Abstract
Exposure to phenols, phthalates, pesticides, and polycyclic aromatic hydrocarbons (PAHs) can harm the skeleton. However, data about the joint effects of these chemicals’ mixture on bone health are limited. The final analysis involved 6766 participants aged over 20 years recruited from the National Health and Nutrition Examination Survey. Generalized linear regression, weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), and quantile g-computation (qgcomp) were performed to investigate the association of the urinary levels of chemicals (three phenols, two chlorophenol pesticides, nine phthalates, and six polycyclic aromatic hydrocarbon [PAH] metabolites) with bone mineral density (BMD) measurements and osteoporosis (OP) risk. Generalized linear regression identified that benzophenone-3, 2,4-dichlorophenol, mono-n-butyl phthalate, 1-napthol, 3-fluorene, 2-fluorene, and 1-phenanthrene were significantly associated with lower BMD and increased OP risk. The WQS index was negatively associated with total femur, femoral neck, and lumbar spine vertebra 1 (L1) BMD among all the participants, with corresponding β (95% confidence interval) values of −0.028 g/cm2 (−0.040, −0.017), −0.015 g/cm2 (−0.025, −0.004), and −0.018 g/cm2 (−0.033, −0.003). In the BKMR analysis, the overall effect of the mixture was significantly associated with femoral neck BMD among males and OP risk among females. The qgcomp model found a significant association between co-exposure and L1 BMD among all the participants and among males. Our study presents compelling epidemiological evidence that co-exposure to phenols, chlorophenol pesticides, phthalates, and PAHs is associated with reduced BMD and elevated OP risk. It provides epidemiologic evidence for the detrimental effects of these chemicals on bone health.
Similar content being viewed by others
Data availability
All raw data is available and will be provided as per requirement.
References
Barr DB et al (2005) Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements. Environ Health Perspect 113:192–200. https://doi.org/10.1289/ehp.7337
Bhat FA et al (2013) Di 2-ethyl hexyl phthalate affects differentiation and matrix mineralization of rat calvarial osteoblasts--in vitro. Toxicol In Vitro 27:250–256. https://doi.org/10.1016/j.tiv.2012.09.003
Bielanowicz A et al (2016) Prepubertal di-n-butyl phthalate exposure alters sertoli and Leydig cell function and lowers bone density in adult male miCe. Endocrinology 157:2595–2603. https://doi.org/10.1210/en.2015-1936
Billionnet C et al (2012) Estimating the health effects of exposure to multi-pollutant mixture. Ann Epidemiol 22:126–141. https://doi.org/10.1016/j.annepidem.2011.11.004
Bobb JF et al (2015) Bayesian kernel machine regression for estimating the health effects of multi-pollutant mixtures. Biostatistics 16:493–508. https://doi.org/10.1093/biostatistics/kxu058
Bohannon AD et al (2000) Exposure to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDT) in relation to bone mineral density and rate of bone loss in menopausal women. Arch Environ Health 55:386–391. https://doi.org/10.1080/00039890009604035
Boström CE et al (2002) Cancer risk assessment, indicators, and guidelines for polycyclic aromatic hydrocarbons in the ambient air. Environ Health Perspect 110(Suppl 3):451–488. https://doi.org/10.1289/ehp.110-1241197
Cai S et al (2019) Association between urinary triclosan with bone mass density and osteoporosis in US adult women, 2005–2010. J Clin Endocrinol Metab 104:4531–4538. https://doi.org/10.1210/jc.2019-00576
Carrico C et al (2015) Characterization of weighted quantile sum regression for highly correlated data in a risk analysis setting. J Agric Biol Environ Stat 20:100–120. https://doi.org/10.1007/s13253-014-0180-3
Centers for Disease Control and Prevention (2022) National Health and Nutrition Examination Survey. 2022
