Abstract
Phthalates are a group of neurotoxicants with cognitive-disrupting potentials. Given the structural diversity of phthalates, the corresponding neurotoxicity is dramatically altered. To identify the potential contributions of different phthalates on the process of cognitive impairment, data of 836 elders from the NHANES 2011–2014 cycles were used. Survey-weighted logistic regression and principal component analysis-weighted quantile sum regression (PCA-WQSR) models were applied to estimate the independent and combined associations of 11 urinary phthalate metabolites with cognitive deficit (assessed by 4 tests: Immediate Recall (IR), Delayed Recall (DR), Animal Fluency (AF), and Digit Symbol Substitution Test (DSST)) and to identify the potential phthalate with high weight. Laboratory mice were further used to examine the effect of phthalates on cognitive function and to explore the potential mechanisms. In logistic regression models, MBzP was the only metabolite positively correlated with four tests, with ORs of 2.53 (quartile 3 (Q3)), 2.26 (Q3), 2.89 (Q4) and 2.45 (Q2), 2.82 (Q4) for IR, DR, AF, and DSST respectively. In PCA-WQSR co-exposure models, low-molecular-weight (LMW) phthalates were the only PC positively linked to DSST deficit (OR: 1.93), which was further validated in WQSR analysis (WQS OR7-phthalates: 1.56 and WQS OR8-phthalates: 1.55); consistent with the results of logistic regression, MBzP was the dominant phthalate. In mice, butyl benzyl phthalate (BBP), the parent phthalate of MBzP, dose-dependently reduced cognitive function and disrupted hippocampal neurons. Additionally, the hippocampal transcriptome analysis identified 431 differential expression genes, among which most were involved in inhibiting the neuroactive ligand-receptor interaction pathway and activating the cytokine-cytokine receptor interaction pathway. Our study indicates the critical role of BBP in the association of phthalates and cognitive deficits among elderly individuals, which might be speculated that BBP could disrupt hippocampal neurons, activate neuroinflammation, and inhibit neuroactive receptors. Our findings provide new insight into the cognitive-disrupting potential of BBP.
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Data availability
The datasets used and analyzed during the current study are available in the NHANES repository (https://www.cdc.gov/nchs/nhanes/about_nhanes.htm) and NCBI repository (https://www.ncbi.nlm.nih.gov/, GSE214261).
References
Ahmadpour D, Mhaouty-Kodja S, Grange-Messent V (2021) Disruption of the blood-brain barrier and its close environment following adult exposure to low doses of di(2-ethylhexyl)phthalate alone or in an environmental phthalate mixture in male mice. Chemosphere 282:131013. https://doi.org/10.1016/j.chemosphere.2021.131013
Arai H, Satake S, Kozaki K (2018) Cognitive frailty in geriatrics. Clin Geriatr Med 34:667–675. https://doi.org/10.1016/j.cger.2018.06.011
Bailey RL, Jun S, Murphy L, Green R, Gahche JJ, Dwyer JT, Potischman N, McCabe GP, Miller JW (2020) High folic acid or folate combined with low vitamin B-12 status: potential but inconsistent association with cognitive function in a nationally representative cross-sectional sample of US older adults participating in the NHANES. Am J Clin Nutr 112:1547–1557. https://doi.org/10.1093/ajcn/nqaa239
Braun JM, Smith KW, Williams PL, Calafat AM, Berry K, Ehrlich S, Hauser R (2012) Variability of urinary phthalate metabolite and bisphenol A concentrations before and during pregnancy. Environ Health Perspect 120, 739–745. https://doi.org/10.1289/ehp.1104139
Cao L, Zhao Z, Ji C, Xia Y (2021) Association between solid fuel use and cognitive impairment: a cross-sectional and follow-up study in a middle-aged and older Chinese population. Environ Int 146:106251. https://doi.org/10.1016/j.envint.2020.106251
Collaborators GDF (2022) Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health 7:e105–e125. https://doi.org/10.1016/S2468-2667(21)00249-8
