Introduction

Evidence before this study

Links between environmental chemicals and human health including hypertension, cardiovascular disease, respiratory disease, food allergy, oral health and cognitive function have emerged (Shiue 2013a, b, c; 2014a, b; 2015a, b, c) in American adults, but the effects from polyaromatic hydrocarbons (PAHs) were less studied, compared to other commonly known environmental chemicals such as heavy metals, arsenic, phenols, parabens, pesticides, phthalates, etc. PAHs constitute a group of chemicals that people could be exposed to via vehicle exhausts, asphalt, coal tar, wild fires, agricultural burning, soil, charbroiled foods, and tobacco smoke. PAH pollution may have significant health implications, and the extent of damage to organisms from PAH exposure could be dependent on several factors including degree and type of PAH exposure (Ball and Truskewycz 2013). The potential for PAHs to adversely affect human immunologic health could have traditionally been evaluated in rodents, under laboratory conditions (Luebke et al. 1997). Recently, researchers have also found how PAHs could be linked to cardiovascular disease in American adults (Xu et al. 2010) or in pregnant women (Woodruff et al. 2011).

Knowledge gap

However, in addition to physical health, it is unclear about the role of PAHs and other environmental chemicals in mental health such as depression. Following this context, therefore, it was aimed to examine and provide further evidence on the relationships between different sets of urinary environmental chemical concentrations and adult depression using a large human sample to account for prior health events in a national and population-based setting in recent years.

Methods

Study sample

As described elsewhere (more details via http://www.cdc.gov/nchs/nhanes.htm), the US National Health and Nutrition Examination Surveys (NHANES) has been a national, population-based, multiyear, cross-sectional study since the 1980s. Study samples are a representative sample of the civilian, noninstitutionalized US population. Information on demographics, serum measurements, lifestyle factors, self-reported health conditions, and urinary environmental chemical concentrations was obtained by household interview. Depression status was measured using Patient Health Questionnaire (Spitzer et al. 1999), a nine-item screening instrument that asked questions about the frequency of symptoms of depression over the recent past 2 weeks. Response categories for the nine-item instrument such as “not at all,” “several days,” “more than half the days,” and “nearly every day” were given a point ranging from 0 to 3 (more details via http://wwwn.cdc.gov/nchs/nhanes/2011-2012/DPQ_G.htm). The overall scoring ranges from 0 to 27 following answering nine items and could have categories from none, mild to moderate, and even severe (more details via http://www.phqscreeners.com/instructions/instructions.pdf). The current recommended cutoff in the clinical setting is 9/10 (Manea et al. 2012). In the current analysis, the 2011–2012 cohort as the most recent study cohort with available information mentioned above was selected for examination. Informed consents were obtained from participants by the NHANES researchers.

Biomonitoring

Urines were only collected in a subsample, being one third of the whole study cohort (still representative), to measure environmental chemical concentrations in urines. To be specific, participants were instructed to collect a partial void in a specimen cup during one morning when they first woke up and to mail it back to the contract laboratory (more details via http://www.cdc.gov/nchs/nhanes/nhanes2011-2012/labdoc_g.htm). Urine specimens were then processed, stored under appropriate frozen (−20 °C) conditions, and shipped to the Division of Environmental Health Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention for laboratory analysis.

The inductively coupled plasma-mass spectrometry (ICP-MS) method (Mulligan et al. 1990) was used to measure the following 12 elements of heavy metals in urine: beryllium (Be), cobalt (Co), molybdenum (Mo), cadmium (Cd), antimony (Sb), cesium (Cs), tungsten (W), tin (Sn), strontium (Sr), manganese (Mn), thallium (TI), lead (Pb), and uranium (U). Urine samples are diluted 1 + 9 with 2 % (v/v), double-distilled, concentrated nitric acid containing both iridium (Ir) and rhodium (Rh) for multi-internal standardization (more details via http://wwwn.cdc.gov/nchs/nhanes/2011-2012/UHM_G.htm). In addition, the test principle utilized high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) for the quantitative detection in urine of the following phthalate metabolites: monomethyl phthalate (MMP), monoethyl phthalate (MEP), monobutyl phthalate (MBP), mono-isobutyl phthalate (MIBP), mono (3-carboxypropyl) phthalate (MCPP), mono(2-ethylhexyl) phthalate (MEHP), monobenzyl phthalate (MBzP), monoisononyl phthalate (MNP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), monocarboxyoctyl phthalate (MCOP), monocarboxynonyl phthalate (MCNP), and cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester (MHNCH) (Silva et al. 2007). Urine samples are processed using enzymatic deconjugation of the glucuronidated metabolites followed by on-line solid-phase extraction (SPE) coupled with reversed phase HPLC-ESI-MS/MS. Assay precision is improved by incorporating isotopically labeled internal standards of the phthalate metabolites and MHNCH (more details via http://wwwn.cdc.gov/nchs/nhanes/2011-2012/PHTHTE_G.htm).

