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Prenatal metal concentrations and physical abnormalities in the Japan Environment and Children’s Study

  • Population Study Article
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A Correction to this article was published on 08 March 2024

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Abstract

Background

The association between prenatal metal exposure and congenital anomalies is unclear. We aimed to examine the association between exposure to cadmium, lead, mercury, selenium, and manganese and physical abnormalities.

Methods

Data from 89,887 pregnant women with singleton pregnancies who participated in the Japan Environment and Children’s Study (JECS) were used. The correlation between maternal blood metal concentrations and physical abnormalities during the second or third trimester was investigated using logistic regression models. Physical anomalies included those observed at birth or at 1 month, primarily from ICD-10 Chapter 17, particularly congenital anomalies associated with environmental factors (e.g., hypospadias, cryptorchidism, cleft lip and palate, digestive tract atresia, congenital heart disease, and chromosomal abnormalities) and minor abnormalities.

Results

After adjusting for covariates, the OR (95% CIs) of physical abnormalities for a one-unit rise in Mn concentrations in all individuals were 1.26 (1.08, 1.48). The OR (95% CIs) of physical abnormalities in the 4th quartile (≥18.7 ng/g) were 1.06 (1.01, 1.13) (p-value for the trend = 0.034) compared with those in the 1st quartile (≤12.5 ng/g).

Conclusion

In Japan, maternal blood Mn concentrations above threshold during pregnancy may slightly increase the incidence of physical abnormalities.

Impact

  • Physical abnormalities (including minor anomalies and congenital anomalies) are associated with prenatal manganese concentrations.

  • They are not associated with cadmium, lead, mercury, and selenium concentrations.

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Fig. 1: Flow chart for the selection of participants.
Fig. 2: Combined effects of metal exposure on physical abnormalities.

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Data availability

Regarding Data of the Paper Publication http://www.env.go.jp/chemi/ceh/en/index.html. Data are unsuitable for public deposition owing to ethical restrictions and legal framework of Japan. It is prohibited by the Act on the Protection of Personal Information (Act No. 57 of 30 May 2003, amendment on 9 September 2015) to publicly deposit the data containing personal information. Ethical Guidelines for Medical and Health Research Involving Human Subjects enforced by the Japan Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare also restrict the open sharing of epidemiologic data. All inquiries about access to data should be sent to: jecs-en@nies.go.jp. The person responsible for handling enquiries sent to this e-mail address is Dr Shoji F. Nakayama, JECS Program Office, National Institute for Environmental Studies.

Change history

References

  1. Hanaoka, T. et al. Prevalence and risk of birth defects observed in a prospective cohort study: the Hokkaido study on environment and children’s health. J. Epidemiol. 28, 125–132 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  2. World Health Organization Congenital anomalies. https://www.who.int/en/news-room/fact-sheets/detail/congenital-anomalies.

  3. Mai, C. T. et al. National population-based estimates for major birth defects, 2010-2014. Birth Defects Res. 111, 1420–1435 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Feldkamp, M. L. et al. Etiology and clinical presentation of birth defects: population based study. BMJ 357, j2249 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Oliveira, C. I. & Fett-Conte, A. C. Birth defects: risk factors and consequences. J. Pediatr. Genet. 2, 85–90 (2013).

    PubMed  PubMed Central  Google Scholar 

  6. Caserta, D. et al. Heavy metals and placental fetal-maternal barrier: a mini-review on the major concerns. Eur. Rev. Med. Pharmacol. Sci. 17, 2198–2206 (2013).

