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Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
April 15, 2009
Vitamin D is currently in vogue. Supplements are being recommended. To ask about possible adverse effects may be an act of heresy. However, several studies suggest that supplementing with vitamin D may be contra-indicated for individuals with intra-body dioxins or similar molecules. Nishimura studied bone changes in relation to dioxin-induced increase in vitamin D levels (1). His group's and other researchers' findings prompt concern for protocols wherein vitamin D supplements are recommended. Nishimura concluded that the bone alterations their group found were induced by the elevated vitamin D, not by the dioxin (which has induced increases in vitamin D levels). Nishimura and colleagues work with mice and cite murine and rat studies. Findings in such studies don't necessarily apply to humans. However, the likelihood of relevance to humans is augmented because breast milk, cord blood, and infants contain dioxins and similar molecules at physiologically relevant levels (eg, 2-8). Here's a quote from Nishimura et al (1): "Vitamin D has long been known to have a stimulatory effect on bone development and has been used as a therapeutic agent for osteoporosis. Why, then, would a TCDD-induced increase in vitamin D activity cause bone toxicity? Integrating knowledge of the direct effects of vitamin D on mineralization with data obtained in the present study may resolve this question.
"Growing attention has focused on the role of 1,25(OH)2D3 as a negative
regulator of various genes associated with osteoblasts and as a possible
contributor to abnormal mineralization (van Leeuwen et al., 2001).
Osteocalcin was shown to be down-regulated by 1,25(OH)2D3 in mouse in
vivo (Zhang et al., 2002), Hyp mouse-derived osteoblasts (Carpenter et
al., 1998), and the MC3T3-E1 cell line in vitro (Lian et al., 1997).
Further evidence of an inhibitory role of 1,25(OH)2D3 in bone formation
has been provided by Smith et al. (2000), who reported that mice
receiving long-termadministration of 1,25(OH)2D3 had a decrease in bone
quantity and quality,with a decrease in cross-sectional area and
cortical thickness and a 50% reduction in stiffness. High circulating
levels of 1,25(OH)2D3 during development in TRPV5−/− mice have been
shown to cause deficient bone mineralization and reduced bone thickness,
despite normal calciumlevels in the serumand hypercalciuria compared
with corresponding control (Lambers et al., 2006). Bone defects with
impaired mineralization during development due to high circulating
levels of 1,25(OH)2D3 was demonstrated in vitamin D-24-hydroxylase
(24-OHase)−/− mice, which caused extremely high levels of circulating
1,25(OH)2D3; the authors concluded that the elevated concentrations of
1,25(OH)2D3 were responsible for an abnormal accumulation of osteoids
(St-Arnaud et al., 2000)...
"Based on the above findings, we conclude that TCDD exposure at neonatal
development stages of mice causes bone toxicity resulting from the
suppression of osteoblastic activity, not from stimulatory effects on
osteoclastic activity, which leads to mineralization defects of bone.
TCDD-induced up-regulation of the active form of vitamin D is likely the
major contributor to the expression of the toxic manifestations of TCDD
in bone formation, which occurs at early phases of this process via
inhibitory effects on osteocalcin expression." In the context of significant dioxin levels in humans, supplementing
with vitamin D merits careful attention and further research.
References: 1. Dioxin-induced up-regulation of the active form of vitamin D is the
main cause for its inhibitory action on osteoblast activities, leading
to developmental bone toxicity
Noriko Nishimura et al.
Toxicology and Applied Pharmacology 236 (2009) 301–309 Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) is known to cause
bone toxicity, particularly during animal development, although its
action mechanism to cause this toxicity has yet to be elucidated. Mouse
pups were exposed to TCDD via dam's milk that were administered orally
with 15 μg TCDD/kg b.w. on postnatal day 1. Here we report that TCDD
causes up-regulation of vitamin D 1α-hydroxylase in kidney, resulting in
a 2-fold increase in the active form of vitamin D, 1,25-dihydroxyvitamin
D3, in serum. This action of TCDD is not caused by changes in
parathyroid hormone, a decrease in vitamin D degrading enzyme, vitamin D
24-hydroxylase, or alterations in serum Ca2+ concentration. Vitamin D is
known to affect bone mineralization. Our data clearly show that
TCDD-exposed mice exhibit a marked decrease in osteocalcin and collagen
type 1 as well as alkaline phosphatase gene expression in tibia by
postnatal day 21, which is accompanied with a mineralization defect in
the tibia, lowered activity of osteoblastic bone formation, and an
increase in fibroblastic growth factor-23, a sign of increased vitamin D
effect. Despite these significant effects of TCDD on osteoblast
activities, none of the markers of osteoclast activities was found to be
affected. Histomorphometry confirmed that osteoblastic activity, but not
bone resorption activity, was altered by TCDD. A prominent lesion
commonly observed in these TCDD-treated mice was impaired bone
mineralization that is characterized by an increased volume and
thickness of osteoids lining both the endosteum of the cortical bone and
trabeculae. Together, these data suggest that the impaired
mineralization resulting from reduction of the osteoblastic activity,
which is caused by TCDD-induced up-regulation of vitamin D, is
responsible for its bone developmental toxicity.