Total and specific urine arsenic concentrations were determined by using inductively coupled-plasma dynamic reaction cell-mass spectrometry (ICP-DRC-MS) (more details via http://wwwn.cdc.gov/nchs/nhanes/2011-2012/UAS_G.htm). In this case, urine is analyzed because urinary excretion is the major pathway for eliminating arsenic from the mammalian body (Vahter 1988). A sensitive method for measuring two dichlorophenols and several other phenols was developed in 2005 (Ye et al. 2005). The method used on-line solid-phase extraction (SPE) coupled to HPLC and tandem mass spectrometry (HPL/CMS/MS) (more details via http://wwwn.cdc.gov/nchs/nhanes/2011-2012/PP_G.htm and http://wwwn.cdc.gov/nchs/nhanes/2011-2012/EPH_G.htm).

To detect and measure metabolites of PAHs (more details via http://wwwn.cdc.gov/nchs/nhanes/2011-2012/PAH_G.htm), the procedure involved enzymatic hydrolysis of glucuronidated/sulfated OH-polyaromatic hydrocarbons metabolites in urine, extraction, derivatization, and analysis using isotope dilution capillary gas chromatography tandem mass spectrometry (GC-MS/MS). Ion transitions specific to each analyte and carbon-13 labeled internal standards are monitored, and the abundances of each ion are measured. Moreover, solid-phase extraction coupled to high-performance liquid chromatography-turbo ion spray ionization-tandem mass spectrometry (on-line SPE-HPLC-TIS-MS/MS) was used for the quantitative detection of perfluorooctane sulfonamide (PFOSA), 2-(N-methyl-perfluorooctane sulfonamido), acetic acid (Me-PFOSA-AcOH), 2-(N-ethyl-perfluorooctane sulfonamido), acetic acid (Et-PFOSA-AcOH), perfluorobutane sulfonate (PFBuS), perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluoroheptanoate (PFHpA), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDeA), perfluoroundecanoate (PFUA), and perfluorododecanoate (PFDoA).

For phenols and parabens that could come from industrial pollution, pesticide use, food consumption, or use of personal care products (more details via: http://wwwn.cdc.gov/nchs/nhanes/2011-2012/EPH_G.htm), a sensitive method for measuring BPA, BP-3, triclosan, and four parabens was developed in 2005 (Ye et al. 2005, 2006). The method uses on-line solid-phase extraction (SPE) coupled to HPLC and tandem mass spectrometry (HPLC-MS/MS). While drinking water, milk, and certain plants with high water content can be the main sources of perchlorate intake for humans, nitrate and thiocyanate are polyatomic anions that can disrupt thyroid function by competitively inhibiting iodide uptake, similar to the action of perchlorate (more details via http://wwwn.cdc.gov/nchs/nhanes/2011-2012/PERNT_G.htm). The laboratory method used was ion chromatography coupled with electrospray tandem mass spectrometry (more details via http://www.cdc.gov/nchs/data/nhanes/nhanes_11_12/PERNT_G_met.pdf).

Statistical analysis

Adults aged 20 years and above were included in the current statistical analysis since adult depression status was asked in such age group. For statistical analysis purpose in the present study, urinary chemicals were all log transformed due to the fact that they were highly skewed to one side. In the first step, associations of historical health events and adult depression were investigated in order to see which disease might be more likely to result in depression. In the second step, associations of urinary different sets of environmental chemical concentrations and adult depression were examined by using t test and survey-weighted logistic regression models, with P < 0.05 considered statistically significant. Covariates including urinary creatinine, age, sex, ratio of family income to poverty (proxy of socioeconomic status), body mass index, serum cotinine (biomarker of smoking status), alcohol habit, physical activity level, and educational level were adjusted. In the third step, significant prior health events were additionally adjusted in the modeling to rule out the possibility of the potential cause to adult depression. Statistical software STATA version 13.0 (STATA, College Station, Texas, USA) was used to perform all the statistical analyses. Since the present study is only a secondary data analysis by extracting data from the NHANES website, no further ethics approval was required.

Results

Among 5560 American adults aged 20–80 years, 363 (7.8 %) people were classified as having depression (Patient Health Questionnaire score ≥ 10). They tended to have history of health events. Table 1 presents associations of historical health events and adult depression. It is clear to see that health conditions such as cardiovascular, neurological, respiratory, digestive and bone diseases, and injury were significantly associated with depression. Tables 2 and 3 show associations of urinary heavy metals and adult depression and by accounting for health events, respectively, while Tables 4 and 5 show associations of urinary phthalates and adult depression and by accounting for health events, respectively. It is clear to see that higher levels of manganese, tin, mono-2-ethyl-5-carboxypentyl, mono-n-butyl, mono-isobutyl, and mono-benzyl were associated with adult depression.

