteins being produced.

Gokulakrishnan examined effects of glucocorticoids on other mechanism of muscle growth, namely the addition of nuclei to fibers by satellite cells, in early development.

"We were surprised at the magnitude of impairment we observed in the replication of satellite cells in the muscles of fetal rats exposed to glucocorticoids," said Gokulakrishnan. "Taking all the results together, we found that the effect of glucocorticoids on fetal muscle growth is quite complex; it depends on the duration, the level of glucocorticoids and the time during pregnancy when it occurs."

For instance, when a mother's food intake is about 85 percent of normal, protein deposition in fetal muscles is affected quite remarkably. But, this mild restriction in food does not affect the accumulation of nuclei.

"However, our results from the current study indicate that treating rats with a dose of glucocorticoids that mimics more severe food restriction affects the reserve of satellite cells, the accumulation of nuclei in the fibers, and therefore, muscle growth," Gokulakrishnan said.

The health of future generations starts with the health of the mother.

Gokulakrishnan continues: "Conditions such as stress or malnutrition are factors that could be identified and mitigated by prenatal care. Once again emphasizing the importance of a proper diet and antenatal care for all pregnant mothers."

"Maternal stress negatively affects growth of the fetus at the cellular level. This has been demonstrated for other organs, including the brain.

"We have now learned that, because this is affecting muscle stem cells, it is possible that these negative effects on the fetus could have life-long consequences.

"This is another example that illustrates how the health of future generations starts with the health of the mother."

Marta Fiorotto MD, Director, Mouse Metabolic Research Unit, USDA/ARS, Children's Nutrition Research Center, Baylor and Texas Children's Hospital.

Perinatal skeletal muscle growth rates are a function of protein and myonuclear accretion. Precocious exposure of the fetus to glucocorticoids (GLC) in utero impairs muscle growth. Reduced muscle protein synthesis rates contribute to this response, but the consequences for myonuclear hyperplasia are unknown. To test the hypothesis that blunting of Pax7+ muscle progenitor cell proliferative activity by GLC in vivo also contributes to reduced fetal muscle growth, pregnant rats were administered dexamethasone (DEX;1 mg/L drinking water) from embryonic day (ED) 13 to ED21. Their responses were compared to pair-fed (PF) and ad libitum-fed controls (CON). Bromo-deoxyuridine (BrdU) was administered before delivery to measure myonuclear accretion. Fetal hind limb and diaphragm muscles were collected at term and analyzed for myofiber cross-sectional area (CSA), total and BrdU+ myonuclei, Pax7+ nuclei, MyoD and myogenin protein and mRNA abundance, and myosin heavy chain (MyHC) isoform composition. Mean fiber CSA, myonuclei/myofiber and Pax7+ nuclei/myofiber ratios were reduced in DEX compared to CON and PF muscles; CSA/myonucleus, BrdU+/total myonuclei, and BrdU+ myonuclei/Pax7+ nuclei were similar among groups. Myogenin abundance was reduced and MyHC-slow was increased in DEX fetuses. The data are consistent with GLC inhibition of muscle progenitor cell proliferation limiting satellite cell and myonuclear accretion. The response of PF-fed compared to CON muscles indicated that decreased food consumption by DEX dams contributed to the smaller myofiber CSA but did not affect Pax7+ nuclear accretion. Thus, the effect on satellite cell reserve and myonuclear number also contributes to the blunting of fetal muscle growth by GLC.

Received 9 August 2016; Received in final form 12 December 2016; Accepted 17 January 2017;
Accepted Preprint first posted online on 17 January 2017

Xiaoyan Chang and Ryan Fleischmann at Baylor also contributed to this work.

This work is a publication of the USDA/ARS Children's Nutrition Research Center and the Department of Pediatrics at Baylor College of Medicine.
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Is it the lack of proper nutrition during pregnancy, or the exposure to
increased levels of glucocorticoids, that negatively affect fetal growth?
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