2. Effects of prenatal PCB and dioxin background exposure on cognitive
and motor abilities in Dutch children at school age.
Vreugdenhil HJ et al.
J Pediatr. 2002 Jan;140(1):48-56. OBJECTIVE: Our purpose was to evaluate whether effects of exposure to
environmental levels of PCBs and dioxins on development in the Dutch
cohort persist until school age. STUDY DESIGN: In the Dutch PCB/dioxin
study, cognitive and motor abilities were assessed with the McCarthy
Scales of Children's Abilities in children at school age. During
infancy, half of this population was fully breast-fed for at least > or
= 6 weeks and the other half formula fed. Prenatal exposure to PCBs was
defined as the sum of PCB118, 138, 153, and 180 in maternal and cord
plasma. In breast milk, additional measurements of 17 dioxins, 6
dioxin-like PCBs, and 20 nondioxin-like PCBs were done. RESULTS:
Negative effects of prenatal PCB and dioxin exposure on cognitive and
motor abilities were seen when parental and home characteristics were
less optimal. These effects were not measurable in children raised in
more optimal environments. CONCLUSIONS: Neurotoxic effects of prenatal
PCB and dioxin exposure may persist into school age, resulting in subtle
cognitive and motor developmental delays. More optimal intellectual
stimulation provided by a more advantageous parental and home
environment may counteract these effects of prenatal exposure to PCBs
and dioxins on cognitive and motor abilities.
3. Immunologic effects of background exposure to polychlorinated
biphenyls and dioxins in Dutch preschool children.
Weisglas-Kuperus N et al.
Environ Health Perspect. 2000 Dec;108(12):1203-7. {free online}
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1240203&blobtype=pdf Prenatal exposure to polychlorinated biphenyls (PCBs) and dioxins is
associated with changes in the T-cell lymphocyte population in healthy
Dutch infants. We investigated whether these changes persist into later
childhood and whether background exposure to PCBs and dioxins is
associated with the prevalence of infectious or allergic diseases and
humoral immunity at preschool age. The total study group consisted of
207 healthy mother-infant pairs. We estimated prenatal exposure to PCBs
and dioxins by the sum of PCBs 118, 138, 153, and 180 (sigmaPCB) in
maternal and cord plasma and in breast-fed infants by the dioxin,
planar, and mono-ortho PCB toxic equivalent (TEQ) levels in human milk.
At 42 months of age, current body burden was estimated by the PCB in
plasma. We assessed the prevalence of infectious and allergic diseases
by parent questionnaire, and measured humoral immunity by antibody
levels for mumps, measles, and rubella after primary vaccination. We
performed immunologic marker analyses of lymphocytes in a subgroup of 85
children. Prenatal PCB exposure was associated with an increased number
of lymphocytes, T-cells, and CD3CD8(+) (cytotoxic), CD4(+)CD45RO(+)
(memory), T-cell receptor (TcR) [alpha]ss(+), and CD3(+)HLA-DR(+)
(activated) T cells and lower antibody levels to mumps and measles at
preschool age. Adjusted for confounders, prenatal PCB exposure was
associated with less shortness of breath with wheeze, and current PCB
body burden was associated with a higher prevalence of recurrent
middle-ear infections and of chicken pox and a lower prevalence of
allergic reactions. A higher dioxin TEQ was associated with a higher
prevalence of coughing, chest congestion, and phlegm. We conclude that
in Dutch preschool children the effects of perinatal background exposure
to PCBs and dioxins persist into childhood and might be associated with
a greater susceptibility to infectious diseases...
4. Effects of perinatal exposure to PCBs and dioxins on play behavior in
Dutch children at school age.
Vreugdenhil HJ et al.
