Maternal Dyslipidemia, Plasma Branched-Chain Amino Acids, and the Risk of Child Autism Spectrum Disorder: Evidence of Sex Difference
In contrast to the well-observed associations between obesity, diabetes, and autism spectrum disorder (ASD), the roles of maternal dyslipidemia and sex disparity in ASD have not been well-studied. We examined the joint associations of maternal plasma cholesterols, branched-chain amino acids (BCAAs) and child sex on child ASD risk. We analyzed data from 756 mother-infant pairs (86 ASD) from the Boston Birth Cohort. Maternal plasma cholesterols and BCAAs were measured in samples collected 24–72 h postpartum. We found that in this urban, low-income prospective birth cohort, low maternal high-density lipoprotein cholesterol (HDL-C), above-median maternal plasma BCAA concentrations, and male sex additively or synergistically increased risk of ASD. Additional studies are necessary to confirm our findings.
KeywordsAutism spectrum disorder Maternal cholesterols Pre- and perinatal risk factors Sex differences Branched-chain amino acids Metabolomics
The authors would like to thank all the study participants and staff as the study would not have been possible without their support and participation. This work is supported by the Health Resources and Services Administration (HRSA) of the US Department of Health and Human Services (HHS) under Grant Numbers R40MC27443 and UJ2MC31074. The Boston Birth Cohort (parent study) is supported in part by the March of Dimes PERI Grants (20-FY02-56, #21-FY07-605); and the National Institutes of Health (NIH) Grants (R21ES011666, 2R01HD041702, R21HD066471, U01AI090727, R21AI079872, and R01HD086013). This information or content and conclusions are those of the authors and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS, or the U.S. Government. The authors do not have any conflicts of interest to disclose.
AAP conceptualized the study, performed the statistical analysis, participated in the interpretation of the data, and drafted the manuscript. YJ conceptualized the study and assisted in statistical analysis and interpretation of the data. JWF and AP conceptualized the study and participated in the interpretation of the data. GW and XH participated in the design and coordination of the study and data cleaning. BZ oversaw and managed participant recruitment, follow-up, and data collection. XW is the founder and principal investigator of the Boston Birth Cohort and oversaw participant recruitment, follow-up and data collection, conceptualized the study, and provided critical input on study design, data analyses, interpretation of data, and initial draft of the manuscript. All authors critically reviewed and approved the final manuscript.
Compliance with Ethical Standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- Anderson, T. W., & Rubin, H. (1956). Statistical inference in factor analysis. Proceedings of the Berkeley Symposium on Mathematical Statistics and Probability, 3(5), 111–150.Google Scholar
- Bent, S., Lawton, B., Warren, T., Widjaja, F., Dang, K., Fahey, J. W., et al. (2018). Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli. Molecular Autism, 9(1), 35. https://doi.org/10.1186/s13229-018-0218-4.CrossRefPubMedPubMedCentralGoogle Scholar
- Cartocci, V., Tonini, C., Di Pippo, T., Vuono, F., Schiavi, S., Marino, M., et al. (2019). Prenatal exposure to valproate induces sex-, age-, and tissue-dependent alterations of cholesterol metabolism: Potential implications on autism. Journal of Cellular Physiology, 234(4), 4362–4374. https://doi.org/10.1002/jcp.27218.CrossRefPubMedGoogle Scholar
- Gillberg, C., Fernell, E., Kocovska, E., Minnis, H., Bourgeron, T., Thompson, L., et al. (2017). The role of cholesterol metabolism and various steroid abnormalities in autism spectrum disorders: A hypothesis paper. Autism Research, 10(6), 1022–1044. https://doi.org/10.1002/aur.1777.CrossRefPubMedPubMedCentralGoogle Scholar
- Ji, Y., Riley, A. W., Lee, L. C., Volk, H., Hong, X., Wang, G., et al. (2018). A prospective birth cohort study on maternal cholesterol levels and offspring attention deficit hyperactivity disorder: New insight on sex differences. Brain Sciences, 8(1), 3. https://doi.org/10.3390/brainsci8010003.CrossRefGoogle Scholar
- Jiang, S., Jiang, J., Xu, H., Wang, S., Liu, Z., Li, M., et al. (2017). Maternal dyslipidemia during pregnancy may increase the risk of preterm birth: A meta-analysis. Taiwanese Journal of Obstetrics and Gynecology, 56(1), 9–15. https://doi.org/10.1016/j.tjog.2016.07.012.CrossRefPubMedGoogle Scholar
- Jin, W., Lin, S., Hou, R., Chen, X., Han, T., Jin, Y., et al. (2016). Associations between maternal lipid profile and pregnancy complications and perinatal outcomes: A population-based study from China. BMC Pregnancy and Childbirth, 16(1), 60. https://doi.org/10.1186/s12884-016-0852-9.CrossRefPubMedPubMedCentralGoogle Scholar
