Comparative Cytotoxicity of Six Iodinated Disinfection Byproducts on

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Comparative cytotoxicity of six iodinated disinfection byproducts on non-transformed epithelial human colon cells Rassil Sayess, Ahmed Khalil, Mittal Shah, David A Reckhow, and Krystal Juliette Godri Pollitt Environ. Sci. Technol. Lett., Just Accepted Manuscript • DOI: 10.1021/acs.estlett.7b00064 • Publication Date (Web): 21 Mar 2017 Downloaded from http://pubs.acs.org on March 27, 2017

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Environmental Science & Technology Letters

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Comparative Cytotoxicity of Six Iodinated Disinfection By-Products

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on Non-Transformed Epithelial Human Colon Cells

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Rassil Sayess1, Ahmed Khalil2, Mittal Shah3, David A. Reckhow1, Krystal J. Godri Pollitt2,* 1

Department of Environmental and Water Resources Engineering, School of Civil and Environmental Engineering, University of Massachusetts, Amherst, United States 01003 2 Department of Environmental Sciences, School of Public Health and Health Sciences, University of Massachusetts, Amherst, United States 01003 3 Institute of Orthopaedics and Musculoskeletal Sciences, University College London, Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, HA7 4LP

*Corresponding author: E-mail: [email protected] Key words: DBPs; Iodinated DBPs; cytotoxicity; epithelial colon cells, nontransformed human cells, drinking water

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Abstract

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Exposure to disinfection by-products (DBPs) in chlorinated drinking water has been positively

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associated with increased risk of colon, bladder, and rectum cancers. Iodinated DBPs (I-DBPs)

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are of concern as this class exhibits enhanced cytotoxicity and genotoxicity compared to

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chlorinated and brominated equivalents in Chinese Hamster Ovary (CHO) cells. We tested the

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impact of six I-DBPs on immortalized normal human colon epithelial cells, CCD 841 CoN. Our

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assay showed the rank order for cytotoxicity of the I-DBPs was as follows: iododacetic acid

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(IAA) > iodoacetamide (IAcAm)> bromoiodoacetamide (BIAcAm)> chloroiodoacetamide

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(CIAcAm)> bromoiodoacetic acid (BIAA)≈ diiodoacetic acid (DIAA). The enhanced

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cytotoxicity for IAA compared with other haloacetic acids agrees with studies conducted on

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CHO cells. IAcAm was found to be 3.5 times more cytotoxic than BIAcAm and 9.4 times more

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cytotoxic than CIAcAm. The cytotoxicity of both dihaloacids (i.e., BIAA, DIAA) was less than

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1% of that of the monohaloacid IAA. Apart from IAA, the nitrogenous I-DBPs demonstrated

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greater cytotoxicity than the carbonaceous I-DBPs. The results are consistent with previous CHO

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studies of dihalogenated I-DBPs but not monohalogenated ones. This study has implications for

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drinking water management strategies aimed at minimizing the formation of I-DBPs associated

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with enhanced cytotoxicity.

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1. Introduction Exposure to disinfection byproducts (DBPs) through chlorinated drinking water is a

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major public health concern given the increased risk of colon, bladder, and rectum cancers.1-12

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There are twenty compounds that have been identified as iodinated I-DBPs, fifteen of which

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have been detected in chlorinated and chloraminated waters (Supporting Information, Table

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S1).13-23 These compounds are of particular concern because of the twenty compounds that have

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been identified, all but one have shown enhanced cyto- and genotoxicity compared to their

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brominated and chlorinated analogues.18,20,24-30

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Published studies of I-DBPs have primarily evaluated toxicity using Chinese Hamster

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Ovary (CHO) cell models.18,21,24,26,30-32 Given that the toxicological response of a chemical will

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vary between species due to natural heterogeneity, the response in CHO cells cannot necessarily

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be extended to humans. While we appreciate the limitations in extending results from in vitro to

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epidemiological studies, the use of a healthy human cell line to evaluate DBP toxicity offers a

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model system to investigate the biological mechanisms underlying the outcomes reported in the

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population wide studies. Across the twenty I-DBPs of interest, only iodoacetic acid (IAA) has

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been the subject of cytotoxicity evaluation in human cell lines (Supporting Information, Table

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S1), of which only two used non-transformed human cells.33,34 Given the position of I-DBPs in

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drinking water as a public health concern, it is important to further assess the toxicity of other I-

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DBPs. In this study, we evaluated the cytotoxicity of a group of nitrogenous and carbonaceous I-

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DBPs on a non-transformed human colon cell line.