Environ Health Perspect. 2002 Oct;110(10):A593-8. {free online}
http://www.ehponline.org/members/2002/110pA593-A598vreugdenhil/EHP110pa593PDF.PDF Polychlorinated biphenyls (PCBs) and dioxins are known as neurotoxic
compounds that may modulate sex steroid hormones. Steroid hormones play
a mediating role in brain development and may influence behaviors that
show sex differences, such as childhood play behavior. In this study we
evaluated the effects of perinatal exposure to environmental levels of
PCBs and dioxins on childhood play behavior and whether the effects
showed sex differences. As part of the follow-up to the Dutch PCB/dioxin
study at school age, we used the Pre-School Activity Inventory (PSAI) to
assess play behavior in the Rotterdam cohort (n = 207). The PSAI
assesses masculine or feminine play behavior scored on three subscales:
masculine, feminine, and composite. Prenatal exposure to PCBs was
defined as the sum of PCB 118, 138, 153, and 180 in maternal and cord
plasma and breast milk. For breast milk we measured additional PCBs as
well as 17 dioxins. Respondents returned 160 questionnaires (age 7.5
years +/- 0.4). Effects of prenatal exposure to PCBs, measured in
maternal and cord plasma, on the masculine and composite scales were
different for boys and girls (p <.05). In boys, higher prenatal PCB
levels were related with less masculinized play, assessed by the
masculine scale (p(maternal) =.042; p(cord) =.001) and composite scale
(p(cord) =.011), whereas in girls higher PCB levels were associated with
more masculinized play, assessed by the composite scale (p(PCBmilk)
=.028). Higher prenatal dioxin levels were associated with more
feminized play in boys as well as girls, assessed by the feminine scale
(p =.048). These effects suggest prenatal steroid hormone imbalances
caused by prenatal exposure to environmental levels of PCBs, dioxins,
and other related organochlorine compounds.
5. An investigation of homes with high concentrations of PCDDs, PCDFs,
and/or dioxin-like PCBs in house dust.
Franzblau A et al.
J Occup Environ Hyg. 2009 Mar;6(3):188-99.Click here to read Links As part of the University of Michigan Dioxin Exposure Study, the 29
congeners of polychlorinated dibenzo-p-dioxins, polychlorinated
dibenzofurans, and dioxin-like polychlorinated biphenyls that have World
Health Organization consensus toxic equivalency factors were measured in
house dust from 764 homes using a population-based sampling design over
selected regions in five Michigan counties. Twenty homes had a total
toxic equivalency in house dust that was more than 2.5 standard
deviations above the mean (i.e., defined to be outliers). This follow-up
investigation describes the outlier house dust measurements and
corresponding soil measurements and explores possible sources of these
toxins in house dust. The congener distributions in the house dust
outliers varied and were dominated (i.e., >50% of the total toxic
equivalency) by either polychlorinated dibenzo-p-dioxins (n = 9),
polychlorinated dibenzofurans (n = 1), or dioxin-like polychlorinated
biphenyls (n = 9). Likely sources of contamination of house dust were
identified in only three cases. In two cases, dust contamination
appeared to be related to contaminated soil adjacent to the home; in one
case, contamination was related to a source within the home (a carpet
pad). In most cases, the source(s) of contamination of house dust could
not be identified but appeared likely to be related to uncharacterized
sources within the homes.
6. Dioxin-like activity in plasma among Danish pregnant women: dietary
predictors, birth weight and infant development.
Halldorsson TI et al.
Environ Res. 2009 Jan;109(1):22-8. The aim of this study was to identify dietary predictors of plasma
dioxin-like activity in women from the Danish National Birth Cohort.
Associations between exposure and birth weight and infant development at
6 months were also explored. Diet was assessed in mid-pregnancy by a
food-frequency questionnaire. One hundred nulliparous 25-35-year-old
women of normal pre-pregnancy body-mass-index were chosen according to
their intake of fatty fish, as fatty fish is a potential route of
exposure. Intake of other foods of animal origin was also explored.
Dioxin-like activity was measured in plasma using the Dioxin-Responsive
Chemically Activated LUciferase eXpression (DR-CALUX) and quantified in
toxic equivalents (CALUX-TEQs). Information on infant attainment of
specific milestones was obtained by maternal report in a standardized
interview. The sample mean was 46 pg CALUX-TEQ/g lipid. Plasma
dioxin-like activity increased by 10.7 pg CALUX-TEQ/g lipid (95% CI:
1.8; 19.7) for the highest compared to the lowest tertile of total
dietary fat intake but decreased by -9.8 pg CALUX-TEQ/g lipid (95% CI:
-19.4; -0.2) for fatty fish intake. The inverse association for fatty
fish was explained by lower intake of high-fat food groups such as red
meat, fats and oils, which were also predictors of dioxin-like activity.
