Table 2.

Metabolic impact of pesticide exposure in high-fat diet-fed animal models. Acceptable Daily Intake (AD)I values were from https://ephy.anses.fr/ and https://ec.europa.eu/food/plant/pesticides/eu-pesticides-database/. ADI value is not reported for some compounds due to insufficient data (organochlorine compounds, prinomectin, moxidectin, GW4064, PCB). ALT, alanine aminotransferase; BW, body weight; FFA, free fatty acid; CPT, carnitine palmitoyl-transferase; FXR, farnesoid X receptor; GD, gestational day; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; HFD, high-fat diet; HOMA-IR, homeostasis model assessment of insulin resistance. NEFA, non-esterified fatty acid; NOAEL, no observable adverse effect level; ND, normal diet; PCB polychlorinated biphenyl; PP, pancreatic polypeptide; PUFA, polyunsaturated fatty acid; PND, postnatal day; SFA, saturated fatty acid; TG, triglyceride; UCP, uncoupling protein; VLDL, Very low density lipoprotein; WT, wild type; ADI, Acceptable Daily Intake.

Type of Pesticide	Chemical Family	Active Substance (ADI mg/kg BW/day)	Experimental Model	Effects of Pesticide Exposure on Diet-Induced Metabolic Disorders	Refs.
Insecticide	Organochlorine	DDE	ND- and HFD-fed male rats Pesticide-enriched diet for 4 weeks	Increase serum ALT and AST levels in ND Decreased serum TG levels and liver lipid content in HFD fed animals Increased CPT activity oxidation and lipid peroxidation in ND- and HFD-fed animals Hepatic oxidative stress in ND- and HFD-fed animals Increased antioxidant enzyme activities more in ND- than in HFD-fed animals Increased UCP2 mRNA levels in ND- and HFD-fed animals	[203]
			ND- and HFD-fed male rats exposed to 100 µkg/BW/day DDE in drinking water for 12 weeks	Increased accumulation in fatty acid (SFA and PUFA) content in both ND- and HFD-fed animals	[204]
Insecticide	Organochlorine	DDE	Oral gavage of ND-fed male mice for 5 days One-week resting period Then oral gavage each week of ND- or HFD-fed males for 13 weeks	After 4 and 8 weeks on the HFD diet, increased fasting hyperglycemia and liver steatosis At week 13, HFD-induced decrease in fasting hyperinsulinemia, HOMA-IR values, and hepatic steatosis	[205]
		DDT	Daily oral gavage of pregnant female mice from GD 11 to PND 5 at 1.7 mg/kg BW ND- and HFD-fed adult female offspring for 12 weeks	Reduced body temperature and energy expenditure and increased body fat in offspring of ND mothers Compared to ND, further HFD-induced reduction of body temperature HFD-induced changes in brown adipose tissue gene expression	[206]
		Chlordane	ND- and HFD-fed male mice (6 weeks) Oral gavage daily at 1.45 mg/kg BW from week 4 to week 6	No change in BW in ND- and HFD-fed animals Increase in HFD induced liver metabolic perturbations (TCA cycle, tryptophan catabolism, nucleotide, lipid and choline, and amino acid metabolism)	[207]
Insecticide	Pyrethroid	Permethrin (0.050)	ND- or HFD-fed male mice Pesticide-enriched diet with 50, 500, or 5000 µg/kg BW/day for 12 weeks	Potentiation of HFD-induced BW gain, total adipose tissue weight, insulin resistance	[208]
		Cypermethrin (0.050)	HFD-fed male mice simultaneously exposed to 50 µg/kg BW/day cypermethrin in drinking water for 20 weeks	No change in BW Increased levels of serum FFA, hepatic lipid, TG Increased liver de novo FFA and TG synthesis Increased uptake of FFA from blood	[185]
	Organophosphorus	Chlorpyrifos (0.001)	ND- and HFD-fed male mice Co-exposure by daily gavage with 5 mg/kg for 12 weeks	Increased BW in both ND- and HFD-fed mice Impaired glucose metabolism and insulin resistance in both HFD- and ND-fed mice	[209]
			ND- and HFD-fed male rats Co-exposure by daily oral gavage to 0.3 and 3 mg/kg BW for 9 weeks	Increased weight gain in ND- but not in HFD-fed rats Obliteration of the increase in plasma TG caused by HFD Decreased plasma insulin, C-peptide, and amylin concentrations in both the ND- and HFD-fed rats Decreased plasma levels of leptin GIP and GLP-1 and PP induced in HFD-fed rats Differential alteration of gut microbiota composition according to the diet	[210]