EFSA (2005) Opinion of the Scientific Panel on food additives, flavourings, processing aids and materials in contact with food (AFC) on a request from the commission related to butylbenzylphthalate (BBP) for use in food contact materials. 241, pp. 1–14
Fröhlich EE, Farzi A, Mayerhofer R, Reichmann F, Jačan A, Wagner B, Zinser E, Bordag N, Magnes C, Fröhlich E, Kashofer K, Gorkiewicz G, Holzer P (2016) Cognitive impairment by antibiotic-induced gut dysbiosis: analysis of gut microbiota-brain communication. Brain Behav Immun 56:140–155. https://doi.org/10.1016/j.bbi.2016.02.020
Galimberti D, Venturelli E, Fenoglio C, Guidi I, Villa C, Bergamaschini L, Cortini F, Scalabrini D, Baron P, Vergani C, Bresolin N, Scarpini E (2008) Intrathecal levels of IL-6, IL-11 and LIF in Alzheimer’s disease and frontotemporal lobar degeneration. J Neurol 255:539–544. https://doi.org/10.1007/s00415-008-0737-6
Hebras J, Marty V, Personnaz J, Mercier P, Krogh N, Nielsen H, Aguirrebengoa M, Seitz H, Pradere JP, Guiard BP, Cavaille J (2020) Reassessment of the involvement of Snord115 in the serotonin 2c receptor pathway in a genetically relevant mouse model. Elife 9. https://doi.org/10.7554/eLife.60862
Hoppin JA, Brock JW, Davis BJ, Baird DD (2002) Reproducibility of urinary phthalate metabolites in first morning urine samples. Environ Health Perspect 110, 515–518. https://doi.org/10.1289/ehp.02110515
Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL, Bohr VA (2019) Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 15:565–581. https://doi.org/10.1038/s41582-019-0244-7
Huang JY, Tian Y, Wang HJ, Shen H, Wang H, Long S, Liao MH, Liu ZR, Wang ZM, Li D, Tao RR, Cui TT, Moriguchi S, Fukunaga K, Han F, Lu YM (2016) Functional genomic analyses identify pathways dysregulated in animal model of autism. CNS Neurosci Ther 22:845–853. https://doi.org/10.1111/cns.12582
Iranpour S, Saadati HM, Koohi F, Sabour S (2020) Association between caffeine intake and cognitive function in adults; effect modification by sex: data from National Health and Nutrition Examination Survey (NHANES) 2013–2014. Clin Nutr 39:2158–2168. https://doi.org/10.1016/j.clnu.2019.09.003
Kim, J.I., Lee, J., Lee, K.S., Lee, Y.A., Shin, C.H., Hong, Y.C., Kim, B.N., Lim, Y.H., 2021. Association of phthalate exposure with autistic traits in children. Environ Int 157, 106775. https://doi.org/10.1016/j.envint.2021.106775
Kivipelto M, Mangialasche F, Ngandu T (2018) Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nat Rev Neurol 14:653–666. https://doi.org/10.1038/s41582-018-0070-3
Lee JJ, Kim JH, Song DS, Lee K (2022) Effect of short- to long-term exposure to ambient particulate matter on cognitive function in a cohort of middle-aged and older adults: KoGES. Int J Environ Res Public Health 19:9913. https://doi.org/10.3390/ijerph19169913
Li J, Zhang L, Wang J, Jia R, Zhang X, Li X, Fu Y, Song L (2022) Differential expression of long non-coding RNAs in the hippocampus of mice exposed to PM(2.5) in Dalian. China Environ Sci Pollut Res Int 29:12136–12146. https://doi.org/10.1007/s11356-021-16496-5
Li N, Papandonatos GD, Calafat AM, Yolton K, Lanphear BP, Chen A, Braun JM (2019) Identifying periods of susceptibility to the impact of phthalates on children’s cognitive abilities. Environ Res 172:604–614. https://doi.org/10.1016/j.envres.2019.03.009
Li X, Zhang, Y., Li, B., Yang, H., Cui, J., Li, X., Zhang, X., Sun, H., Meng, Q., Wu, S., Li, S., Wang, J., Aschner, M., Chen, R., 2020. Activation of NLRP3 in microglia exacerbates diesel exhaust particles-induced impairment in learning and memory in mice. Environ Int 136, 105487. https://doi.org/10.1016/j.envint.2020.105487
Lin E, Kuo PH, Liu YL, Yang AC, Tsai SJ (2019) Association and interaction effects of interleukin-12 related genes and physical activity on cognitive aging in old adults in the Taiwanese population. Front Neurol 10:1065. https://doi.org/10.3389/fneur.2019.01065