Plasma dioxin-like activity was not associated with birth weight, but an
inverse correlation was observed with total developmental score
(Spearman r=-0.23, p=0.046). Our study indicates that dietary patterns
associated with high fat intake may lead to increased plasma dioxin-like
activity and in utero exposure might be related to early infant development. 7. Dioxin-like activity in plasma among Danish pregnant women: dietary
predictors, birth weight and infant development.
Halldorsson TI et al.
Environ Res. 2009 Jan;109(1):22-8. The aim of this study was to identify dietary predictors of plasma
dioxin-like activity in women from the Danish National Birth Cohort.
Associations between exposure and birth weight and infant development at
6 months were also explored. Diet was assessed in mid-pregnancy by a
food-frequency questionnaire. One hundred nulliparous 25-35-year-old
women of normal pre-pregnancy body-mass-index were chosen according to
their intake of fatty fish, as fatty fish is a potential route of
exposure. Intake of other foods of animal origin was also explored.
Dioxin-like activity was measured in plasma using the Dioxin-Responsive
Chemically Activated LUciferase eXpression (DR-CALUX) and quantified in
toxic equivalents (CALUX-TEQs). Information on infant attainment of
specific milestones was obtained by maternal report in a standardized
interview. The sample mean was 46 pg CALUX-TEQ/g lipid. Plasma
dioxin-like activity increased by 10.7 pg CALUX-TEQ/g lipid (95% CI:
1.8; 19.7) for the highest compared to the lowest tertile of total
dietary fat intake but decreased by -9.8 pg CALUX-TEQ/g lipid (95% CI:
-19.4; -0.2) for fatty fish intake. The inverse association for fatty
fish was explained by lower intake of high-fat food groups such as red
meat, fats and oils, which were also predictors of dioxin-like activity.
Plasma dioxin-like activity was not associated with birth weight, but an
inverse correlation was observed with total developmental score
(Spearman r=-0.23, p=0.046). Our study indicates that dietary patterns
associated with high fat intake may lead to increased plasma dioxin-like
activity and in utero exposure might be related to early infant development. 8. PCDD/F and dioxin-like PCB in human blood and milk from German mothers.
Wittsiepe J et al.
Chemosphere. 2007 Apr;67(9):S286-94. Epub 2007 Jan 10. Blood samples of pregnant women aged between 19 and 42 years at the time
they gave birth and milk samples from the same women following delivery
were collected between September 2000 and January 2003 from 169
participants living in an industrialized area of Germany (Duisburg birth
cohort study). All samples were analyzed for their content of
polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) as well as
dioxin-like and indicator polychlorinated biphenyls (PCB). Levels of
WHO-TEq were in the range of 4.34-97.3 pg/g(lipid base) (median: 26.37,
arithmetic mean: 28.36) for blood, or 3.01-78.7 pg/g(lipid base)
(median: 26.40, arithmetic mean: 27.27) for milk, respectively. The four
congeners 12378-PeCDD, 23478-PeCDF, 33'44'5-PeCB (# 126) and
233'44'5-HxCB (# 156) contribute the main share to total WHO-TEq. The
contribution of PCDD/F in relation to PCB to total WHO-TEq was 60:40% in
blood and 52:48% in milk. Good correlations of the contaminant levels in
lipid base between both matrices were found. The distribution between
blood and milk depends on the molecular weight of the substances. Higher
chlorinated PCDD/F- and PCB-congeners were found in 2-4-fold higher
concentrations in blood in relation to milk and the concentrations of
lower chlorinated PCB-congeners were up to 2-fold higher in milk in
relation to blood. The body burden of PCDD/F and PCB increases with age
and decreases over the total nursing period. Women who had lived outside
highly industrialized countries showed lower concentrations of PCDD/F
and PCB. In some cases, elevated levels of PCB were observed when the
women had previously lived in Eastern Europe for a long time. In
comparison with recent data, the decline in human PCDD/F and PCB levels
observed during the nineties seems to have stopped. The individual
exposures of the infants due to breastfeeding within the first 18 months
were calculated to be from 4.4 to 318 ng WHO-TEq (median: 106,
arithmetic mean: 118). The actual mean daily exposure of a breastfed
infant can be estimated to 131 pg WHO-TEq/kg(body weight).
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