Risk analysis of serum chemical residues for metabolic associated fatty liver disease based on exposome-lipidome wide association study

doi:10.3724/SP.J.1123.2023.12014

Abstract

Abstract:

Metabolic associated fatty liver disease (MAFLD) is a common liver disease with a prevalence of up to 25%; it not only adversely affects human health but also aggravates the economic burden of society. An increasing number of studies have suggested that the occurrence of chronic noncommunicable diseases is affected by both environmental exposures and genetic factors. Research has also shown that environmental pollution may increase the risk of MAFLD and promote its occurrence and development. However, the relationship between these concepts, as well as the underlying exposure effects and mechanism, remains incompletely understood. Lipidomics, a branch of metabolomics that studies lipid disorders, can help researchers investigate abnormal lipid metabolites in various disease states. Lipidome-exposome wide association studies are a promising paradigm for investigating the health effects of cumulative environmental exposures on biological responses, and could provide new ideas for determining the associations between metabolic and lipid changes and disease risk caused by chemical-pollutant exposure. Hence, in this study, targeted exposomics and nontargeted lipidomics studies based on ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) were used to characterize exogenous chemical pollutants and endogenous lipid metabolites in the sera of patients with MAFLD and healthy subjects. The results demonstrated that fipronil sulfone, malathion dicarboxylic acid, and monocyclohexyl phthalate may be positively associated with the disease risk of patients diagnosed as simple fatty liver disease (hereafter referred to as MAFLD(0)). Moreover, fipronil sulfone, acesulfame potassium, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDA), 4-hydroxybenzophenone, and 3,5-di-tert-butyl-4-hydroxybenzoic acid (DBPOB) may be positively associated with the disease risk of patients diagnosed as fatty liver complicated by single or multiple metabolic disorders. Association analysis was carried out to explore the lipid metabolites induced by chemical residues. Triglyceride (TG) and diglyceride (DG) were significantly increased in MAFLD and MAFLD(0). The numbers of carbons of significantly changed DGs and TGs were mainly in the ranges of 32-40 and 35-60, respectively, and both were mainly characterized by changes in polyunsaturated lipids. Most of the lipid-effect markers were positively correlated with chemical residues and associated with increased disease risk. Our research provides a scientific basis for studies on the association and mechanism between serum chemical-pollutant residues and disease outcomes.

Key words: metabolic associated fatty liver disease (MAFLD), exposomics, lipidomics, omics-wide association study

CLC Number:

O658

CHEN Qianqian, YOU Lei, GUAN Pengwei, FANG Chengnan, QIN Wangshu, LIU Xinyu, XU Guowang. Risk analysis of serum chemical residues for metabolic associated fatty liver disease based on exposome-lipidome wide association study[J]. Chinese Journal of Chromatography, 2024, 42(2): 164-175.

Figures/Tables 8

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IS	ESI mode	C(IS)/ (μg/mL)	Platform
FFA16∶0-d₃	ESI^-	0.67	lipidomics
FFA18∶0-d₃	ESI^-	0.67	lipidomics
LPC 19∶0	ESI⁺	0.33	lipidomics
PC 38∶0	ESI^-	0.67	lipidomics
PE 30∶0	ESI^-	0.33	lipidomics
SM(d18∶1/12∶0)	ESI⁺	0.17	lipidomics
Cer(d18∶1/17∶0)	ESI^-	0.17	lipidomics
Coumaphos-d₁₀	ESI⁺	0.5	exposomics
Dimethoate-d₆	ESI⁺	2.5	exposomics
Imidacloprid-d₄	ESI⁺	5	exposomics
Prometryn-d₄	ESI⁺	1	exposomics
Linuron-d₆	ESI⁺	5	exposomics
Metalaxyl-d₆	ESI⁺	0.5	exposomics
Myclobutanil-d₉	ESI⁺	1	exposomics
Carbendazim-d₄	ESI⁺	0.5	exposomics
Sulfamerazine-¹³C₆	ESI⁺	2.5	exposomics
Sulfamethazine-(phenyl-¹³C₆)	ESI⁺	1.5	exposomics
Metronidazole-¹³C₂,¹⁵N₂	ESI⁺	5	exposomics
Clenbuterol-d₉	ESI⁺	5	exposomics
Furaltadone-d₅	ESI⁺	10	exposomics
2,4-D-¹³C₆	ESI^-	5	exposomics
Triclosan-¹³C₁₂	ESI^-	15	exposomics
Fipronil-d₄	ESI^-	0.5	exposomics
Chloramphenicol-d₅	ESI^-	2	exposomics
PFOA-¹³C₈	ESI^-	3	exposomics
PFOS-¹³C₈	ESI^-	3	exposomics

