- Supplementation of high doses of vitamin D during the gestational period do not cause reproductive, teratogenic and genotoxic damage in mice
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- Very strange: 50% of mice should be killed by 34,000 IU (20 gram mouse)
Supplementation of high doses of vitamin D during the gestational period do not cause reproductive, teratogenic and genotoxic damage in mice
Food and Chemical Toxicology Sept 2024, https://doi.org/10.1016/j.fct.2024.115007
Vitamin D deficiency during pregnancy may have adverse effects on embryo-fetal and postnatal development. Indeed, vitamin D supplementation has been indicated for pregnant women. However, there are no studies that indicate the safe dose of this supplementation during the gestational period. Therefore, the present study assessed the effects of high doses of vitamin D and vitamin D combined with calcium on reproductive performance, embryo-fetal development, and DNA integrity in Swiss mice.
A total of 140 pregnant female mice treated with vitamin D and vitamin D combined with calcium were analyzed in two experiments.
- In one experiment, mice received intramuscular supplementation at doses of 600,000, 6,000,000, or 60,000,000 IU of vitamin D.
- These same doses were also associated with the dose of 8.56 mg/kg of calcium.
- In the other experiment, mice received a single oral dose of 6,000, 60,000, or 600,000 IU of vitamin D.
These same doses were also associated with the dose of 8.56 mg/kg of calcium. The treatments were always carried out in the 10th gestational day. The results show that neither intramuscularly nor orally administered vitamin D and vitamin D combined with calcium affected reproductive performance, embryo-fetal development, or DNA integrity at the different doses tested. These pioneering results confirm the safety of using this type of high doses of supplementation, including during pregnancy.
Introduction
Low vitamin D levels during pregnancy may cause adverse effects on embryo-fetal and postnatal development and result in premature birth [1]. Moreover, low serum levels of vitamin D have been correlated with an increased risk for infectious diseases, changes in tooth development [1], schizophrenia [2], type 1 diabetes [3] and asthma [4] in humans. Furthermore, postnatal changes, such as rickets and delayed bone mineralization persisting until nine years of age [5], [6], have also been reported in the literature. These facts show the necessity of vitamin D for embryofetal health and fetal programming [7], [8], [9].
Notably, vitamin D deficiency/insufficiency is associated with the development of metabolic syndrome and obesity [10], [11], [12], [13], two important current public health issues [10], [11], [12], [13], [14], [15], [16]. The literature is still discordant in stating whether metabolic syndrome results in obesity or whether it is obesity that causes metabolic syndrome. However, the association between these is well described [17]. Metabolic syndrome is characterized by the presence of obesity (especially abdominal), high blood pressure, altered lipid and glucose metabolism, elevated fasting glycemia, increased serum triglyceride levels and reduced HDL-c [18], [19], [20]. Furthermore, it is very common to observe atherogenic diseases and insulin resistance [21]. To make the diagnosis, at least three of these changes must be associated [22]. According to Castro et al. [23], obesity is important for the development of metabolic syndrome and in this context low serum levels of Vitamin D and its components are observed [24], [25], [26]. Thus, it is believed that the reduction of Vitiman D in obese patients and/or patients with metabolic syndrome occurs because Vitamin D is sequestered by adipocytes due to the high affinity of Vitamin D and the lipids accumulated in these cells. Continuing, the sequestration of Vitamin D determines the reduction of the stimulus of cascades of hypothalamic reactions. Thus, the individual will have an increased feeling of hunger and a decrease in energy expenditure. These two factors may favor an increase in the degree of obesity and an increasing reduction in bioavailable Vitamin D [20], [27], [28], [29].
Women during pregnancy gain weight due to the development of the fetus, fluid retention and above all due to the increase in fat reserves [30]. However, some women gain more weight than others and most pregnant women do not easily return to their usual weight after delivery [31], [32], [33], that is, they have difficulty losing the weight gained during pregnancy.
It should also note that many pregnant women have obesity and metabolic syndrome [34], [35], [36]. These facts show the necessity of vitamin D for the maintenance of maternal weight during pregnancy and after birth. Therefore, vitamin D supplementation is necessary, especially because exposure to sunlight and dietary intake does not provide sufficient amounts of this vitamin [8], [9], [37]. These facts are preponderant causes for the epidemic of Vitamin D deficiency/insufficiency globally [38], that is, this condition is present in both developed and underdeveloped countries [39], [40]. It is also noteworthy that this is also found in tropical/equatorial regions (where there is a lot of sunshine) [12] and in temperate countries (where there is low sunshine) [41]. It is also observed that even in populations that use the Mediterranean diet (rich in Vitamin D) deficiency/insufficiency of this vitamin still occurs [42].
Facts that prove this need for supplementation is the study by Cui et al. [43] who reported found that globally, 15.7% (95% Crl 13.7-17.8), 47.9% (95% Crl 44.9-50.9), and 76·6% (95% Crl 74.0-79.1) of participants had serum 25- hydroxyvitamin D levels less than 30, 50, and 75 nmol/L, respectively. That same study reports that the prevalence slightly decreased from 2000-2010 to 2011-2022, but it was still at a high level; people living in high latitude areas had a higher prevalence; the prevalence in winter-spring was 1.7 (95% Crl 1.4-2.0) times that in summer-autumn; the Eastern Mediterranean region and Lower-middle-income countries had a higher prevalence; females were vulnerable to vitamin D deficiency.