Insecticide	Organophosphorus	Chlorpyrifos (0.001)	ND- and HFD-fed male mice for 4 weeks Oral gavage with 2 m/kg BW/day chlorpyrifos during the last 10 days of the experiment	No significant body weight increase in HFD-fed animals No significant increase in plasma TG in HFD-fed animals Decreased expression of genes involved in liver lipogenesis in ND- and HFD-fed animals	[195]
			HFD- and ND-fed male mice for 4 weeks Chlorpyrifos (2 mg/kg) single oral gavage at the end of the experiment	Increased TG serum levels in ND fed animals Hypoglycemia in HFD-fed animals.	[196]
		Parathion (0.0006)	Subcutaneous injection of PDN 1–4 in rats at 0.1 and 0.2 mg/kg/day once daily A 6 week HFD feeding of 15 week-old male and female rats	Increased serum cholesterol levels in fasted HFD-fed males Decreased serum NEFA levels in fasted ND-fed females Enhancement of HFD-induced BW gain in females exposed to 0.1 mg/kg/day parathion Decreased BW gain in HFD fed females exposed to 0.2 mg/kg BW parathion	[197]
Insecticide	Organophosphorus	Acephate (0.03)	Daily gavage of female rats with 2.5 mg/kg BW/day from pregnancy day 7 until lactation day 21 Overfeeding of pups by decreasing the number of pups per nest Analysis at PND 90	Decreased BW in both animal groups at PND 1 Decreased BW in overfed animals at PND 90 Increased peritoneal and mesenteric fat mass only in normal fed animals at PND 90 Decreased energy intake in overfed animals at PND90 Increased fasting glucose in normal- and overfed animals Increased fasting insulin in normal-fed animals Increased glucose intolerance and insulin resistance in normal-fed animals Reversion of many of the programmed postnatal overfeeding induced metabolic disturbances at PND 90	[198]
	Neonicotinoid	Imidacloprid (0.06)	ND- and HFD-fed male mice Pesticide-enriched diet Exposure to dose ranging from TDI to NOAEL for 12 weeks	Potentiation of HFD-induced weight gain, insulin resistance, and adipocyte size and impaired glucose metabolism	[199]
Insecticide antiparasitic	Avermectin	Abamectin (0.0025) Doramectin, (0.0005) Ivermectin (0.010), Eprinomectin Moxidectin GW4064	HFD-fed male mice simultaneous exposed to 1.3 mg/kg B avermectin analogs by intraperitoneal injection for 14 days	Suppression of HFD-induced metabolic disturbances in mice by most compounds, excepting eprinomectin and moxidectin	[200]
		Ivermectin (0.010)	HFD fed WT and FXR null mice simultaneous exposed to ivermectin by intraperitoneal injection at 1.3 mg/kg BW/day for 14 days	Decreased serum levels of glucose and cholesterol, high-density lipoprotein and low-density lipoprotein and VLDL cholesterol levels, in wild-type mice Ivermectin effects suppressed in FXR null mice	[201]
Fungicide	Strobilurin	Azoxystrobin (0.2)	HFD-fed male mice for 13 weeks Oral gavage at 25 mg/kg BW/day at week 8 for 5 weeks	Reduction in BW Improvement of glucose tolerance Decrease liver TG accumulation Decrease liver lipogenesis	[184]
Herbicide	Triazine	Atrazine (0.02)	HFD-fed male mice simultaneously exposed to atrazine in drinking water at 100 µg/kg BW/day for 20 weeks	No change in BW Increased levels of serum FFA, hepatic lipids, and TG Increased liver de novo FFA and TG synthesis pathways Increased uptake of FFA from blood	[221]
			HFD- and ND-fed male rats simultaneously exposure to atrazine in drinking water with 30 to 300 µg/kg BW/day for 5 months	Body weight gain in HFD- and ND-fed rats Increased insulin levels in HFD-fed rats Insulin resistance in ND- and HFD-fed rats	[148]
Mixture	POP	Organochlorine pesticide and PCB mixture	Leptin-deficient ob/ob ND fed male mice Oral gavage twice weekly for 7 weeks at environmentally relevant levels	Increased steatosis in ob/ob mice Increased hepatic triglyceride content in ob/ob mice	[202]