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2. Materials and Methods

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2.1. Reagents and Chemical

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Dulbecco’s Phosphate Buffer Saline (D-PBS; 30-2200TM stored at 4 °C), Eagle’s

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Minimum Essential Medium (EMEM; 30-2003TM stored at 4 °C), Penicillin-Streptomycin

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Solution (30-2300TM stored at -20 °C), dimethylsulfoxide (DMSO, 4-XTM stored at 4 °C),

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Trypsin-EDTA Solution (1X, 30-2101TM stored at -20 °C), and fetal bovine serum (FBS) (30-

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2020 TM stored at -20 °C) were purchased from American Type Culture Collection (ATCC).

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PrestoBlue® Cell Viability Reagent was obtained from ThermoFisher Scientific and stored at 4

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°C. Diiodoacetic acid (DIAA, >90%), bromoiodoacetic acid (BIAA, >85%),

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bromoiodoacetamide (BIAcAm, >85%), and chloroiodoacetamide (CIAcAm,>99%) were

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purchased from CanSyn Chemical Corporation (Toronto, Canada). Iodoacetamide (IAcAm,

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>99%) and iodoacetic acid (IAA, >98%) were purchased from Sigma-Aldrich. Triton® X-100

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(Molecular Biology Grade) was obtained from Promega.

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2.2. Preparation of Solutions

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Table 1 presents the six tested I-DBPs. IAA stock solution was prepared by dissolving

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IAA in EMEM solution containing 10% FBS and 1% Penicillin-Streptomycin. For the other five

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compounds, stock solutions were prepared by dissolving each compound in EMEM containing

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10% FBS, 1% Penicillin-Streptomycin, and 0.1% DMSO. The prepared EMEM solutions

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containing each of the six I-DBPs had a pH between 7 and 7.5, were stored at 4 °C, and were

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used within 4 weeks. I-DBPs were assumed to be stable within that range of pH and timeline.

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This was further confirmed by similar cell counts between the first cytotoxicity assay and the last

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for every tested concentration. Serial dilutions in the appropriate media were used to make a total

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of 6 concentrations for each compound to be analyzed for cytotoxicity.

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Table 1: Summary of the concentration ranges for each of the six I-DBPs Compound

Abbreviation

Molecular structure

Iodoacetic Acid

Iodoacetic acid Iodoacetic Acid

Diiodoacetic acid

IAA Bromoiodoacetic Acid

BIAA

Bromoiodoacetamide Bromoiodoacetic Acid

IAcAm Iodoacetic Acid Bromoiodoacetamide

264.84

Chloroiodoacetamide Diiodoacetic Acid

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Bromoiodoacetamide

Diiodoacetic Acid Chloroiodoacetamide

25 - 2000

Chloroiodoacetamide

184.96

50 - 5000

219.41

0.1 - 4000

263.86

10 - 5000

Chloroiodoacetamide

CIAcAm

Iodoacetamide

Bromoiodoacetamide

Diiodoacetic Acid

Diiodoacetic Acid

Bromoiodoacetic Acid Bromoiodoacetamide

Iodoacetamide

Chloroiodoacetamide

Bromoiodoacetic Acid


Iodoacetamide

Iodoacetamide

5 - 2000

Bromoiodoacetamide

Iodoacetic Acid

Chloroiodoacetamide

311.84

DIAA Iodoacetic Acid

Iodoacetamide

Tested Concentration range (µM) 0.1 - 50

Diiodoacetic Acid

Iodoacetamide

Bromoiodoacetic Iodoacetamide acidIodoacetic Acid

Molecular weight Diiodoacetic Acid (g/mol) 185.95


Bromoiodoacetamide

Chloroiodoacetamide

BIAcAm

2.3. Cell Culture

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Immortalized (non-neoplastic) normal human colon epithelial cells, CCD 841 CoN

