Table 1.

Metabolic impact of pesticide exposure in normal diet-fed animal models. Acceptable Daily Intake (ADI) values were from https://ephy.anses.fr/ and https://ec.europa.eu/food/plant/pesticides/eu-pesticides-database/. ADI, acceptable daily intake; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BW, body weight; CAR, constitutive androstane receptor; GD, gestational day; HFD, high-fat diet; IL1-β, interleukin-1 beta LDH, lactate dehydrogenase; MDA, malonaldehyde; NOAEL, no observable adverse effect level; ND, normal diet; NF-ĸB, nuclear factor kappa B, PND, postnatal day; SOD, Super oxide dismutase; TG, triglyceride, TNF-α, tumor necrosis factor alpha; ADI, Acceptable Daily Intake.

Type of Pesticide	Chemical Family	Active Substance (ADI mg/kg BW/day)	Experimental Model	Metabolic Effects	Refs.
Insecticide	Organophosphorus	Diazinon (0.002)	ND-fed male rats Oral daily gavage with 15 mg/kg for 4 weeks	Increased serum ALT and AST activity, serum lipid content, peripheral inflammation biomarkers	[188]
		Malathion (0.03)	ND-fed male rats Oral daily gavage with 200 mg/kg for 28 days	Increased levels of lipid peroxidation biomarkers Decreased levels of antioxidant enzymes Chronic inflammation	[192]
			ND-fed male rats Oral daily gavage with 27 mg/kg for 30 days	Increased liver MDA levels Decreased liver glutathione levels, superoxide dismutase, and catalase activities Increased liver IL1-β, TNF-α, and NF-ĸB mRNA expression levels	[139]
Insecticide	Organophosphorus	Chlorpyrifos (0.001)	ND-fed pregnant rats Oral gavage with 1, 2.5, or 4 mg/kg BW/day from gestational day 7 to postnatal day 21	Increased adiposity and weight gain only in males with 2.5 mg/kg chlorpyrifos	[140]
			ND-fed female rats Oral daily gavage with 1 or 3.5 mg/kg BW/day during gestation and lactation	Decreased offspring BW gain at PND 60 Increased fasting glycemia Increased ALT activity Decreased plasma TG levels Change in microbiota composition	[166]
	Organochlorine	Endosulfan (0.006)	ND-fed male mice Oral daily gavage for 2 weeks with doses ranging from 0.5 to 3.5 mg/kg BW	Weight loss Changes in various liver metabolic pathways (energy, amino acid, and lipid metabolism) Gut microbiota alteration	[134]
	Neonicotinoid	Imidacloprid (0.06)	ND-fed female rats Oral daily gavage with 9 or 45 mg/kg BW for 4 weeks	Biomarkers of hepatotoxicity	[141]
		Imidacloprid (0.06)	ND-fed pregnant rats Oral daily gavage with 1/45th or 1/22th LD50 from mating to gestation and lactation	Hepatic necrosis and inflammation in the non-exposed second generation	[142]
		Thiamethoxam (0.026)	ND-fed male rabbits Oral daily gavage with 250 mg/kg BW for 90 days	Hepatic oxidative stress and inflammation	[143]
Insecticide	Pyrethroid	Deltamethrin (0.01)	ND-fed male rats Oral daily gavage with 15 mg/BW for 30 days	Liver inflammation (increased levels of serum and liver lipid peroxidation biomarkers) Changes in antioxidant enzyme activity Increased expression of inflammatory cox2 gene	[144]
		Alpha cypermethrin (0.00125)	Female rats Pesticide-enriched diet at 0.02 mg/kg BW/day One month before and during gestation	Increased glucose, cholesterol, TG levels and AST and ALT activity in mothers and newborns Increased maternal BW and liver weight in mothers Change in pup liver weight Increased liver inflammation and lipid content in both dams and newborns Increased circulating and liver levels of oxidative stress biomarkers and decreased antioxidant status in both dams and newborns	[145]
		Alpha cypermethrin (0.00125)	Pregnant female ND-fed rats Pesticide enriched diet (1.5 mg/kg) During gestation and lactation and for 5 months after weaning	Reduction of body weight, food and energy intake in offspring Increase in plasma glucose, urea cholesterol and creatinine levels in both male and female rats Increase in liver oxidative stress	[146]
Insecticide	Pyrethroid	Lambda cyhalothrin (0.0025)	ND-fed male rats Oral daily gavage with 6.2 or 31.1 mg/kg BW for 7, 30, 45, or 60 days	Increased levels of hepatic stress biomarkers (MDA, AST, ALT) and antioxidant enzyme activities Increased liver TNF-alpha and interleukin gene expression	[137]
			ND-fed male rats Gastric intubation with 1, 2, 4, and 8 mg/kg BW for 6 consecutive days	Changes in the expression of genes coding for xenobiotic metabolism enzymes and for liver oxidation	[138]
Herbicide	Triazine	Atrazine (0.02)	HFD- and ND-fed male rats Oral exposure in drinking water 30 to 300 µg/kg BW/day for 5 months	BW gain in HFD- and ND-fed rats Increased insulin levels in HFD-fed rats Insulin resistance in ND- and HFD-fed rats	[148]