    CAS  PubMed  Google Scholar 

  7. Mistry, H. D., Broughton Pipkin, F., Redman, C. W. & Poston, L. Selenium in reproductive health. Am. J. Obstet. Gynecol. 206, 21–30 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Krachler, M., Rossipal, E. & Micetic-Turk, D. Trace element transfer from the mother to the newborn-investigations on triplets of colostrum, maternal and umbilical cord sera. Eur. J. Clin. Nutr. 53, 486–494 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Ciesielski, T. et al. Cadmium exposure and neurodevelopmental outcomes in U.S. children. Environ. Health Perspect. 120, 758–763 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Murata, K., Iwata, T., Dakeishi, M. & Karita, K. Lead toxicity: does the critical level of lead resulting in adverse effects differ between adults and children? J. Occup. Health 51, 1–12 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Bose-O’Reilly, S., McCarty, K. M., Steckling, N. & Lettmeier, B. Mercury exposure and children’s health. Curr. Probl. Pediatr. Adolesc. Health Care 40, 186–215 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Claus Henn, B. et al. Maternal and cord blood manganese concentrations and early childhood neurodevelopment among residents near a mining-impacted Superfund site. Environ. Health Perspect. 125, 067020 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Gunier, R. B. et al. Manganese in teeth and neurodevelopment in young Mexican-American children. Environ. Res. 142, 688–695 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lin, C. C. et al. In utero exposure to environmental lead and manganese and neurodevelopment at 2 years of age. Environ. Res. 123, 52–57 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Taylor, D. et al. Recent developments in selenium research. Br. J. Biomed. Sci. 66, 107–116 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Jin, L. et al. Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population. Reprod. Toxicol. 35, 25–31 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Ou, Y. et al. Associations between toxic and essential trace elements in maternal blood and fetal congenital heart defects. Environ. Int. 106, 127–134 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Langley, R. L. et al. Adverse neurodevelopmental effects and hearing loss in children associated with manganese in well water, North Carolina. J. Environ. Occup. Sci. 4, 62–69 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Liu, J. et al. Placental concentrations of manganese and the risk of fetal neural tube defects. J. Trace Elem. Med. Biol. 27, 322–325 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Pi, X. et al. Concentrations of selected heavy metals in placental tissues and risk for neonatal orofacial clefts. Environ. Pollut. 242, 1652–1658 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Sharma, T. et al. Heavy metal levels in adolescent and maternal blood: association with risk of hypospadias. ISRN Pediatr. 2014, 714234 (2014).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  22. Yalçin, S. S., Dönmez, Y., Aypar, E. & Yalçin, S. Element profiles in blood and teeth samples of children with congenital heart diseases in comparison with healthy ones. J. Trace Elem. Med. Biol. 63, 126662 (2021).

    Article  PubMed  Google Scholar 

  23. Guo, Y. et al. High maternal selenium levels are associated with increased risk of congenital heart defects in the offspring. Prenat. Diagn. 39, 1107–1114 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Ni, W. et al. Association between selected essential trace element concentrations in umbilical cord and risk for cleft lip with or without cleft palate: A case-control study. Sci. Total Environ. 661, 196–202 (2019).

    Article  ADS  CAS  PubMed  Google Scholar 

  25. Pi, X. et al. Higher concentration of selenium in placental tissues is associated with reduced risk for orofacial clefts. Clin. Nutr. 38, 2442–2448 (2019).

    Article  CAS  PubMed  Google Scholar 

  26. Takatani, T. et al. Individual and mixed metal maternal blood concentrations in relation to birth size: an analysis of the Japan Environment and Children’s Study (JECS). Environ. Int. 165, 107318 (2022).

    Article  CAS  PubMed  Google Scholar 

  27. Cedergreen, N. Quantifying synergy: a systematic review of mixture toxicity studies within environmental toxicology. PLoS One 9, e96580 (2014).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  28. Kawamoto, T. et al. Rationale and study design of the Japan environment and children’s study (JECS). BMC Public Health 14, 25 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mezawa, H. et al. Prevalence of congenital anomalies in the Japan environment and children’s study. J. Epidemiol. 29, 247–256 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Nakayama, S. F. et al. Blood mercury, lead, cadmium, manganese and selenium levels in pregnant women and their determinants: the Japan Environment and Children’s Study (JECS). J. Expo. Sci. Environ. Epidemiol. 29, 633–647 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Currie, L. A. Detection and quantification limits: origins and historical overview. Anal. Chim. Acta 391, 127–134 (1999).

    Article  CAS  Google Scholar 

  32. Kobayashi, S. et al. Association of blood mercury levels during pregnancy with infant birth size by blood selenium levels in the Japan Environment and Children’s Study: a prospective birth cohort. Environ. Int. 125, 418–429 (2019).

    Article  CAS  PubMed  Google Scholar 

  33. Keil, A. P. et al. A quantile-based g-computation approach to addressing the effects of exposure mixtures. Environ. Health Perspect. 128, 47004 (2020).

    Article  PubMed  Google Scholar 

  34. Tsuji, M. et al. The association between whole blood concentrations of heavy metals in pregnant women and premature births: the Japan Environment and Children’s Study (JECS). Environ. Res. 166, 562–569 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Inadera, H. et al. Association of blood cadmium levels in pregnant women with infant birth size and small for gestational age infants: the Japan Environment and Children’s study. Environ. Res. 191, 110007 (2020).

    Article  CAS  PubMed  Google Scholar 

  36. Goto, Y. et al. Association of prenatal maternal blood lead levels with birth outcomes in the Japan Environment and Children’s Study (JECS): a nationwide birth cohort study. Int. J. Epidemiol. 50, 156–164 (2021).