Liu S, Yang R, Yang Q, He G, Chen B, Dong R (2022) The independent and interactive effects of phthalates exposure and hypertension on the indicators of early renal injury in US adults: evidence from NHANES 2001–2004. Environ Res 213:113733. https://doi.org/10.1016/j.envres.2022.113733
Liu Y, Zhou LJ, Wang J, Li D, Ren WJ, Peng J, Wei X, Xu T, Xin WJ, Pang RP, Li YY, Qin ZH, Murugan M, Mattson MP, Wu LJ, Liu XG (2017) TNF-α differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury. J Neurosci 37:871–881. https://doi.org/10.1523/JNEUROSCI.2235-16.2016
Lu S, Yang D, Ge X, Li L, Zhao Y, Li C, Ma S, Yu Y (2020) The internal exposure of phthalate metabolites and bisphenols in waste incineration plant workers and the associated health risks. Environ Int 145:106101. https://doi.org/10.1016/j.envint.2020.106101
Marras C, Canning CG, Goldman SM (2019) Environment, lifestyle, and Parkinson’s disease: implications for prevention in the next decade. Mov Disord 34:801–811. https://doi.org/10.1002/mds.27720
Martínez-Ibarra A, Martínez-Razo LD, MacDonald-Ramos K, Morales-Pacheco M, Vázquez-Martínez ER, López-López M, Rodríguez Dorantes M, Cerbón M (2021) Multisystemic alterations in humans induced by bisphenol A and phthalates: experimental, epidemiological and clinical studies reveal the need to change health policies. Environ Pollut 271:116380. https://doi.org/10.1016/j.envpol.2020.116380
Min A, Liu F, Yang X, Chen M (2014) Benzyl butyl phthalate exposure impairs learning and memory and attenuates neurotransmission and CREB phosphorylation in mice. Food Chem Toxicol 71:81–89. https://doi.org/10.1016/j.fct.2014.05.021
Mohammadi A, Dobaradaran S, Schmidt TC, Malakootian M, Spitz J (2022) Emerging contaminants migration from pipes used in drinking water distribution systems: a review of the scientific literature. Environ Sci Pollut Res Inthttps://doi.org/10.1007/s11356-022-23085-7
Nassan FL, Gunn JA, Hill MM, Coull BA, Hauser R (2019) High phthalate exposure increased urinary concentrations of quinolinic acid, implicated in the pathogenesis of neurological disorders: is this a potential missing link? Environ Res 172:430–436. https://doi.org/10.1016/j.envres.2019.02.034
Nassan FL, Gunn JA, Hill MM, Williams PL, Hauser R (2020) Association of urinary concentrations of phthalate metabolites with quinolinic acid among women: a potential link to neurological disorders. Environ Int 138:105643. https://doi.org/10.1016/j.envint.2020.105643
Ni Y, Hu L, Yang S, Ni L, Ma L, Zhao Y, Zheng A, Jin Y, Fu Z (2021) Bisphenol A impairs cognitive function and 5-HT metabolism in adult male mice by modulating the microbiota-gut-brain axis. Chemosphere 282:130952. https://doi.org/10.1016/j.chemosphere.2021.130952
Ou GY, Lin WW, Zhao WJ (2021) Construction of long noncoding RNA-associated ceRNA networks reveals potential biomarkers in Alzheimer’s disease. J Alzheimers Dis 82:169–183. https://doi.org/10.3233/JAD-210068
Pais R, Ruano L., O, P.C., Barros H (2020) Global cognitive impairment prevalence and incidence in community dwelling older adults-a systematic review. Geriatrics (Basel) 5. https://doi.org/10.3390/geriatrics5040084
Partridge L, Deelen J, Slagboom PE (2018) Facing up to the global challenges of ageing. Nature 561:45–56. https://doi.org/10.1038/s41586-018-0457-8
Periñán MT, Brolin K, Bandres-Ciga S, Blauwendraat C, Klein C, Gan-Or Z, Singleton A, Gomez-Garre P, Swanberg M, Mir P, Noyce A (2022) Effect modification between genes and environment, and Parkinson’s disease risk. Ann Neurol 92:715–724. https://doi.org/10.1002/ana.26467
Pitard A, Viel JF (1997) Some methods to address collinearity among pollutants in epidemiological time series. Stat Med 16:527–544. https://doi.org/10.1002/(sici)1097-0258(19970315)16:5%3c527::aid-sim429%3e3.0.co;2-c
Power R, Prado-Cabrero A, Mulcahy R, Howard A, Nolan JM (2019) The role of nutrition for the aging population: implications for cognition and Alzheimer’s disease. Annu Rev Food Sci Technol 10:619–639. https://doi.org/10.1146/annurev-food-030216-030125
