International Journal of Epidemiology, 2014, 1–2 doi: 10.1093/ije/dyu004
Letter to the Editor Paracetamol, oxidative stress, vitamin D and autism spectrum disorders From John J Cannell 5
10
15
20
25
30
35
Vitamin D Council, 1411 Marsh Street, Suite 203, San Luis Obispo, CA 93401, USA. E-mail:
[email protected]
Brandlistuen et al. recently documented the detrimental role that gestational paracetamol exposure has on childhood neurodevelopment, putatively due to oxidative stress.1 Although the authors did not use the words ‘autism spectrum disorder’ (ASD), clearly some of the adverse neurodevelopmental effects they demonstrated are consistent with ASD. This is not the first time that paracetamol has been implicated in ASD. In an ecological analysis, Bauer and Kriebel found a strong correlation between use of paracetamol and prevalence of ASD.2 If paracetamol causes ASD, and if oxidative stress is the mechanism, then the antioxidant capability of the mother and child would be key to explaining why some exposed children develop ASD and some do not. Activities of superoxide dismutase, glutathione reductase and glutathione peroxidase are all strongly associated with serum vitamin D levels.3 Asemi et al. found, in a randomized controlled trial of 48 pregnant women, that vitamin D supplementation increased total plasma antioxidant capacity (P-interaction ¼ 0.002), and total glutathione concentrations (P-interaction ¼ 0.02) compared with controls.4 Another randomized controlled trial of vitamin D3 found that it increased human antioxidant capabilities.5 Thus, the fetuses of vitamin D-deficient mothers would be less able to bear the oxidative stress caused by gestational paracetamol exposure. A recent review concluded that vitamin D deficiency may be a major risk factor for ASD, in part due to lack of the antioxidant properties of vitamin D.6 Three recent studies, using community controls, have found that vitamin D levels are significantly lower in children with ASD.7,8,9 Two of the studies (Mostafa et al. and
Gong et al.) also found that ASD severity, as rated on standard ASD rating scales, is inversely correlated with vitamin D levels. Mostafa et al. found an R value of .86 for the association of serum vitamin D with ASD severity on rating scales. This model (oxidative stress triggering ASD in vitamin D-deficient pregnant women and young children) is one of the theories of ASD with significant support.10 Other insults that increase oxidative stress are implicated in ASD, such as infections, toxins, fever and inflammation. It may be that paracetamol exposure is one of several oxidative stressors that trigger ASD development in vitamin D-deficient pregnant women and young children.
40
45
50
Potential conflict of interest: J.J.C. is executive director of the non-profit Vitamin D Council and receives remuneration from Purity Products.
References
55
1. Brandlistuen RE, Ystrom E, Nulman I et al. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol 2013;42:1702–13. 2. Bauer AZ, Kriebel D. Prenatal and perinatal analgesic exposure and autism: an ecological link. Environ Health 2013;12:41. 3. Saedisomeolia A, Taheri E, Djalali M et al. Vitamin D status and its association with antioxidant profiles in diabetic patients: A cross-sectional study in Iran. Indian J Med Sci 2013;67:29–37. 4. Asemi Z, Hashemi T, Karamali M, Samimi M, Esmaillzadeh A. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr 2013;143:1432–38. 5. Nikooyeh B, Nyestani TR, Tayebinejad W et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence
C The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association V
1
60
65
70
International Journal of Epidemiology, 2014, Vol. 0, No. 0
5
10
for antioxidative properties of vitamin D. J Hum Nutr Diet 2013. doi: 10.1111/jhn.1242. 6. Kocˇovska´ E, Fernell E, Billstedt E, Minnis H, Gillberg C. Vitamin D and autism: clinical review. Res Dev Disabil 2012;33:1541–50. 7. Gong ZL, Luo CM, Wang L et al. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport 2013;25:23–27. 8. Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian
2 children with autism. J Altern Complement Med 2010; 16:641–45. 9. Mostafa GA, Al-Ayadhi LY. Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation 2012;9:201. 10. Gentile I, Zappulo E, Militerni R, Pascotto A, Borgia G, Bravaccio C. Etiopathogenesis of autism spectrum disorders: fitting the pieces of the puzzle together. Med Hypotheses 2013; 81:26–35.
15