    Article  PubMed  Google Scholar 

  37. Yamamoto, M. et al. Association between blood manganese level during pregnancy and birth size: the Japan environment and children’s study (JECS). Environ. Res. 172, 117–126 (2019).

    Article  CAS  PubMed  Google Scholar 

  38. Miyashita, C. et al. Association between the concentrations of metallic elements in maternal blood during pregnancy and prevalence of abdominal congenital malformations: the Japan environment and children’s study. Int. J. Environ. Res. Public Health 18, 10103 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sanders, A. P. et al. Association between arsenic, cadmium, manganese, and lead levels in private wells and birth defects prevalence in North Carolina: a semi-ecologic study. BMC Public Health 14, 955 (2014).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  40. Chung, S. E. et al. Maternal blood manganese and early neurodevelopment: the mothers and children’s environmental health (MOCEH) study. Environ. Health Perspect. 123, 717–722 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chen, L. et al. Manganese concentrations in maternal-infant blood and birth weight. Environ. Sci. Pollut. Res. Int. 21, 6170–6175 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Pinsino, A., Roccheri, M. C., Costa, C. & Matranga, V. Manganese interferes with calcium, perturbs ERK signaling, and produces embryos with no skeleton. Toxicol. Sci. 123, 217–230 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Guilarte, T. R. et al. Evidence for cortical dysfunction and widespread manganese accumulation in the nonhuman primate brain following chronic manganese exposure: a 1H-MRS and MRI study. Toxicol. Sci. 94, 351–358 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Ding, D., Roth, J. & Salvi, R. Manganese is toxic to spiral ganglion neurons and hair cells in vitro. Neurotoxicology 32, 233–241 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Oikawa, S. et al. Mechanism for manganese enhancement of dopamine-induced oxidative DNA damage and neuronal cell death. Free Radic. Biol. Med. 41, 748–756 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Fitzgerald, P. & Dinan, T. G. Prolactin and dopamine: what is the connection? A review article. J. Psychopharmacol. 22, 12–19 (2008).

    Article  PubMed  Google Scholar 

  47. Dos Santos, N. R. et al. Manganese exposure and association with hormone imbalance in children living near a ferro-manganese alloy plant. Environ. Res. 172, 166–174 (2019).

    Article  PubMed  Google Scholar 

  48. Memon, N. S. et al. Correlation of manganese with thyroid function in females having hypo- and hyperthyroid disorders. Biol. Trace Elem. Res. 167, 165–171 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Mijal, R. S. & Holzman, C. B. Blood cadmium levels in women of childbearing age vary by race/ethnicity. Environ. Res. 110, 505–512 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Järup, L. et al. Health effects of cadmium exposure—a review of the literature and a risk estimate. Scand. J. Work Environ. Health 24, 1–51 (1998).

    PubMed  Google Scholar 

  51. Zheng, S. et al. The antagonistic effect of selenium on lead-induced inflammatory factors and heat shock protein mRNA level in chicken cartilage tissue. Biol. Trace Elem. Res. 173, 177–184 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Zwolak, I. & Zaporowska, H. Selenium interactions and toxicity: a review. Selenium interactions and toxicity. Cell Biol. Toxicol. 28, 31–46 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Bernard, A. M. Biokinetics and stability aspects of biomarkers: recommendations for application in population studies. Toxicology 101, 65–71 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Spencer, A. Whole blood manganese levels in pregnancy and the neonate. Nutrition 15, 731–734 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Bower, C. et al. Age at diagnosis of birth defects. Birth Defects Res. A Clin. Mol. Teratol. 88, 251–255 (2010).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all the mothers and their children who participated in the JECS. We wish to express our sincere appreciation to the collaborating hospitals and clinics. We also express our gratitude to all the JECS staff members in Hokkaido, Miyagi, Fukushima, Chiba, Kanagawa, Koshin, Toyama, Aichi, Kyoto, Osaka, Hyogo, Tottori, Kochi, Fukuoka, and South Kyushu/Okinawa Regional Centers, the National Center for JECS (program office), and the Medical Support Center.