Chen S et al (2023) Association of urinary bisphenol A with cardiovascular and all-cause mortality: National Health and Nutrition Examination Survey (NHANES) 2003-2016. Environ Sci Pollut Res Int 30:51217–51227. https://doi.org/10.1007/s11356-023-25924-7
Chen YY et al (2020) Association between polycyclic aromatic hydrocarbons exposure and bone turnover in adults. Eur J Endocrinol 182:333–341. https://doi.org/10.1530/eje-19-0750
Cui Y et al (2022) Multiple vitamin co-exposure and mortality risk: a prospective study. Clin Nutr 41:337–347. https://doi.org/10.1016/j.clnu.2021.12.010
de Boer J et al (2002) Premature aging in mice deficient in DNA repair and transcription. Science 296:1276–1279. https://doi.org/10.1126/science.1070174
DeFlorio-Barker SA, Turyk ME (2016) Associations between bone mineral density and urinary phthalate metabolites among post-menopausal women: a cross-sectional study of NHANES data 2005-2010. Int J Environ Health Res 26:326–345. https://doi.org/10.1080/09603123.2015.1111312
DiNardo JC, Downs CA (2018) Dermatological and environmental toxicological impact of the sunscreen ingredient oxybenzone/benzophenone-3. J Cosmet Dermatol 17:15–19. https://doi.org/10.1111/jocd.12449
Duan W et al (2018) Association between polycyclic aromatic hydrocarbons and osteoporosis: data from NHANES, 2005-2014. Arch Osteoporos 13:112. https://doi.org/10.1007/s11657-018-0527-4
Ema M et al (1994) Characterization of the developmental toxicity of di-n-butyl phthalate in rats. Toxicology 86:163–174. https://doi.org/10.1016/0300-483x(94)90002-7
Farzan SF et al (2016) Urinary polycyclic aromatic hydrocarbons and measures of oxidative stress, inflammation and renal function in adolescents: NHANES 2003-2008. Environ Res 144:149–157. https://doi.org/10.1016/j.envres.2015.11.012
Ferguson KK et al (2019) Urinary concentrations of phenols in association with biomarkers of oxidative stress in pregnancy: assessment of effects independent of phthalates. Environ Int 131:104903. https://doi.org/10.1016/j.envint.2019.104903
Fertuck KC et al (2001) Interaction of PAH-related compounds with the alpha and beta isoforms of the estrogen receptor. Toxicol Lett 121:167–177. https://doi.org/10.1016/s0378-4274(01)00344-7
Frederiksen H et al (2013) Temporal variability in urinary phthalate metabolite excretion based on spot, morning, and 24-h urine samples: considerations for epidemiological studies. Environ Sci Technol 47:958–967. https://doi.org/10.1021/es303640b
Gu L et al (2022) Associations between mixed urinary phenols and parabens metabolites and bone mineral density: four statistical models. Chemosphere 311:137065. https://doi.org/10.1016/j.chemosphere.2022.137065
Guo J et al (2018) Associations of urinary polycyclic aromatic hydrocarbons with bone mass density and osteoporosis in U.S. adults, NHANES 2005-2010. Environ Pollut 240:209–218. https://doi.org/10.1016/j.envpol.2018.04.108
Hurst CH, Waxman DJ (2003) Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicol Sci 74:297–308. https://doi.org/10.1093/toxsci/kfg145
Hwang JK et al (2013a) Bisphenol A reduces differentiation and stimulates apoptosis of osteoclasts and osteoblasts. Life Sci 93:367–372. https://doi.org/10.1016/j.lfs.2013.07.020
Hwang KA et al (2013b) Genistein, a soy phytoestrogen, prevents the growth of BG-1 ovarian cancer cells induced by 17β-estradiol or bisphenol A via the inhibition of cell cycle progression. Int J Oncol 42:733–740. https://doi.org/10.3892/ijo.2012.1719
Katchy A et al (2014) Coexposure to phytoestrogens and bisphenol a mimics estrogenic effects in an additive manner. Toxicol Sci 138:21–35. https://doi.org/10.1093/toxsci/kft271
Keil AP et al (2020) A quantile-based g-computation approach to addressing the effects of exposure mixtures. Environ Health Perspect 128:47004. https://doi.org/10.1289/ehp5838
Khalil N et al (2016) Association of perfluoroalkyl substances, bone mineral density, and osteoporosis in the U.S. population in NHANES 2009-2010. Environ Health Perspect 124:81–87. https://doi.org/10.1289/ehp.1307909