IS	ESI mode	C(IS)/ (μg/mL)	Platform
FFA16∶0-d₃	ESI^-	0.67	lipidomics
FFA18∶0-d₃	ESI^-	0.67	lipidomics
LPC 19∶0	ESI⁺	0.33	lipidomics
PC 38∶0	ESI^-	0.67	lipidomics
PE 30∶0	ESI^-	0.33	lipidomics
SM(d18∶1/12∶0)	ESI⁺	0.17	lipidomics
Cer(d18∶1/17∶0)	ESI^-	0.17	lipidomics
Coumaphos-d₁₀	ESI⁺	0.5	exposomics
Dimethoate-d₆	ESI⁺	2.5	exposomics
Imidacloprid-d₄	ESI⁺	5	exposomics
Prometryn-d₄	ESI⁺	1	exposomics
Linuron-d₆	ESI⁺	5	exposomics
Metalaxyl-d₆	ESI⁺	0.5	exposomics
Myclobutanil-d₉	ESI⁺	1	exposomics
Carbendazim-d₄	ESI⁺	0.5	exposomics
Sulfamerazine-¹³C₆	ESI⁺	2.5	exposomics
Sulfamethazine-(phenyl-¹³C₆)	ESI⁺	1.5	exposomics
Metronidazole-¹³C₂,¹⁵N₂	ESI⁺	5	exposomics
Clenbuterol-d₉	ESI⁺	5	exposomics
Furaltadone-d₅	ESI⁺	10	exposomics
2,4-D-¹³C₆	ESI^-	5	exposomics
Triclosan-¹³C₁₂	ESI^-	15	exposomics
Fipronil-d₄	ESI^-	0.5	exposomics
Chloramphenicol-d₅	ESI^-	2	exposomics
PFOA-¹³C₈	ESI^-	3	exposomics
PFOS-¹³C₈	ESI^-	3	exposomics

