Neurology -- Correspondence for Brenner et al., 63 (2) 276-281

Correspondence published:

Season of birth and risk of brain tumors in adults: Pauline Ko, Darryl Eyles, Thomas Burne, Alan Mackay-Sim, John J. McGrath (22 December 2004)

Reply to Ko: Alina Brenner, MD, PhD, P. D. Inskip, ScD (22 December 2004)

Season of birth and risk of brain tumors in adults 22 December 2004

Pauline Ko,
School of Biomedical Sciences
Room 518, School of Biomedical Sciences, University of Queensland, St Lucia QLD 4072, AUSTRALIA,
Darryl Eyles, Thomas Burne, Alan Mackay-Sim, John J. McGrath
Send Correspondence to journal:
Re: Season of birth and risk of brain tumors in adults

p.ko{at}uq.edu.au Pauline Ko, et al.

The recent paper by Brenner et al reported that, compared to those born in summer, those born in winter had an increased risk of brain tumours as adults. [1] Other studies have also reported an association between season of birth and childhood brain tumors. [2,3]
We would like to propose a specific risk modifying factor that may be causally related to these findings – low prenatal vitamin D3. Levels of vitamin D3 are known to fluctuate across the season (lowest in winter/spring). Recently, rat experiments have demonstrated that prenatal vitamin D3 depletion is associated with altered brain development. [4] Given the anti- proliferative and pro-apoptotic properties of vitamin D3 in various cell types, we recently examined the effects of maternal vitamin D3 deprivation on cell proliferation and apoptosis in the rat brain at several developmental stages (Embryonic Days 19, 21, and Postnatal Days 0 and 7) [5].
Our results confirm that vitamin D3 regulates these processes in the developing rat brain at both cellular and molecular levels. Compared to control animals, embryos and pups from vitamin D3 depleted dams had significantly fewer apoptotic cells and significantly more mitotic cells in the four brain regions examined (cingulate, dentate, basal ganglia, hypothalamus). Targeted gene arrays specific for apoptosis and cell cycle genes confirmed a pattern of transcription dysregulation in the depleted group consistent with the known properties of vitamin D3. While there is research aiming to exploit the pro-apoptotic and prodifferentiating properties of vitamin D3 in order to develop analogues for the treatment of cancers, our findings highlight the important role that this seco- steroid hormone plays in normal development via these same properties.
We propose that fluctuations in prenatal vitamin D may underlie the association between season of birth and risk of brain tumours. While the mechanism of action underlying this association remains to be determined, it is feasible that the increased cellular proliferation found in the developing brains of embryos exposed to low prenatal vitamin D may contribute to cancer pathways. In light of the fact that vitamin D operates via a nuclear receptor, and enlists a range of transcriptional factors involved in chromatin remodelling, it is also feasible that fluctuations in vitamin D3 may alter epigenetic programs established during early brain development.
If transient prenatal hypovitaminosis D contributes to even a small proportion of cases of brain tumors, it warrants further scrutiny. This putative risk factor is readily addressed via cheap and safe public health interventions such as vitamin supplementation.
References
1. Brenner AV, Linet MS, Shapiro WR, Selker RG, Fine HA, Black PM, Inskip PD. Season of birth and risk of brain tumors in adults. Neurology 2004; 63:276-281.
2. McNally RJ, Cairns DP, Eden OB, et al. An infectious aetiology for childhood brain tumours? Evidence from space-time clustering and seasonality analyses. Br J Cancer 2002; 86:1070-1077.
3. Heuch JM, Heuch I, Akslen LA, Kvale G. Risk of primary childhood brain tumors related to birth characteristics: a Norwegian prospective study. Int J Cancer 1998;77: 498-503.
4. Eyles D, Brown J, Mackay-Sim A, McGrath J, Feron F. Vitamin D3 and brain development, Neuroscience 2003:118; 641– 653.
5. Ko P, Burkert R, McGrath J, Eyles D. Maternal vitamin D3 deprivation and the regulation of apoptosis and cell cycle during rat brain development. Developmental Brain Research, in press

Reply to Ko 22 December 2004

Alina Brenner, MD, PhD,
Radiation Epidemiology Branch,
National Cancer Institute, NIH, DHHS, 6120 Executive Blvd, Suite 7090,Bethesda, MD 20892-7238,
P. D. Inskip, ScD
Send Correspondence to journal:
Re: Reply to Ko

brennera{at}mail.nih.gov Alina Brenner, MD, PhD, et al.

As we stated in our paper, the relationship between risk of brain tumors in adults and season of birth warrants cautious interpretation. To the best of our knowledge, this is the first and only report of such an association. While we gave close consideration to potential limitations of the study, the possibility of a chance finding could not be excluded. We thank Dr. Ko for calling attention to experimental findings relating prenatal vitamin D levels and brain development. However, the association between adult brain tumors and season of birth needs to be confirmed before one can assume that it is real. If it is, then seasonally varying vitamin D deficiency might be added to the list of candidate explanations.