Kim K et al (2022) Endocrine-disrupting chemicals and their adverse effects on the endoplasmic reticulum. Int J Mol Sci 23. https://doi.org/10.3390/ijms23031581
Kim S et al (2013) Effects of octylphenol and bisphenol A on the expression of calcium transport genes in the mouse duodenum and kidney during pregnancy. Toxicology 303:99–106. https://doi.org/10.1016/j.tox.2012.10.023
Kjeldsen LS et al (2013) Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity. Toxicol Appl Pharmacol 272:453–464. https://doi.org/10.1016/j.taap.2013.06.028
Korashy HM, El-Kadi AO (2006) The role of aryl hydrocarbon receptor in the pathogenesis of cardiovascular diseases. Drug Metab Rev 38:411–450. https://doi.org/10.1080/03602530600632063
Lai CC et al (2022) Di-(2-ethylhexyl) phthalate exposure links to inflammation and low bone mass in premenopausal and postmenopausal females: evidence from ovariectomized mice and humans. Int J Rheum Dis 25:926–936. https://doi.org/10.1111/1756-185x.14386
Lee DH, Jacobs DR Jr (2015) Methodological issues in human studies of endocrine disrupting chemicals. Rev Endocr Metab Disord 16:289–297. https://doi.org/10.1007/s11154-016-9340-9
Li Z et al (2012) Excretion profiles and half-lives of ten urinary polycyclic aromatic hydrocarbon metabolites after dietary exposure. Chem Res Toxicol 25:1452–1461. https://doi.org/10.1021/tx300108e
Liu H et al (2008) Screening for osteoporosis in men: a systematic review for an American College of Physicians guideline. Ann Intern Med 148:685–701. https://doi.org/10.7326/0003-4819-148-9-200805060-00009
Looker AC et al (1997) Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res 12:1761–1768. https://doi.org/10.1359/jbmr.1997.12.11.1761
Looker AC et al (2012) Lumbar spine and proximal femur bone mineral density, bone mineral content, and bone area: United States, 2005-2008. Vital Health Stat 11:1–132
Mantovani A (2016) Endocrine disrupters and the safety of food chains. Horm Res Paediatr 86:279–288. https://doi.org/10.1159/000441496
Min KB, Min JY (2014) Urinary phthalate metabolites and the risk of low bone mineral density and osteoporosis in older women. J Clin Endocrinol Metab 99:E1997–E2003. https://doi.org/10.1210/jc.2014-2279
Moorthy B et al (2015) Polycyclic aromatic hydrocarbons: from metabolism to lung cancer. Toxicol Sci 145:5–15. https://doi.org/10.1093/toxsci/kfv040
Morin N et al (2015) Bisphenol A in solid waste materials, leachate water, and air particles from Norwegian waste-handling facilities: presence and partitioning behavior. Environ Sci Technol 49:7675–7683. https://doi.org/10.1021/acs.est.5b01307
Nakamura T et al (2007) Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 130:811–823. https://doi.org/10.1016/j.cell.2007.07.025
Nojiri H et al (2011) Cytoplasmic superoxide causes bone fragility owing to low-turnover osteoporosis and impaired collagen cross-linking. J Bone Miner Res 26:2682–2694. https://doi.org/10.1002/jbmr.489
Ostrowska Z et al (2001) Assessment of the relationship between circadian variations of salivary melatonin levels and type I collagen metabolism in postmenopausal obese women. Neuro Endocrinol Lett 22:121–127
Reeves KW et al (2021) Urinary Phthalate biomarkers and bone mineral density in postmenopausal women. J Clin Endocrinol Metab 106:e2567–e2579. https://doi.org/10.1210/clinem/dgab189
Ribeiro-Varandas E et al (2014) Bisphenol A disrupts transcription and decreases viability in aging vascular endothelial cells. Int J Mol Sci 15:15791–15805. https://doi.org/10.3390/ijms150915791
Saillenfait AM et al (2009) Differential developmental toxicities of di-n-hexyl phthalate and dicyclohexyl phthalate administered orally to rats. J Appl Toxicol 29:510–521. https://doi.org/10.1002/jat.1436
Silva E et al (2002) Something from “nothing”--eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol 36:1751–1756. https://doi.org/10.1021/es0101227
Stickens D et al (2004) Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131:5883–5895. https://doi.org/10.1242/dev.01461