Table 1 Associations between health conditions and adult depression aged 20–80 years (n = 5560)
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Table 2 Associations between urinary heavy metals (one third of the study population) and adult depression
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Table 3 Associations between urinary heavy metals and adult depression accounting for health events
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Table 4 Associations between urinary phthalates (one third of the study population) and adult depression
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Table 5 Associations between urinary phthalates and adult depression accounting for health events
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Similarly, Tables 6 and 7 show associations of urinary PAHs and adult depression and by accounting for health events, respectively. It is clear to see that urinary 2-hydroxyfluorene, 3-hydroxyfluorene, 9-hydroxyfluorene, 1-hydroxyphenanthrene, 2-hydroxyphenanthrene, 3-hydroxyphenanthrene, 1-hydroxypyrene, 1-hydroxynaphthalene (1-naphthol), 2-hydroxynaphthalene (2-naphthol), and 4-hydroxyphenanthrene were also associated with depression. However, there were no associations observed in urinary arsenic, phenols, parabens, pesticides, perchlorate, nitrate, thiocyanate, and polyfluorinated compounds.

Table 6 Associations between urinary polyaromatic hydrocarbons (one third of the study population) and adult depression
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Table 7 Associations between urinary polyaromatic hydrocarbons and adult depression accounting for health events
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Discussion

Previous research synthesis

Evidence of risk effects of chemicals on mental health has gradually emerged in recent years, in particular on the effects of endocrine-disrupting chemicals on brain function, concomitantly with an increase in neuropsychiatric disorders including autism, attention deficit, hyperactivity disorder, learning disabilities, and aggressiveness (Kajta and Wójtowicz 2013). Even low doses might increase the risk of depression and consequently neural degeneration. Depression is a leading cause of disability worldwide and occurs in people of all ages and backgrounds (Bromet et al. 2011). However, studies looking into this emerging area, namely chemicals and depression or general mental health, are still limited.

Urinary heavy metals such as manganese and tin were associated with adult depression in the present study. Manganese is an often overlooked but important nutrient, required in small amounts for multiple essential functions in the body. However, too much of it could promote toxicity in the brainstem, leading to mental health conditions and improper cognitive performance (Samsel and Seneff 2015; Jain and Ferrando 2011; Solís-Vivanco et al. 2009). The underlying mechanism is likely through oxidative stress and excitotoxicity in the cerebellum, frontal cortex, caudate, globus pallidus, olfactory cortex, and putamen (Erikson et al. 2008). Tin, as a stannous chloride, can facilitate the neuromuscular transmission by accelerating the transmitter release from the nerve terminals in the mouse, in vitro and in vivo (Silva et al. 2002). It could, therefore, produce stimulation or depression of the central nervous system.

The neurotoxicity of phthalates could also be linked with mental health state such as anxiety or depression. In the limited animal research, it was preliminarily observed that benzyl butyl phthalate exposure caused a decrease in the number of neurotransmitters, which in turn downregulates the levels of CREB phosphorylation by the cAMP/protein kinase A (PKA)-mediated signaling (Min et al. 2014). In the present study, further observations were made on other phthalate metabolites including mono-2-ethyl-5-carboxypentyl, mono-n-butyl, mono-isobutyl, and mono-benzyl that would need future experimental research to confirm or refute. In addition, urinary PAHs were found to be associated with adult depression by using a large human sample for the first time. It is known that exposure to PAHs occurs through one of the following routes: inhalation, ingestion with or without aspiration, or dermal exposure. Inhalational abuse is associated with central nervous system depression, metabolic acidosis, and arrhythmia, although the exact mechanism of the CNS depression is unknown (Tormoehlen et al. 2014). Some experimental evidence could have also suggested effects on NMDA, dopamine and GABA receptors.

Strengths and limitations

The present study has a few strengths. First, this study was conducted in a large and nationally representative human sample with mixed ethnicities and socioeconomic status in recent years. Second, this is the first time examining the associations of urinary PAHs and phthalates and adult depression. However, there are still some limitations that cannot be ignored. First, there could still be other emerging chemicals from the living environments that we might not yet know and would need future research to further identify and examine. Second, the data on recurrence of depression was not available (Michel et al. 2007). Third, the causality cannot be established in the present study due to the cross-sectional study design in nature. Therefore, future studies with longitudinal and/or experimental study designs to confirm or refute the observations obtained in the present study and, if at all, to understand the persisting risk effects along the life course from those mentioned above environmental chemicals would be suggested.

Conclusion

Urinary heavy metals (manganese and tin), phthalates, and PAHs but not arsenic, phenols, parabens, pesticides, perchlorate, nitrate, thiocyanate and polyfluorinated compounds were associated with adult depression, being independent of historical health events. Further elimination of such harmful chemicals might need to be considered in future mental health and environmental policies.