- Joseph, R. M., O’Shea, T. M., Allred, E. N., Heeren, T., Hirtz, D., Paneth, N., et al. (2017). Prevalence and associated features of autism spectrum disorder in extremely low gestational age newborns at age 10 years. Autism Research, 10(2), 224–232. https://doi.org/10.1002/aur.1644.CrossRefPubMedGoogle Scholar
- Knol, M. J., VanderWeele, T. J., Groenwold, R. H., Klungel, O. H., Rovers, M. M., & Grobbee, D. E. (2011). Estimating measures of interaction on an additive scale for preventive exposures. European Journal of Epidemiology, 26(6), 433–438. https://doi.org/10.1007/s10654-011-9554-9.CrossRefPubMedPubMedCentralGoogle Scholar
- Kujala, U. M., Peltonen, M., Laine, M. K., Kaprio, J., Heinonen, O. J., Sundvall, J., et al. (2016). Branched-chain amino acid levels are related with surrogates of disturbed lipid metabolism among older men. Frontiers in Medicine, 3, 57. https://doi.org/10.3389/fmed.2016.00057.CrossRefPubMedPubMedCentralGoogle Scholar
- Laz, T., Rahman, M., & Berenson, A. (2013). Trends in serum lipids and hypertension prevalence among non-pregnant reproductive-age women: United states national health and nutrition examination survey 1999–2008. Maternal and Child Health Journal, 17(8), 1424–1431. https://doi.org/10.1007/s10995-012-1148-y.CrossRefPubMedPubMedCentralGoogle Scholar
- Lepsch, J., Eshriqui, I., Farias, D. R., Vaz, J. S., Cunha Figueiredo, A. C., Adegboye, A. R. A., et al. (2017). Association between early pregnancy vitamin D status and changes in serum lipid profiles throughout pregnancy. Metabolism, 70, 85–97. https://doi.org/10.1016/j.metabol.2017.02.004.CrossRefPubMedGoogle Scholar
- Li, M., Fallin, M. D., Riley, A., Landa, R., Walker, S. O., Silverstein, M., et al. (2016). The association of maternal obesity and diabetes with autism and other developmental disabilities. Pediatrics, 137(2), e20152206. https://doi.org/10.1542/peds.2015-2206.CrossRefPubMedPubMedCentralGoogle Scholar
- Limperopoulos, C., Bassan, H., Sullivan, N. R., Soul, J. S., Robertson, R. L., Jr., Moore, M., et al. (2008). Positive screening for autism in ex-preterm infants: Prevalence and risk factors. Pediatrics, 121(4), 758–765. https://doi.org/10.1542/peds.2007-2158.CrossRefPubMedPubMedCentralGoogle Scholar
- Loomes, R., Hull, L., & Mandy, W. P. L. (2017). What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis. Journal of the American Academy of Child and Adolescent Psychiatry, 56(6), 466–474. https://doi.org/10.1016/j.jaac.2017.03.013.CrossRefPubMedGoogle Scholar
- Lussu, M., Noto, A., Masili, A., Rinaldi, A. C., Dessì, A., De Angelis, M., et al. (2017). The urinary 1 H-NMR metabolomics profile of an Italian autistic children population and their unaffected siblings. Autism Research, 10(6), 1058–1066. https://doi.org/10.1002/aur.1748.CrossRefPubMedGoogle Scholar
- Mouridsen, S. E., Rich, B., & Isager, T. (2016). Diseases of the circulatory system among adult people diagnosed with infantile autism as children: A longitudinal case control study. Research in Developmental Disabilities, 57, 193–200. https://doi.org/10.1016/j.ridd.2016.07.002.CrossRefPubMedGoogle Scholar
- Napoli, C., D’Armiento, F. P., Mancini, F. P., Postiglione, A., Witztum, J. L., Palumbo, G., et al. (1997). Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. The Journal of Clinical Investigation, 100(11), 2680–2690. https://doi.org/10.1172/jci119813.CrossRefPubMedPubMedCentralGoogle Scholar
- National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). (2002). Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation, 106(25), 3143. https://doi.org/10.1161/circ.106.25.3143.CrossRefGoogle Scholar
- Tierney, E., Bukelis, I., Thompson, R. E., Ahmed, K., Aneja, A., Kratz, L., et al. (2006). Abnormalities of cholesterol metabolism in autism spectrum disorders. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 141B(6), 666–668. https://doi.org/10.1002/ajmg.b.30368.CrossRefGoogle Scholar
- Tseng, P. T., Chen, Y. W., Stubbs, B., Carvalho, A. F., Whiteley, P., Tang, C. H., et al. (2019). Maternal breastfeeding and autism spectrum disorder in children: A systematic review and meta-analysis. Nutritional Neuroscience, 22(5), 354–362. https://doi.org/10.1080/1028415X.2017.1388598.CrossRefPubMedGoogle Scholar
- Waage-Baudet, H., Lauder, J. M., Dehart, D. B., Kluckman, K., Hiller, S., Tint, G. S., et al. (2003). Abnormal serotonergic development in a mouse model for the Smith–Lemli–Opitz syndrome: Implications for autism. International Journal of Developmental Neuroscience, 21(8), 451–459. https://doi.org/10.1016/j.ijdevneu.2003.09.002.CrossRefPubMedGoogle Scholar
- West, P. R., Amaral, D. G., Bais, P., Smith, A. M., Egnash, L. A., Ross, M. E., et al. (2014). Metabolomics as a tool for discovery of biomarkers of autism spectrum disorder in the blood plasma of children. PLoS ONE, 9(11), e112445. https://doi.org/10.1371/journal.pone.0112445.CrossRefPubMedPubMedCentralGoogle Scholar