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(CRL-1790), were obtained from ATCC at passage 13 and were used in all experiments between

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passage 15 and 17. The CCD 841 CoN cells were isolated from a 21-week gestation fetus that

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did not show any abnormalities.35 This cell line was selected given the positive association

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reported by epidemiological studies between exposure to chlorinated water and increased risk of

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colon cancer.6,9,10 The cells were cultured and maintained in T75 tissue culture flasks with

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EMEM-C containing 10% non-heat inactivated FBS and 1% Penicillin-Streptomycin Solution at

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37 °C in a humidified 5% CO2 incubator. Cells were maintained until 80% confluence before

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subsequent assays described below.

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2.4. Human Cell Cytotoxicity Assay CCD 841 CoN cells were seeded (12,500 cells per well) in clear, sterile, 96-well

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microplates with EMEM-C media and cultured at 37 °C in a humidified 5% CO2 incubator.

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Upon reaching 80% confluence, the media was replaced with fresh media containing different

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concentrations of the six compounds (exposure media), EMEM-C (positive control for IAA), or

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EMEM-C with 0.1% DMSO (positive control for five other compounds). The plates were then

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incubated for 12 hours at 37 °C in the humidified 5% CO2 incubator. At hour 11, Triton® X-100

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(1 µL) was added to the positive controls and incubated for one hour. Following the exposure

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period, cells were washed with D-PBS. EMEM-C (90 µL) and PrestoBlue (10 µL) were added to

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each well and incubated for 1 hour at 37 °C in the humidified 5% CO2 incubator. A

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SpectraMax® MiniMax™ Imaging Cytometer (Molecular Devices) was used to measure the

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fluorescence at 535 nm for excitation and 615 nm for emission at 52 points per well. For each

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compound, 2 to 5 biological replicates were tested at each concentration. Exposures were

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repeated on 3 or 4 separate days (experimental replicates), yielding a total of 9 to 15 replicates

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per concentration per compound. The negative control for IAA was EMEM-C while that for the

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other five compounds was EMEM-C with 0.1% DMSO. Cell viability was evaluated as the

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number of viable cells while cell cytotoxicity was evaluated as the reduction in the number of

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viable cells compared to the negative control.

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2.5. Data Analysis

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Cytotoxicity data was normalized to the averaged percent of the corresponding negative

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controls from individual experiments. The average mean viability values obtained from the

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biological and experimental replicates from all the experiments were used to construct a cell

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viability concentration-response curve. The data from each compound were used to generate

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Four-Parameter Logistic nonlinear regression functions using the “log(inhibitor) vs. response”

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equation (Eq. 1).

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𝑌 = 𝐵𝑜𝑡𝑡𝑜𝑚 + (𝑇𝑜𝑝 − 𝐵𝑜𝑡𝑡𝑜𝑚)/(1 + 10(𝐿𝑜𝑔𝐼𝐶50 −𝑋)×𝐻𝑖𝑙𝑙𝑆𝑙𝑜𝑝𝑒) )

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where Y is the percent of cells that are viable, X is the tested concentration, and HillSlope is the

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slope of the sigmoidal curve. The Top and Bottom values were constrained to 100 (all cells are

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viable) and 0 (all cells are not viable), respectively.

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Eq. 1

To fit the curve for each compound, the parameters were adjusted to minimize the mean

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square error between the fitted values and observations. The root mean squared error was then

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calculated for each of the fitted curves to reflect every compound. The optimized curves were

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used to calculate the LC50 and LC10 values, or the lowest concentration at which 50% and 10%

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reduction in cell density is observed as compared to control cells, respectively. The LC50 value

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was used to rank the cytotoxicity of the six I-DBPs for this cell line. All data were analyzed

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using the programming language R.