Przybyla J, Houseman EA, Smit E, Kile ML (2017) A path analysis of multiple neurotoxic chemicals and cognitive functioning in older US adults (NHANES 1999–2002). Environ Health 16:19. https://doi.org/10.1186/s12940-017-0227-3
Qin J, Dong R, Wu M, Yuan Y, Zhang H, Meng P, Zhang M, Chen J, Li S, Chen B (2021) Phthalate exposure in association with the use of personal care products among general population from Shanghai. Environ Sci Pollut Res Int 28:28470–28478. https://doi.org/10.1007/s11356-021-12375-1
Qureshi MS, Yusoff AR, Wirzal MD, Sirajuddin Barek J, Afridi HI, Üstündag Z (2016) Methods for the determination of endocrine-disrupting phthalate esters. Crit Rev Anal Chem 46, 146-159https://doi.org/10.1080/10408347.2015.1004157
Radke EG, Braun JM, Nachman RM, Cooper GS (2020) Phthalate exposure and neurodevelopment: a systematic review and meta-analysis of human epidemiological evidence. Environ Int 137:105408. https://doi.org/10.1016/j.envint.2019.105408
Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. Faseb j 22:659–661. https://doi.org/10.1096/fj.07-9574LSF
Reeves KW, Vieyra G, Grimes NP, Meliker J, Jackson RD, Wactawski-Wende J, Wallace R, Zoeller RT, Bigelow C, Hankinson SE, Manson JE, Cauley JA, Calafat AM (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
Schuch JB, Polina ER, Rovaris DL, Kappel DB, Mota NR, Cupertino RB, Silva KL, Guimarães-da-Silva PO, Karam RG, Salgado CAI, White MJ, Rohde LA, Grevet EH, Bau CHD (2016) Pleiotropic effects of Chr15q25 nicotinic gene cluster and the relationship between smoking, cognition and ADHD. J Psychiatr Res 80:73–78. https://doi.org/10.1016/j.jpsychires.2016.06.002
Screnci D, McKeage MJ, Galettis P, Hambley TW, Palmer BD, Baguley BC (2000) Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs. Br J Cancer 82:966–972
Shiue I (2015) Arsenic, heavy metals, phthalates, pesticides, hydrocarbons and polyfluorinated compounds but not parabens or phenols are associated with adult remembering condition: US NHANES, 2011–2012. Environ Sci Pollut Res Int 22:6381–6386. https://doi.org/10.1007/s11356-015-4261-9
Shiue I, Starr J (2012) Circulating urine phthalates are not associated with a decline in cognition in adults and the elderly: NHANES, 1999–2002. Neuroepidemiology 39:143–144. https://doi.org/10.1159/000341535
Silano V, Barat Baviera JM, Bolognesi C, Chesson A, Cocconcelli PS, Crebelli R, Gott DM, Grob K, Lampi E, Mortensen A, Rivière G, Steffensen IL, Tlustos C, Van Loveren H, Vernis L, Zorn H, Cravedi JP, Fortes C, Tavares Poças MF, Waalkens-Berendsen I, Wölfle D, Arcella D, Cascio C, Castoldi AF, Volk K, Castle L (2019) Update of the risk assessment of di-butylphthalate (DBP), butyl-benzyl-phthalate (BBP), bis(2-ethylhexyl)phthalate (DEHP), di-isononylphthalate (DINP) and di-isodecylphthalate (DIDP) for use in food contact materials. Efsa j 17:e05838. https://doi.org/10.2903/j.efsa.2019.5838
Sobus JR, DeWoskin RS, Tan YM, Pleil JD, Phillips MB, George BJ, Christensen K, Schreinemachers DM, Williams MA, Hubal EA, Edwards SW (2015) Uses of NHANES biomarker data for chemical risk assessment: trends, challenges, and opportunities. Environ Health Perspect 123:919–927. https://doi.org/10.1289/ehp.1409177
Sun GC, Lee YJ, Lee YC, Yu HF, Wang DC (2021) Exercise prevents the impairment of learning and memory in prenatally phthalate-exposed male rats by improving the expression of plasticity-related proteins. Behav Brain Res 413:113444. https://doi.org/10.1016/j.bbr.2021.113444
Tanaka Y, Furuyashiki T, Momiyama T, Namba H, Mizoguchi A, Mitsumori T, Kayahara T, Shichi H, Kimura K, Matsuoka T, Nawa H, Narumiya S (2009) Prostaglandin E receptor EP1 enhances GABA-mediated inhibition of dopaminergic neurons in the substantia nigra pars compacta and regulates dopamine level in the dorsal striatum. Eur J Neurosci 30:2338–2346. https://doi.org/10.1111/j.1460-9568.2009.07021.x
Tao C, Li Z, Fan Y, Li X, Qian H, Yu H, Xu Q, Lu C (2021) Independent and combined associations of urinary heavy metals exposure and serum sex hormones among adults in NHANES 2013–2016. Environ Pollut 281:117097. https://doi.org/10.1016/j.envpol.2021.117097
