Association of exposure to prenatal phthalate esters and bisphenol A and polymorphisms in the ESR1 gene with the second to fourth digit ratio in school-aged children: Data from the Hokkaido study

Steroids. 2020 Jul;159:108637. doi: 10.1016/j.steroids.2020.108637. Epub 2020 Mar 9.


Phthalates and bisphenol A (BPA) are estrogenic endocrine disruptors. Polymorphisms in the gene encoding estrogen receptor 1 (ESR1) may contribute to the ratio of the lengths of the second and fourth digits (2D:4D), which is considered an index of prenatal exposure to sex hormones. Thus, we investigated whether ESR1 polymorphisms modify the effects of prenatal exposure to phthalates and BPA on 2D:4D in a birth cohort. Maternal serum in the first trimester was used to determine prenatal exposure to these compounds. Six hundred twenty-three children (7 years of age) provided mean 2D:4D from photocopies and were genotyped for single nucleotide polymorphisms in ESR1, particularly PvuII (T > C, dbSNP: rs2234693), XbaI (A > G, dbSNP: rs9340799), and rs2077647 (A > G). The associations among compound exposure, mean 2D:4D, and ESR1 polymorphisms were assessed by multiple linear regression adjusted for potential cofounding factors. Boys with the AG/GG genotype at rs2077647 in the group exposed to high levels of mono(2-ethylhexyl) phthalate (MEHP) or Σ Di(2-ethylhexyl) phthalate (DEHP) showed feminized 2D:4D compared with boys with the AA genotype at rs2077647 who had low exposure to MEHP or ΣDEHP (MEHP: increase in mean 2D:4D of 1.51%, 95% confidence interval [CI]: 0.40-2.63; ΣDEHP: increase in mean 2D:4D of 1.37%, 95% CI: 0.25-2.49). No significant differences were found among girls. There were no associations between mean 2D:4D and metabolites other than MEHP or BPA. These data suggest that ESR1 polymorphisms modify the effects of prenatal exposure to DEHP on mean 2D:4D among boys.

Keywords: Bisphenol A; Digit ratio of the hand; ESR1 polymorphism; Phthalate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Benzhydryl Compounds / administration & dosage
  • Benzhydryl Compounds / adverse effects*
  • Body Weights and Measures
  • Child
  • Cohort Studies
  • Esters / administration & dosage
  • Esters / adverse effects*
  • Estrogen Receptor alpha / genetics*
  • Female
  • Humans
  • Male
  • Phenols / administration & dosage
  • Phenols / adverse effects*
  • Phthalic Acids / administration & dosage
  • Phthalic Acids / adverse effects*
  • Polymorphism, Genetic / genetics*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / genetics
  • Prospective Studies


  • Benzhydryl Compounds
  • ESR1 protein, human
  • Esters
  • Estrogen Receptor alpha
  • Phenols
  • Phthalic Acids
  • bisphenol A