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3. Results and Discussion

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3.1. CCD 841 CoN cytotoxicity

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Figure 1 presents a dose-response curve for the six I-DBPs. The viability of CCD 841

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CoN cells was found to decrease in a concentration-dependent manner within the tested range of

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concentrations for the six compounds (Supporting Information, Table S2). The LC10

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concentrations were 2.4 µM for IAA, 3.2 µM for IAcAm, 13.4 µM for BIAcAm, 21.3 µM for

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CIAcAM, 5.5 µM for DIAA, and 332.1 µM for BIAA. The LC50 values ranged from 8.6 µM for

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IAA to about 1 mM for DIAA and BIAA. In CCD 841 CoN cells, the rank order for cytotoxicity 7



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of the six I-DBP compounds based on their LC50 values was as follows: IAA > IAcAm >

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BIAcAm > CIAcAm > DIAA ≈ BIAA (Table 2).

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Figure 1: Concentration-response curves of the six I-DBPs on CCD 841 CoN cells.

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Table 2: Summary of the CCD 841 CoN cell cytotoxicity of the I-DBPs I-DBP

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LC10a

LC50b (µM)

R2 c

Toxic rank order IAA 2 8.6 0.83 1 IAcAm 3 39.1 0.76 2 BIAcAm 13 136.3 0.52 3 CIAcAm 21 369.0 0.69 4 DIAA 6 954.7 0.51 5 BIAA 332 982.2 0.81 6 a the concentration at which the cell viability was reduced by 10% as compared to the negative control determined by the non-linear Four-Parameter Logistic nonlinear regression functions b the concentration at which the cell viability was reduced by 50% as compared to the negative control determined by the non-linear Four-Parameter Logistic nonlinear regression functions c the root mean squared error for the non-linear curve fitting

IAA exhibited the highest cytotoxicity to CCD 841 CoN cells among the six I-DBPs.

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This finding is in line with published literature which reports enhanced cytotoxicity for IAA

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compared with other haloacetic acids in CHO cells.18,26,30-32 The increased cytotoxicity of IAA

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has been attributed to the length of the carbon-halogen bond and the number of halogens per

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atom. 26 As the size of the halogen increases, the dissociation energy declines making iodine an

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excellent leaving group compared to the other halogens; this consequently leads to higher

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cytotoxicity. The pattern of decreasing toxicity of I>Br>Cl has been previously observed for all

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identified I-DBPs except for iodoacetaldehyde.18,21,26,30-32 Enhanced toxic potency is also

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attributable to fewer halogens per atom.34 However, previous studies showed that the haloacids

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was less cytotoxic than the haloamides in CHO-AS52 cells.21,27 These results were consistent

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with the results of the dihalogenated compounds in this study but not for the mono-halogentated

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ones: IAA was two times more cytotoxic than IAcAm in CCD 841 CoN cells. This may indicate

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that human colon cells are more sensitive to IAA than IAcAm. Since haloamides were not

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explored in other cell lines than CHO cells, the significance is unclear.

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3.2. Comparative cytotoxicity of CCD 841 CoN cells and other cell lines

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Differences across cytotoxicity assays, as well as inherent sensitivity across cell lines to

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particular compounds, will affect the overall response of a cell line to a compound.37 Although it

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is not ideal to relate the sensitivity of human cells with mouse or hamster cells because of their

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characteristic and species specific differences, a comparison of the toxicity rank of different cell

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lines to a toxicant could potentially offer some useful insight to these cell lines. IAA is the only

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compound where such comparison is possible since it has been studied in hamster (CHO-AS52

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and CHO-K1), mouse (NIH3T3), and human (HepG2, Caco-2, and CCD 841 CoN) cell lines

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(Figure 2).24,26,32,37,38,39 NIH3T3 cells, CHO-AS52 cells, and CHO-K1 cells were exposed for 72

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hours, 24,26,32,38 HepG2 cells were exposed for 24 hours, 39 and Caco-2 cells were exposed for 4

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hours to IAA, 37 compared to a 12-hour exposure period in this study. The results demonstrate

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comparable LC50 between CCD 841 CoN cells from this study and HepG2 liver cells, 39 while

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the LC50 was about two times more than that for the Caco-2 cells. 37 Compared to cell lines of

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mouse and hamster origins (CHO-AS52, CHO-K1, and NIH3T3), CCD 841 CoN cells were less

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impacted by IAA. 24,26,32,38 One explanation for the observed differences in LC50 between human

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and other cell lines could be the higher resilience of human cells in comparison to small animal

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(e.g., mice and hamster) cells. Another reason could be the difference in exposure times whereby

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the exposure to the human cell lines (4 hours to 24 hours) was lower than that of the small

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animals (72 hours).