Terada S, Nakashima M, Wakutani Y, Nakata K, Kutoku Y, Sunada Y, Kondo K, Ishizu H, Yokota O, Maki Y, Hattori H, Yamada N (2019) Social problems in daily life of patients with dementia. Geriatr Gerontol Int 19:113–118. https://doi.org/10.1111/ggi.13554
Tran CM, Do TN, Kim KT (2021) Comparative analysis of neurotoxicity of six phthalates in zebrafish embryos. Toxics 9. https://doi.org/10.3390/toxics9010005
Urbancova K, Lankova D, Sram RJ, Hajslova J, Pulkrabova J (2019) Urinary metabolites of phthalates and di-iso-nonyl cyclohexane-1,2-dicarboxylate (DINCH)-Czech mothers’ and newborns’ exposure biomarkers. Environ Res 173:342–348. https://doi.org/10.1016/j.envres.2019.03.067
USEPA, 2014. Priority Pollutants. http://water.epa.gov/scitech/methods/cwa/pollutants.cfm
Vit O, Petrak J (2017) Integral membrane proteins in proteomics. How to break open the black box? J Proteomics 153:8–20. https://doi.org/10.1016/j.jprot.2016.08.006
Wang W, Leung AOW, Chu LH, Wong MH (2018) Phthalates contamination in China: status, trends and human exposure-with an emphasis on oral intake. Environ Pollut 238:771–782. https://doi.org/10.1016/j.envpol.2018.02.088
Wang, Y., Zhu, H., Kannan, K., 2019. A review of biomonitoring of phthalate exposures. Toxics 7. https://doi.org/10.3390/toxics7020021
Weng X, Tan Y, Fei Q, Yao H, Fu Y, Wu X, Zeng H, Yang Z, Zeng Z, Liang H, Wu Y, Wen L, Jing C (2022) Association between mixed exposure of phthalates and cognitive function among the U.S. elderly from NHANES 2011–2014: three statistical models. Sci Total Environ 828, 154362. https://doi.org/10.1016/j.scitotenv.2022.154362
Xie X, Wang Z, Zhou X, Wang X, Chen X (2011) Study on the interaction of phthalate esters to human serum albumin by steady-state and time-resolved fluorescence and circular dichroism spectroscopy. J Hazard Mater 192:1291–1298. https://doi.org/10.1016/j.jhazmat.2011.06.038
Yeh TS, Yuan C, Ascherio A, Rosner BA, Willett WC, Blacker D (2021) Long-term dietary flavonoid intake and subjective cognitive decline in US men and women. Neurology 97:e1041–e1056. https://doi.org/10.1212/WNL.0000000000012454
Zhang Q, Chen XZ, Huang X, Wang M, Wu J (2019) The association between prenatal exposure to phthalates and cognition and neurobehavior of children-evidence from birth cohorts. Neurotoxicology 73:199–212. https://doi.org/10.1016/j.neuro.2019.04.007
Zhang YJ, Guo JL, Xue JC, Bai CL, Guo Y (2021) Phthalate metabolites: characterization, toxicities, global distribution, and exposure assessment. Environ Pollut 291:118106. https://doi.org/10.1016/j.envpol.2021.118106
Zhao YL, Qu Y, Ou YN, Zhang YR, Tan L, Yu JT (2021) Environmental factors and risks of cognitive impairment and dementia: a systematic review and meta-analysis. Ageing Res Rev 72:101504. https://doi.org/10.1016/j.arr.2021.101504
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This work was supported by the National Natural Science Foundation of China (grant numbers 82003494, 81973091, 82173562), ZhiShan Scholar Program of Southeast University (grant numbers 2242022R40061), and China Postdoctoral Science Foundation (grant numbers 2020M681672).
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Yongquan Yu and Shou-Lin Wang conceptualized the study and contributed to the overall organizing of the experiments; Yucheng Wang, Shuge Shu and Di Zhang conducted the data analysis; Yu Dong, Jiayi Xu, Ying Zhang, and Wei Shi performed the experiments. All authors read and approved the final manuscript.
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Yu, Y., Wang, Y., Dong, Y. et al. Butyl benzyl phthalate as a key component of phthalate ester in relation to cognitive impairment in NHANES elderly individuals and experimental mice. Environ Sci Pollut Res 30, 47544–47560 (2023). https://doi.org/10.1007/s11356-023-25729-8
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DOI: https://doi.org/10.1007/s11356-023-25729-8