Does ‘imprinting’ with low prenatal vitamin d contribute to the risk of various adult disorders?

Medical Hypotheses (2001) 56(3), 367–371
doi: 10.1054/mehy.2000.1226, available online at on Does ‘imprinting’ with low prenatal
vitamin D contribute to the risk of
various adult disorders?

J. McGrath
Queensland Centre for Schizophrenia Research, Wolston Park Hospital, Wacol, Queensland, Australia Hypovitaminosis D is a candidate risk-modifying factor for a diverse range of disorders apart from rickets and osteoporosis. Based on epidemiology, and on in vitro and animal experiment, vitamin D has been linked tomultiple sclerosis, certain cancers (prostate, breast and colorectal), insulin-dependent diabetes mellitus andschizophrenia. I hypothesise that low pre- and perinatal vitamin D levels imprint on the functional characteristics ofvarious tissues throughout the body, leaving the affected individual at increased risk of developing a range of adult-onset disorders. The hypothesis draws from recent advances in our understanding of the early origin of adult diseaseand proposes a ‘critical window’ during which vitamin D levels may have a persisting impact on adult health outcomes.
Methods to test the hypothesis are outlined. If correct, the hypothesis has important implications for public health.
Careful attention to maternal vitamin D status could translate into diverse improvements in health outcomes for thefollowing generation. 2001 Harcourt Publishers Ltd PRE- AND PERINATAL EXPOSURES AND
imprinting may be mediated by clonal selection and METABOLIC IMPRINTING
metabolic differentiation. Clonal selection may havelong-lasting effects if early nutritional or hormonal expo- The hypothesis that environmental factors may ‘imprint’ sures differentially advantage certain cell lines: the more on the fetus and contribute to adult health has been stim- numerous facilitated daughter cells may have persisting consequences for the adult organism. Imprinting may Metabolic imprinting has two key features; (a) there is a also operate by ‘metabolic differentiation’: the process of critical window during fetal development or early life cells acquiring a stable quantitative pattern of basal and when the fetus is particularly sensitive to exposures; and inducible gene expression. These mechanisms may relate (b) the exposure leads to changes that persist throughout to enzymes, hormones and their receptors and other components of cellular molecular biology. Metabolic dif- posed several mechanisms for metabolic imprinting.
ferentiation includes epigenetic mechanisms related to Apart from induced variations in organ structure (e.g.
chromatin structure, DNA methylation, and autoregula- vascularization and/or innervation during organogenesis) and alterations in cell numbers (e.g. changes in neuronalcount/density after prenatal malnutrition), metabolic HEALTH AND VITAMIN D: CLUES FROM