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Figure 2: Comparison of the LC50 calculated from the cytotoxicity of IAA on different mammalian cell lines from the literature 24,26,32,37,38,39 and the present study. The grey bars indicate an animal (CHO and mouse) cell line (72-hour exposure). The white bar indicates human cancer liver (24-hour exposure) and cancer colon (4-hour exposure) cell lines. The black bar indicates the human healthy colon cell line used in this study (12-hour exposure).

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The cytotoxicity of DIAA, BIAA, IAcAm, BIAcAm, and CIAcAm have previously only

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been tested using CHO-AS52 cells.21,30 A comparison of the LC50 for these five compounds on

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CCD 841 CoN cells (this study) and on CHO-AS52 cells from the literature is presented in

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Figure 3. The three iodoamides were associated with lower LC50 values (39.1 - 369 µM)

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compared to the dihaloacids (~1000 µM) indicating that apart from IAA, nitrogenous-DBPs were

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more cytotoxic than carbonaceous-DBPs. The trend across DBPs for both cell lines was found to

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be similar. It is worth noting that the exposure period for CHO-AS52 cells was 72 hours

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compared to 12 hours in our study. Furthermore, the range of exposure concentrations evaluated

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in our study (Table 1) extended beyond those evaluated in CHO-AS52 cells.21,30 The results from

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our study shows that the sensitivity of CCD 841 CoN cells to these five compounds was lower

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than those reported in the literature despite the higher exposure concentrations.21,30 This may

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indicate a higher resilience of human colon cells to these toxicants than CHO cells, leading to the

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decrease in observed sensitivity. However, since the exposure period is lower for the CCD 841

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CoN cells (12 hours) compared to the CHO-AS52 cells (72 hours), this observation is not

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conclusive.

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Figure 3: Comparison of the LC50 between five I-DBPs on CCD 841 CoN cells (this study; 12hour exposure) and CHO-AS52 cells (72-hour exposure). 21,30 The LC50 is shown on a log scale. To the best of our knowledge, the data presented here is the first to study the impact of

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DBPs on a cell line known to be associated with epidemiological evidence. We have shown that

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apart from IAA, the three tested iodoamides were more cytotoxic in CCD 841 CoN cells than the

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haloacids. Given their enhanced cytotoxicity observed in a human cell line, IAA and the three

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iodoamides (IAcAm, BIAcAm, and CIAcAm) should be prioritized when developing strategies

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to control DBP formation in treated drinking water.

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Supporting Information Available:

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References

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S1. Occurrence of I-DBPs in treated water, the cytotoxicity models used, and information inferred from cytotoxicity assays S2. Viability of CCD CoN 841 cells for the 6 I-DBPs at different concentrations

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37. Procházka, E., Escher, B. I., Plewa, M. J., Leusch, F. D. L., 2015. In vitro cytotoxicity and adaptive stress responses to selected haloacetic acid and halobenzoquinone water disinfection byproducts. Chem. Res. Toxicol., 28, 2059-2069. 38. Wei, X., Wang, S., Zheng, W., Wang, X., Liu, X., Jiang, S., Pi, J., Zheng, Y., He, G., & Qu, W. (2013). Drinking water disinfection byproduct iodoacetic acid induces tumorigenic transformation of NIH3T3 cells. Environ. Sci. Technol., 47, 5913-5920. 39. Wang, S., Zheng, W., Liu, X., Xue, P., Jian, S., Lu, D., Zhang, Q., He, G., Pi, J., Andersen, M. E., Tan, H., & Qu, W (2014). Iodoacetic acid activates nrf2-mediated antioxidant response in vitro and in vivo. Environ. Sci. Technol., 48, 13478-13488.

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Comparative Cytotoxicity of Six Iodinated Disinfection Byproducts on

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