Funding

The JECS was funded by the Ministry of the Environment, Japan. The findings and conclusions of this article are solely the responsibility of the authors and do not represent the official views of the Japanese Government.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Yuichi Nakamura, Yoshitaka Seto, Ryota Honjo, Akiko Ando & Atsushi Manabe

  2. Maternity and Perinatal Care Center, Hokkaido University Hospital, Sapporo, Japan

    Yuichi Nakamura, Kazutoshi Cho, Yoshitaka Seto, Ryota Honjo, Akiko Ando, Yuta Furuse & Atsushi Manabe

  3. Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan

    Sumitaka Kobayashi, Sachiko Itoh, Chihiro Miyashita, Takeshi Yamaguchi, Hiroyoshi Iwata, Naomi Tamura & Reiko Kishi

  4. Department of Social Medicine, Asahikawa Medical University, Asahikawa, Japan

    Yasuaki Saijo

  5. Division of Clinical Medicine, Japanese Red Cross Hokkaido College of Nursing, Kitami, Japan

    Yoshiya Ito

  6. Nagoya City University, Nagoya, Japan

    Michihiro Kamijima

  7. National Institute for Environmental Studies, Tsukuba, Japan

    Shin Yamazaki

  8. National Center for Child Health and Development, Tokyo, Japan

    Yukihiro Ohya

  9. Hokkaido University, Sapporo, Japan

    Reiko Kishi

  10. Tohoku University, Sendai, Japan

    Nobuo Yaegashi

  11. Fukushima Medical University, Fukushima, Japan

    Koichi Hashimoto

  12. Chiba University, Chiba, Japan

    Chisato Mori

  13. Yokohama City University, Yokohama, Japan

    Shuichi Ito

  14. University of Yamanashi, Chuo, Japan

    Zentaro Yamagata

  15. University of Toyama, Toyama, Japan

    Hidekuni Inadera

  16. Kyoto University, Kyoto, Japan

    Takeo Nakayama

  17. Osaka University, Suita, Japan

    Tomotaka Sobue

  18. Hyogo Medical University, Nishinomiya, Japan

    Masayuki Shima

  19. Tottori University, Yonago, Japan

    Hiroshige Nakamura

  20. Kochi University, Nankoku, Japan

    Narufumi Suganuma

  21. University of Occupational and Environmental Health, Kitakyushu, Japan

    Koichi Kusuhara

  22. Kumamoto University, Kumamoto, Japan

    Takahiko Katoh

Authors
  1. Yuichi Nakamura
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  2. Sumitaka Kobayashi
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  3. Kazutoshi Cho
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  4. Sachiko Itoh
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  5. Chihiro Miyashita
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  7. Hiroyoshi Iwata
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  8. Naomi Tamura
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  9. Yasuaki Saijo
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  10. Yoshiya Ito
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  11. Yoshitaka Seto
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Consortia

The Japan Environment and Children’s Study (JECS) Group

  • Michihiro Kamijima
  • , Shin Yamazaki
  • , Yukihiro Ohya
  • , Reiko Kishi
  • , Nobuo Yaegashi
  • , Koichi Hashimoto
  • , Chisato Mori
  • , Shuichi Ito
  • , Zentaro Yamagata
  • , Hidekuni Inadera
  • , Takeo Nakayama
  • , Tomotaka Sobue
  • , Masayuki Shima
  • , Hiroshige Nakamura
  • , Narufumi Suganuma
  • , Koichi Kusuhara
  •  & Takahiko Katoh

Contributions

Y.N., S.K., K.C., S.I., C.M., T.Y. and R.K. conceived and designed the study. Y.N., S.K., K.C., S.I., C.M., T.Y., Y.S., Y.I. and R.K. performed the data collection. Y.N., S.K., K.C., H.I. and N.T. performed the statistical analysis and contributed to the manuscript preparation and literature search. Y.N., S.K., K.C., S.I., C.M. and T.Y. interpreted the data. Y.N., S.K., K.C., S.I., C.M., T.Y., H.I., N.T., Y.S., Y.I. and R.K. contributed to the critical revision of the manuscript for important intellectual content. S.K., K.C., A.M. and R.K. contributed to the funds collection and were supervisors of the study. All authors approved the version of the manuscript to be published.

Corresponding author

Correspondence to Sumitaka Kobayashi.

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Informed consent was obtained from all participants (patients).

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The original online version of this article was revised: the authors identified a siginificant modification related to the results of the regression analysis. The primary focus of the analysis, manganese, remains almost unchanged. However, there are slight alterations in the 95% confidence intervals and p-values for cadmium, lead, mercury, and selenium in Table 3, Supplementary Table 2 and Supplementary Table 3.

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Nakamura, Y., Kobayashi, S., Cho, K. et al. Prenatal metal concentrations and physical abnormalities in the Japan Environment and Children’s Study. Pediatr Res (2023). https://doi.org/10.1038/s41390-023-02851-4

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