Characteristic	Total		Control		MAFLD(0)		MAFLD&1		MAFLD&2		MAFLD&3		MAFLD&4
Gender (male/female)	146	/191	14	/16	15	/37	50	/71	45	/47	18	/17	4	/3
Age/years	45.9	±10.6	41.8	±9.0	46.2	±10.0	44.6	±9.4	47.7	±11.4^*	48.5	±12.7^*	48.0	±12.8
BMI/(kg/m²)	26.6	±3.0	24.0	±1.7	25.5	±1.5^***	25.9	±2.8^***	28.0	±3.0^***	28.4	±2.7^***	30.8	±4.4^***
SBP/mmHg	133.5	±18.8	120.0	±11.0	121.0	±12.6	132.4	±17.2^***	141.8	±21.3^***	141.7	±12.8^***	150.3	±10.7^***
DBP/mmHg	81.9	±11.7	74.6	±8.0	73.6	±8.7	81.9	±11.3^***	86.4	±11.7^***	86.8	±10.6^***	90.1	±8.6^**
Height/cm	165.5	±8.3	165.9	±7.0	163.2	±7.0	165.3	±8.7	167	±8.6	165.9	±8.6	163.8	±10.4
Weight/kg	73.1	±11.8	65.8	±5.0	67.9	±7.2	71.1	±11.2^*	78.3	±12.9^***	78.5	±12.3^***	82.0	±8.3^**
GLU/(mmol/L)	5.7	±1.6	5.0	±0.3	5.1	±0.5	5.5	±1.2^***	6.2	±2.0^***	6.4	±2.1^***	8.0	±3.7^**
TG/(mmol/L)	1.5	±1.0	1.0	±0.3	1.2	±0.4	1.6	±1.0^***	1.6	±0.9^***	1.9	±1.0^***	3.1	±1.9
TC/(mmol/L)	4.8	±0.9	4.3	±0.7	4.3	±0.5	4.9	±0.8^**	5.0	±0.9^***	5.3	±0.9^***	5.4	±0.8
HDL-c/(mmol/L)	1.2	±0.2	1.4	±0.2	1.3	±0.2	1.2	±0.3^***	1.2	±0.2^***	1.2	±0.3^***	1.2	±0.1
LDL-c/(mmol/L)	3.0	±0.7	2.6	±0.6	2.6	±0.5	3.1	±0.7^***	3.2	±0.8^***	3.5	±0.7^***	3.2	±0.7
Hb/(g/L)	144.5	±16.5	143.3	±15.5	139.6	±15.5	144.7	±16.5	145.6	±18.2	147.9	±14.1	150.3	±13.7
Cre/(μmol/L)	66.2	±13.6	65.1	±13.7	62.7	±12.8	66.5	±13.3	66.7	±12.3	67.5	±13.3	79.6	±30.1
UA/(μmol/L)	331.3	±77.1	296.3	±62.6	303.8	±49.6	329.1	±69.4^*	339.0	±84.2^**	371.2	±96.1^***	421.3	±69.2^**
Urea/(mmol/L)	4.6	±1.1	4.4	±1.0	4.4	±1.0	4.7	±1.1	4.6	±1.1	4.7	±0.9	6.3	±1.5^**
AST/(U/L)	19.8	±7.9	17.7	±3.8	17.1	±4.8	20.2	±7.6	19.8	±7.5	22.8	±11.2	25.4	±18.7
ALT/(U/L)	25.7	±17.4	17.8	±8.2	19.5	±9.7	27.5	±18.2^**	27.0	±18.8^*	30.0	±18.7^**	37.1	±28.5
AST/ALT	0.9	±0.4	1.1	±0.4	1.0	±0.3	0.9	±0.3^***	0.9	±0.3^***	0.9	±0.6^**	0.7	±0.1