Evidence linking vitamin D and various disorders is basedon in vitro, animal and ecological-level research. None of Correspondence to: J. McGrath MBBS, PhD, FRANZCP, Queensland Centre
these features in isolation would be sufficient ‘proof’ that for Schizophrenia Research, Wolston Park Hospital, Wacol, Queensland, vitamin D is involved in causal pathways; however, the Australia. Phone: +617 3271 8595; Fax: +617 2171 8567; E-mail: coherence of the data suggests that low vitamin D is a candidate risk-modifying factor for a range of diseases Diseases that have urban excess include breast other than rickets and osteoporosis. The table displays some of the evidence linking vitamin D and diseases such is also strongly linked to air pollution, a local factor as multiple sclerosis, breast cancer, prostate cancer, col- that influences the availability of UVB. Colorectal orectal cancer, insulin dependent diabetes and schizo- phrenia. The epidemiological similarities between some of these diseases have already been noted for prostate Migrant studies. The offspring of dark-skinned migrants to cold climates are prone to low vitamin D. Those with dark skin require slightly longer exposure to UVB in order to produce previtamin D, disorders can be summarised under several headings: and their behaviour (e.g. dress, outdoor activity,diet) may amplify the risk of hypovitaminosis D.
In vitro and animal experiments. Vitamin D can Multiple sclerosis has a lower incidence in first ameliorate the expression of animal models of generation Asian migrants to the UK than second generation migrants (those born in the UK) Vitamin D can lead to increased differentiation in schizophrenia in the second but not the first Incidence/prevalence associations with latitude.
Oral Vitamin D intake. Apart from sunshine Many diseases have gradients in incidence, exposure, Vitamin D can be derived from certain prevalence and outcome that are correlated with foods in the diet, cod liver oil intake and vitamin latitude. Latitude acts as a risk indicator (or proxy) supplementation. Case-control and cohort studies for the population distribution of serum vitamin D have found links between low oral vitamin D intake levels. A negative correlation between latitude and and increased risk of prostate and colorectal cancer disease incidence is found for disorders such as HYPOTHESIS
Ultraviolet B radiation (UVB). The geographicaldistribution of several diseases has been linked to While the incidence of rickets has declined markedly measures related to the availability of UVB. This over the last century, hypovitaminosis D is still relatively exposure is strongly correlated with latitude and A large US survey reported that 12% of women aged associated with measures related to sunshine 20 to 39 (peak ages for child-bearing) had serum 25- hydroxyvitamin D levels below the threshold defined for are at risk of hypovitaminosis D because of the increased needs of the fetus and the potential for these women to schizophrenia birth rates have also been linked to reduce their outdoor activity, leading to diminished sup- Season of birth. The amount of ultraviolet radiation I propose that low pre- and perinatal vitamin D ‘im- fluctuates across the seasons such that individuals prints’ on a range of tissues, leaving the affected individ- born in winter and early spring tend to be exposed ual at increased risk of developing a range of disorders to lower levels of vitamin D than those born in including osteoporosis, multiple sclerosis, breast cancer, other months. Disorders that have an excess of prostate cancer, colorectal cancer, insulin-dependent dia- winter/spring births suggest that early life betes mellitus and schizophrenia. The early life exposure exposures to low vitamin D may be a risk- contributes to risk status in addition to other factors such modifying exposure. There is robust evidence from as genetic susceptibility and adult exposures (including hypovitaminosis during adult life). With respect to the putative mechanisms of metabolic imprinting, it is pro- similar but weaker evidence for multiple sclerosis posed that vitamin D mediated alterations in neuronal proliferation, differentiation, migration and apoptosis Urban-rural gradient. Urban residence is associated may be implicated in schizophrenia. Vitamin D receptors have been found in differentiating zones of the central Medical Hypotheses (2001) 56(3), 367–371
Biological factors
related to
vitamin D
Season of birth
Urban-rural gradient
Other risk indicators
Migrant studies
Epidemiological clues linking diseases to vitamin D and ultraviolet radiation
Duration of sunshine
Evidence linking vitamin D and selected disorders Medical Hypotheses (2001) 56(3), 367–371
If the hypothesis gains support then a randomized controlled trial of vitamin D supplementation during Factors related to clonal selection and metabolic differen- pregnancy would be indicated; however, the assessment tiation may be particularly important in the vitamin D of outcomes would require several decades of observa- related cancers (breast, prostate, colorectal), multiple scle- tions. Animal experiments could examine the impact on rosis and insulin-dependent diabetes mellitus. low prenatal vitamin D on a range of health outcomes; This hypothesis gains biological plausibility from the however, not all human diseases have robust animal demonstration of persisting alterations in cellular respons- models. The hypothesis also suggests new directions for ivity and organ differentiation after early-life exposure to genetic research: as the hypothesis implicates a prenatal vitamin D deficiency, maternal genes related to vitamin D Interestingly, low prenatal vitamin D has recently been metabolism warrant consideration in addition to those of implicated in the pathogenesis of syndrome ‘X’ (increased insulin resistance, hyperlipidaemia, hypertension, centralobesity, increased fibrinogen and increased risk of non- IMPLICATIONS FOR PUBLIC HEALTH
that low prenatal vitamin D might contribute to low birth Programs that aim to reduce the prevalence of hypovita- weight and program aspects of pancreatic islet beta cell minosis D in pregnant women could translate into a function. These features would then amplify the con- lower incidence of candidate disorders in their offspring.
sequences of adult hypovitaminosis, thus leading to in- Just as folate supplementation has been shown to reduce creased risk of syndrome ‘X’. A diverse range of evidence suggests that low prenatal vitamin D is a candidate expo- vitamin D status (diet, sunlight exposure) could reduce sure for a range of adverse adult health outcomes. the burden of a range of diseases. The population attrib-utable fraction of a particular disease that could be linkedto low prenatal vitamin D is not clear. In addition, the TESTING THE HYPOTHESIS
specificity of the outcomes is weak. However, this feature One could measure vitamin D levels in a large cohort of is a distinct advantage from the public health perspective.
pregnant women, and then follow-up their offspring for If an intervention designed to reduce one particular ex- several decades in order to search for a dose-response posure translates into reduced incidence of several com- relationship (a biological gradient) between low Vitamin mon disorders, then these exposures are deemed more D and increased risk of the candidate disorders. If sera from pregnant women and/or cord blood from their off-spring were ‘banked down’ during past decades, maternal ACKNOWLEDGMENT
vitamin D levels and rates of candidate disorders in the This project was supported by the Stanley Foundation From an ecological perspective, ‘natural’ and oppor- tunistic experiments that impact on Vitamin D may pro- REFERENCES
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Medical Hypotheses (2001) 56(3), 367–371



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