Toms JD, Lesperance ML (2003) Piecewise regression: a tool for identifying ecological thresholds. 84:2034–2041. https://doi.org/10.1890/02-0472
Trasande L et al (2022) Phthalates and attributable mortality: a population-based longitudinal cohort study and cost analysis. Environ Pollut 292:118021. https://doi.org/10.1016/j.envpol.2021.118021
Tyner SD et al (2002) p53 mutant mice that display early ageing-associated phenotypes. Nature 415:45–53. https://doi.org/10.1038/415045a
Wang N et al (2020) Association of bone mineral density with nine urinary personal care and consumer product chemicals and metabolites: a national-representative, population-based study. Environ Int 142:105865. https://doi.org/10.1016/j.envint.2020.105865
Wang YX et al (2019) Urinary levels of bisphenol A, F and S and markers of oxidative stress among healthy adult men: variability and association analysis. Environ Int 123:301–309. https://doi.org/10.1016/j.envint.2018.11.071
Wilson J et al (2016) Effects of defined mixtures of persistent organic pollutants (POPs) on multiple cellular responses in the human hepatocarcinoma cell line, HepG2, using high content analysis screening. Toxicol Appl Pharmacol 294:21–31. https://doi.org/10.1016/j.taap.2016.01.001
Xie Z et al (2023) Associations of metal mixtures with metabolic-associated fatty liver disease and non-alcoholic fatty liver disease: NHANES 2003-2018. Front Public Health 11:1133194. https://doi.org/10.3389/fpubh.2023.1133194
Ye X et al (2008) Urinary metabolite concentrations of organophosphorous pesticides, bisphenol A, and phthalates among pregnant women in Rotterdam, the Netherlands: the Generation R study. Environ Res 108:260–267. https://doi.org/10.1016/j.envres.2008.07.014
Zhang Y et al (2016) Biological impact of environmental polycyclic aromatic hydrocarbons (ePAHs) as endocrine disruptors. Environ Pollut 213:809–824. https://doi.org/10.1016/j.envpol.2016.03.050
Ziolkowska A et al (2006) Expression of osteoblast marker genes in rat calvarial osteoblast-like cells, and effects of the endocrine disrupters diphenylolpropane, benzophenone-3, resveratrol and silymarin. Chem Biol Interact 164:147–156. https://doi.org/10.1016/j.cbi.2006.09.009
Funding
This work was supported by the National Natural Science Foundation of China (grant nos. 82273711, 72061137006).
Author information
Authors and Affiliations
Contributions
Dong-sheng Di: conceptualization, formal analysis, writing—original draft, writing—review & editing; Ru-yi Zhang: investigation, methodology, validation, review & editing; Hao-long Zhou: investigation, methodology, validation; Mu-hong Wei: investigation, methodology, validation; Yuan Cui: investigation, methodology, validation; Jian-li Zhang: investigation, methodology; Ting-ting Yuan: investigation, methodology; Qian Liu: investigation, methodology; Ting-ting Zhou: investigation, methodology; Qi Wang: conceptualization, funding acquisition, supervision, writing—review & editing.
Corresponding author
Ethics declarations
Ethical approval
The NHANES agreement has been reviewed and approved by the NCHS Research Ethics Committee. All participants provided written informed consent before participating.
Consent to participate
Not applicable here.
Consent for publication
The manuscript is approved by all authors for publication.
Competing interests
The authors declare no competing interests.
Additional information
Responsible Editor: Lotfi Aleya
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
ESM 1
(DOCX 19149 kb)
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Di, D., Zhang, R., Zhou, H. et al. Joint effects of phenol, chlorophenol pesticide, phthalate, and polycyclic aromatic hydrocarbon on bone mineral density: comparison of four statistical models. Environ Sci Pollut Res 30, 80001–80013 (2023). https://doi.org/10.1007/s11356-023-28065-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-023-28065-z