Characteristic	Total		Control		MAFLD(0)		MAFLD&1		MAFLD&2		MAFLD&3		MAFLD&4
Gender (male/female)	146	/191	14	/16	15	/37	50	/71	45	/47	18	/17	4	/3
Age/years	45.9	±10.6	41.8	±9.0	46.2	±10.0	44.6	±9.4	47.7	±11.4^*	48.5	±12.7^*	48.0	±12.8
BMI/(kg/m²)	26.6	±3.0	24.0	±1.7	25.5	±1.5^***	25.9	±2.8^***	28.0	±3.0^***	28.4	±2.7^***	30.8	±4.4^***
SBP/mmHg	133.5	±18.8	120.0	±11.0	121.0	±12.6	132.4	±17.2^***	141.8	±21.3^***	141.7	±12.8^***	150.3	±10.7^***
DBP/mmHg	81.9	±11.7	74.6	±8.0	73.6	±8.7	81.9	±11.3^***	86.4	±11.7^***	86.8	±10.6^***	90.1	±8.6^**
Height/cm	165.5	±8.3	165.9	±7.0	163.2	±7.0	165.3	±8.7	167	±8.6	165.9	±8.6	163.8	±10.4
Weight/kg	73.1	±11.8	65.8	±5.0	67.9	±7.2	71.1	±11.2^*	78.3	±12.9^***	78.5	±12.3^***	82.0	±8.3^**
GLU/(mmol/L)	5.7	±1.6	5.0	±0.3	5.1	±0.5	5.5	±1.2^***	6.2	±2.0^***	6.4	±2.1^***	8.0	±3.7^**
TG/(mmol/L)	1.5	±1.0	1.0	±0.3	1.2	±0.4	1.6	±1.0^***	1.6	±0.9^***	1.9	±1.0^***	3.1	±1.9
TC/(mmol/L)	4.8	±0.9	4.3	±0.7	4.3	±0.5	4.9	±0.8^**	5.0	±0.9^***	5.3	±0.9^***	5.4	±0.8
HDL-c/(mmol/L)	1.2	±0.2	1.4	±0.2	1.3	±0.2	1.2	±0.3^***	1.2	±0.2^***	1.2	±0.3^***	1.2	±0.1
LDL-c/(mmol/L)	3.0	±0.7	2.6	±0.6	2.6	±0.5	3.1	±0.7^***	3.2	±0.8^***	3.5	±0.7^***	3.2	±0.7
Hb/(g/L)	144.5	±16.5	143.3	±15.5	139.6	±15.5	144.7	±16.5	145.6	±18.2	147.9	±14.1	150.3	±13.7
Cre/(μmol/L)	66.2	±13.6	65.1	±13.7	62.7	±12.8	66.5	±13.3	66.7	±12.3	67.5	±13.3	79.6	±30.1
UA/(μmol/L)	331.3	±77.1	296.3	±62.6	303.8	±49.6	329.1	±69.4^*	339.0	±84.2^**	371.2	±96.1^***	421.3	±69.2^**
Urea/(mmol/L)	4.6	±1.1	4.4	±1.0	4.4	±1.0	4.7	±1.1	4.6	±1.1	4.7	±0.9	6.3	±1.5^**
AST/(U/L)	19.8	±7.9	17.7	±3.8	17.1	±4.8	20.2	±7.6	19.8	±7.5	22.8	±11.2	25.4	±18.7
ALT/(U/L)	25.7	±17.4	17.8	±8.2	19.5	±9.7	27.5	±18.2^**	27.0	±18.8^*	30.0	±18.7^**	37.1	±28.5
AST/ALT	0.9	±0.4	1.1	±0.4	1.0	±0.3	0.9	±0.3^***	0.9	±0.3^***	0.9	±0.6^**	0.7	±0.1