Weekly supplementation with 50,000 IU vitamin D for eight weeks or 6,000 IU vitamin D per day until reaching serum levels of 25(OH)D higher than 30 ng/mL is also suggested for adults deficient in vitamin D.
After normalization, normal vitamin D levels are maintained with supplementation ranging from 1,500 to 2,000 IU per day [44]. The vitamin D levels of women considering pregnancy or who are pregnant should be monitored every three months, and these women should be treated with at least 4,400 IU per day, if necessary [45], [46]. Conversely, lactating women require 6,400 IU per day to ensure that breast milk is a rich source of vitamin D [47]. In cases of severe vitamin D deficiency, single intramuscular doses of up to 600,000 IU are reported as therapeutic doses in the literature [48], [49] and this prescription even includes pregnant women. However, the safety of this supplementation during the gestational period has not yet been demonstrated, and higher doses may be required to treat patients with autoimmune conditions because they poorly metabolize vitamin D [50].
Calcium is an element necessary for bone mineralization [51], a process that also affects vitamin D. Therefore, when the calcium levels are reduced there is an increase in the active form of vitamin D that raises intestinal absorption [52]. In pregnant women, there is a necessity of the highest number of calcium intake (which can be done by ingesting chelated calcium), especially, in the third trimester of pregnancy when the fetal bone reaches the highest peak of growth. Consequently, there is a corresponding increase in the absorption of this element in the intestinal mucosa of the mother. These physiologic processes lead to an increase in activated vitamin D 1,25 (OH) 2D synthesis [52], [53], [54].
In view of the above, the present study aimed to investigate the effects of high doses of vitamin D supplementation and its combination with calcium on reproductive performance, embryo-fetal development, and DNA integrity in pregnant Swiss mice.
Section snippets
Chemical agents
Vitamin D, cholecalciferol 25(OH)2D, (Lot 1408221) and Chelated calcium was provided by the Compounding Pharmacy Formédica Ltd. (National Registry of Legal Entities (Cadastro Nacional da Pessoa Jurídica – CNPJ) 82.342.403/0001-83), whose managing pharmacist is Sandra Kuniyoshi.
Vitamin D: doses, routes and period of administration
Two double-blind experiments were conducted: In one experiment, mice received intramuscular supplementation at a dose corresponding to 600,000 IU in a 70-kg patient [48], whereas in the other experiment, the mice received…
Biometric parameters
The animals were randomly assigned to different lots and experimental groups. Animals receiving the two highest intramuscularly doses of vitamin D combined with calcium exhibited weight reductions compared with the control group, whereas orally vitamin D did not significantly impact body weight (p>0.05). The final weight, weight gain, uterine weight, and net weight gain did not differ (p>0.05) between any groups in (Table S1).
The absolute and relative organ weight did not differ between groups,…
Discussion
The assessment of biometric parameters showed no signs of maternal toxicity. The only significant variation identified as the relative spleen weight of the animals treated with the lowest dose of vitamin D in combination with calcium. This difference is an isolated incidence. The absence of variations in biometric parameters along with the absence of clinical signs of intoxication (opacity of eyes and hair, mucosal dryness, hair bristling, behavioral changes, changes in walking, i.e., locomotor…
Conclusion
Based on the above considerations, infer that vitamin D and vitamin D are associated with calcium, at intramuscular doses of 600,000IU, 6,000,000IU and 60,000,000IU and at orally doses of 6,000IU, 60,000IU and 600,000IU, tested in pregnant Swiss mice is not maternal-toxic, not genotoxic and do not change the reproductive performance and embryofetal development, what suggest safety of use also during the gestational period.
81+ VitaminDWiki pages have HIGH DOSE in the title
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VitaminDWiki – Overview Toxicity of vitamin D dosing chart
600,000 IU daily for a week MIGHT be toxic
VitaminDWiki – Injection contains:
- Vitamin D injections last longer (3 month vs 2 month) than loading doses
- Getting Vitamin D into your blood and cells shows the many ways of getting Vitamin D
- Injections are currently made by medical professionals into muscle
- Home injection of Vitamin D appears to be possible in the future
- Injections are useful for people who might forget to take their periodic supplement (children, elderly, etc) and those who cannot swallow or have poor digestion
- While Vitamin D2 is historically the common form, Vitamin D3 is far better
- Should check (if there is time) for possible allergic reaction to Vitamin D or lack of Magnesium for both for loading dose and injection
- Note 600,000 IU Vitamin D loading dose via capsules is 1/20th the cost($2.40) of an injection, and does not require a prescription
- 100,000 IU single dose of vitamin D - 2010 has the following
- Vitamin D injection lasts longer and has bigger response than weekly oral – Jan 2017 has the following
- Non-oral Vitamin D should be a better form for MS, food allergy, PTSD, etc. – many studies might include injection
Very strange: 50% of mice should be killed by 34,000 IU (20 gram mouse)
The oral LD50 (lethal dose for 50% of the population) of cholecalciferol in rats/mice is 43.6 mg/kg
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