	Glycine derivate	Glyphosate (0.5)	Pregnant ND-fed mice Oral exposure to 0.5% glyphosate solution in drinking water during gestation and lactation ND-fed male rats Oral exposure to 0.1 ppb Roundup formulation (eq to 0.05 µg/L glyphosate) in drinking water for 2 years	Decreased body weight in offspring PND7 and 21 Increased lipid levels in offspring in liver and plasma Liver proteome disruption reflecting steatosis and necrosis	[150,151]
Herbicide	Glycine derivate	Glyphosate (0.5)	ND-fed male rats Oral daily gavage with 5, 50, or 500 mg/kg BW for 35 days	Increased levels of serum and liver MDA Decreased liver SOD activity Increased liver catalase activity Increased liver mRNA expression of inflammatory genes	[153]
	Dinitroaniline	Pendimethalin (0.125)	ND-fed male rats Oral daily gavage with 62.5, 125, or 250 mg/kg BW/day for 14 days	Increased biomarkers of liver lipid peroxidation and protein carbonylation Decreased antioxidant enzyme activities Liver hyperplasia and swelling, occurrence of pyknotic nuclei, activated Kupffer cells and leukocyte infiltrations, large cytoplasmic vacuolization and dilatation in blood sinusoid	[154]
		2.4 Dichlorophenoxyacetic acid (2,4-D) (0.02)	ND-fed pregnant rats Co-exposure through drinking water at 126 mg/kg BW from GD 14 to PND 14 Observation at PND 14	Decreased pup BW Decreased mother BW and liver weight, but also in food and water intake Increased plasma ALT, LDH, and AST activity in both pups and dams Increased MDA levels and antioxidant enzyme activities in dams and pups Liver inflammation in both dams and pups	[155]
Fungicide	Triazole	Penconazole (0.03)	ND-fed male mice Oral exposure to 30 mg/L in drinking water for 4 weeks	Increased levels of serum ALT, AST and hepatic TGs, total cholesterol; lipid droplet accumulation and inflammation	[190]
		Cyproconazole (0.02)	ND-fed WT and humanized CAR male mice Pesticide-enriched diet with 50 or 500 ppm	Induction of CAR-dependent gene expression Increased liver weight Hepatic lipid accumulation	[157]
	Triazole	Cyproconazole (0.02) Epoxiconazole (0.008) Prochloraz (0.01)	ND-fed male rats Pesticide-enriched diet: individual compounds or mixture (NOAEL/100; NOAEL; NOAELx10)	Changes in the expression of hepatic genes involved fatty acid and phospholipid metabolism, cytochrome P450, transporters (Abcb1a, Abcc3) In most cases, treatment with mixtures caused stronger effects as compared to the individual substances	[158]
	Imidazole	Imazalil (0.025)	ND-fed male mice Pesticide-enriched diet with 25, 50, or 100 mg/kg BW daily for 4 weeks	No significant changes in hepatic TG Dysbiosis and colonic inflammation	[160]
	Benzimidazole	Carbendazim (0.02)	ND fed male mice 0.1, 0.5, or 5 mg/kg BW per day in drinking water for 14 weeks	Increased intestinal fat absorption Reduced liver lipid synthesis Increased fat lipid storage Intestinal dysbiosis Inflammatory response in various tissues	[191]
Fungicide	Sulfamide	Tolylfluanid (0.1)	ND-fed male mice Pesticide-enriched diet with 100 ppm for 12 weeks	Increased BW and adiposity, glucose intolerance, and insulin resistance, impaired circulating levels of leptin and adiponectin, disturbed fat oxidation and lipolysis in adipocytes No change in liver homeostasis	[161]
Mixture Insecticide and fungicide	Triazine Phenoxybutyric Carbamate Quinone Dithiocarbamate Carbamate	Cyromazine (0.06), MCPB (0.01), Pirimicarb (0.035), Quinoclamine (0.002), Thiram (0.01), Ziram (0.006)	ND-fed pregnant female rats Oral gavage with total dose of 28, 104, or 210 mg/kg/day of the mixture from GD 7 to GD 17 Analysis at 4 months of age	Decreased birth weight in exposed male offspring Increased leptin levels in female offspring Variations Change in the expression of 3 genes in fat tissues in a sexually dimorphic manner	[167]
Mixture of insecticide, herbicide, and fungicide	Carboxamide Phthalimide Organophosphorus Neonicotinoid Dithiocarbamate Carbamate	Boscalid (0.04) Captan (0.1) Chlorpyrifos (0.001) Thiachloprid Thiophanate (0.08) Ziram (0.006)	ND-fed male and female mice Pesticide mixture-enriched diet, exposure to the ADI of each pesticide for 52 weeks	Overweight and glucose intolerance and steatosis in males Liver oxidative stress and alteration in gut microbiota in females	[193]
Mixture of insecticide, herbicide, and fungicide	Chloroacetanilide Nitrile Carbamate Quaternary ammonium Organophosphorus Morpholine Glycine derivative Neonicotinoid	Acetochlor (0.0036) Bromoxynil (0.01) Carbofuran (0.00015) Chlormequat (0.04) Ethephon (0.03) Fenpropimorph (0.003) Glyphosate (0.5) Imidacloprid (0.06)	ND-fed pregnant rats Pesticide-enriched diet; exposure at a nominal dose corresponding to the same proportion as their respective environmental exposure value (from French use) from GD 4 to GD 21	Decreased liver weight in dams Increased liver weight in male offspring Decreased liver lipid content in male offspring Changes in liver metabolome (lipid metabolism biomarkers) and serum metabolome in fetuses	[168]