Chemical contaminant	Chinese name	Frequency/%	C/(ng/mL)
Imipramine hydrochloride	盐酸丙咪嗪	46.29	0.101	±0.067
Tritolyl phosphate	磷酸三甲苯酯	83.09	0.128	±0.667
Ethylhexyl dimethyl PABA	二甲基PABA乙基己酯	38.58	0.290	±0.229
Cortisone	可的松	99.41	17.512	±4.279
Cortisol	皮质醇	99.11	36.361	±18.992
Thiamethoxam	噻虫嗪	98.52	15.761	±10.035
5-Formylsalicylic acid	5-甲酰水杨酸	45.99	0.157	±0.110
Lufenuron	虱螨脲	75.37	0.241	±0.147
Dibutyl phosphate	磷酸二丁酯	70.33	0.470	±0.272
Diphenyl phosphate	磷酸二苯酯	64.99	0.473	±0.527
Carbamazepine	卡马西平	37.69	4.786	±64.549
Ampicillin	氨苄青霉素	35.91	12.742	±2.702
Metribuzin	嗪草酮	40.95	1.474	±0.644
Ofloxacin	氧氟沙星	61.42	2.594	±1.632
Bentazone	灭草松	31.45	0.020	±0.024
Perfluoroheptanesulfonic acid	全氟庚基磺酸	100	0.330	±0.248
Bisphenol A	双酚A	71.22	8.346	±14.892
Pentachlorophenol	五氯苯酚	55.49	1.890	±4.426
Methyl 4-hydroxybenzoate	尼泊金甲酯	53.12	7.128	±10.557
Salicylic acid	水杨酸	57.57	20.644	±74.532
Betamethasone acetate	醋酸倍他米松	75.67	1.471	±1.094
Mometasone furoate	糠酸莫美他松	99.41	1.008	±0.594
Chlorothalonil	百菌清	40.95	1.971	±4.493
Perfluorobutanesulfonate (PFBS)	全氟丁基磺酸钾	96.74	0.842	±0.908
Perfluorobutanoic acid (PFBA)	全氟丁酸	79.23	0.227	±0.254
Perfluorodecanoic acid (PFDA)	全氟癸酸	64.39	1.546	±1.830
Perfluorododecanoic acid (PFDoDA)	全氟十二酸	62.02	0.743	±0.564
Perfluoroheptanoic acid (PFHpA)	全氟庚酸	67.06	0.120	±0.125
Perfluorohexanesulfonate (PFHxS)	全氟己基磺酸钠	100	2.975	±2.300
Perfluorononanoic acid (PFNA)	全氟壬酸	99.70	2.103	±1.565
perfluoro-n-pentanoic acid-1 (PFPeA)	全氟戊酸	98.81	3.996	±2.268
Perfluorooctanesulfonate (PFOS)	全氟辛烷磺酸	90.80	10.922	±7.973
Perfluorooctanoic acid (PFOA)	全氟辛酸	100	19.963	±11.887
Perfluoroundecanoic acid (PFUnDA)	全氟十一酸	99.41	1.394	±0.856
Sodium 4-chlorophenoxyacetate (4-CPA)	4-氯苯氧乙酸钠	78.93	5.594	±23.45
1H,1H,2H,2H-Perfluorooctanesulfonic acid	1H,1H,2H,2H-全氟辛烷磺酸	35.31	0.839	±0.293
Bis[2-(perfluorohexyl)ethyl] phosphate	双[2-(全氟己基)乙基]磷酸	48.66	1.066	±1.064
9-Chloro-3-oxa-perfluorononanesulfonic acid	9-氯-3-氧杂全氟壬烷磺酸钾	90.80	3.361	±3.098
Octisalate	水杨酸-2-乙基己基酯	76.26	0.477	±0.483
4-Hydroxybenzophenone	4-羟基二苯甲酮	52.52	0.078	±0.069
Monocyclohexyl phthalate	邻苯二甲酸单环己酯	87.54	0.417	±0.478
Monoethyl phthalate	邻苯二甲酸单乙酯	47.77	1.828	±2.101
DBPOB	3,5-二叔丁基-4-羟基苯甲酸	39.47	3.825	±3.363
Pyridate hydroxy type	哒草特	59.05	0.129	±0.067
Flumequine	氟甲喹	48.66	4.714	±3.378
Fipronil sulphone	氟虫腈砜	99.70	0.755	±0.508
Acesulfame potassium	安赛蜜	71.81	10.310	±30.662
Indole-3-butyric acid	吲哚乙酸	69.73	3.182	±2.513
Sucralose	三氯蔗糖	43.92	1.975	±1.974
Sodium saccharin	糖精钠	49.85	3.505	±15.701
Cyclamic acid	环拉酸	67.95	9.750	±22.408
3,5,6-Trichloro-2-pyridinol	3,5,6-三氯吡啶-2-醇	32.94	0.655	±0.783
Malathion dicarboxylic acid	马拉硫磷二羧酸	74.48	6.043	±1.414
2-Hydroxy-4-methoxybenzophenone	2-羟基-4-二苯甲酮-5-磺酸	52.52	7.024	±9.605
Diclofenac acid	双氯芬酸	37.98	2.856	±1.842