Maternal and developmental toxicity after exposure to formulation of chlorothalonil and thiophanate-methyl during organogenesis in rats

SILVA, JAQUELINE N. DA; MONTEIRO, NAYARA R.; ANTUNES, PATRICIA A.; FAVARETO, ANA PAULA A.

doi:10.1590/0001-3765202020191026

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BIOMEDICAL SCIENCES • An. Acad. Bras. Ciênc. 92 (4) • 2020 • https://doi.org/10.1590/0001-3765202020191026 linkcopy

Maternal and developmental toxicity after exposure to formulation of chlorothalonil and thiophanate-methyl during organogenesis in rats

Authorship SCIMAGO INSTITUTIONS RANKINGS

Chlorothalonil and thiophanate-methyl are fungicides widely used in agriculture. The aim of this study was to assess maternal toxicity and embryotoxic potential of exposure to chlorothalonil and thiophanate-methyl during organogenesis period in rats. Pregnant rats were divided into four groups: control and exposed to 400 (CT400), 800 (CT800) and 1200 mg^-1kg bw^-1 day (CT1200) of commercial formulation constituted of 200 g of thiophanate-methyl kg⁻¹ and 500 g of chlorothalonil kg⁻¹ by gavage, from 6^th to 15^th gestational day. Maternal toxicity, liver, kidney and placenta histology, reproductive performance, and external, skeletal and visceral malformations of fetuses were evaluated. Maternal liver weight was decreased in CT1200 group and focal necrosis and microvesicular steatosis, inflammatory infiltrate and hepatocytes with pyknotic nucleus were observed in CT800 and CT1200 groups. Reproductive performance was similar among groups. The percentage of fetuses small for pregnancy age was increase in CT400 and CT800 groups. Moreover, incidence of skeletal anomalies was increased in the three groups exposed to fungicides. Chlorothalonil and thiophanate-methyl exposure showed affect the prenatal development and induce maternal toxicity.

Key words
developmental toxicity; embryo; fetus; malformations; pesticide; rat

Parameter	Control	CT400	CT800	CT1200
¹Weight gain (%)	54.80 (50.16 – 57.22)	44.69 (39.33 – 50.19)	31.31 (11.61 – 80.37)	22.90 (2.88 – 44.69)
²Liver (g)	14.48 ± 1.11a	12.38 ± 0.91ab	12.57 ± 2.80ab	11.54 ± 2.65b
²Kidney (right) (mg)	996.25 ± 102.81	863.33 ± 80.91	931.43 ± 100.40	942.50 ± 77.04
²Kidney (left) (mg)	945.00 ± 79.64	851.67 ± 86.12	928.57 ± 108.54	937.50 ± 89.08
²Heart (mg)	805.00 ± 105.02	748.33 ± 43.55	817.14 ± 54.07	770.00 ± 204.73
²Lung (g)	1.54 ± 0.17	1.55 ± 0.13	1.70 ± 0.34	1.66 ± 0.35
²Spleen (mg)	581.25 ± 63.79	540.00 ± 82.95	505.71 ± 81.82	515.00 ± 155.47

Parameter	Control	CT400	CT800	CT1200
¹Uterus weight+fetuses (g)	63.41 ± 9.33	63.62 ± 10.36	51.31 ± 12.92	47.54 ± 25.37
¹Corpora lutea	14.00 ± 1.63	14.67 ± 2.42	13.2 ± 1.64	14.4 ± 2.61
¹Implants	12.00 ± 1.53	13.33 ± 1.21	11.80 ± 1.48	11.00 ± 1.87
¹Resorptions	0.14 ± 0.38	0.50 ± 0.84	1.60 ± 1.51	0.40 ± 0.89
¹Live fetuses	11.86 ± 1.68	12.83 ± 1.17	10.20 ± 0.84	9.40 ± 4.04
²Fertility Potencial (%)	92.31 (85.12 – 92.82)	93.09 (92.44 – 93.33)	93.33 (91.67 – 100.00)	68.75 (66.67 – 92.86)
²Pre-implantation loss (%)	7.69 (7.18 – 14.88)	6.90 (6.67 – 7.55)	6.67 (0.00 – 8.33)	31.25 (7.14 – 33.33)
²Post-implantation loss (%)	0.00 (0.00 – 0.00)	0.00 (0.00 – 6.25)	10.00 (8.33 – 16.67)	0.00 (0.00 – 0.00)
¹Fetus weight(g)	3.67 ± 0.14	3.35 ± 0.57	3.38 ± 0.77	3.00 ± 1.29
³AIP	74/83 (89.16)a	43/77 (55.84)b	32/51 (62.74)b	40/47 (85.11)a
³PIP	3/83 (3.61)a	24/77 (31.17)b	13/51 (25.49)c	6/47 (12.76)ac
³GIP	6/83 (7.23)	10/77 (12.99)	6/51 (11.76)	1/47 (2.13)
¹Craniocaudal medium lenght (mm)	36.40 ± 2.16	34.09 ± 1.67	34.43 ± 3.72	31.22 ± 8.14
²Sex ratio (%)	100.00 (71.43 – 126.67)	74.11 (58.48 – 121.43)	100.00 (83.33 – 175.00)	100.00 (71.43 – 175.00)

¹Absolute anogenital distance (mm)
Male	3.71 ± 0.40	3.51 ± 0.23	3.81 ± 0.44	3.24 ± 0.99
Female	2.19 ± 0.40	2.19 ± 0.18	2.32 ± 0.31	1.93 ± 0.65
¹Relative anogenital distance (mm/body weight^1/3)
Male	2.30 ± 0.25	2.34 ± 0.22	2.51 ± 0.15	3.20 ± 1.65
Female	1.43 ± 0.26	1.50 ± 0.21	1.60 ± 0.21	1.33 ± 0.38

Parameter	Control	CT400	CT800	CT1200
¹Weight (g)	0.49 ± 0.04	0.41 ± 0.05	0.47 ± 0.13	0.39 ± 0.13
¹ Placental index	0.13 ± 0.01	0.30 ± 0.44	0.14 ± 0.02	0.14 ± 0.04
Labyrinth
²Wall of the fetal vessels	10.00 (8.00 – 13.00)a	14.00 (11.00 – 17.00)b	8.00 (6.00 – 10.00)c	7.00 (5.00 – 12.00)c
²Lumen of the fetal vessels	61.00 (54.00 – 66.75)a	49.00 (40.00 – 53.25)b	64.00 (64.00 – 72.00)c	67.50 (61.75 – 74.25)c
²Maternal blood space	14.00 (11.00 – 18.75)a	17.00 (14.00 – 21.00)a	7.50 (5.00 – 11.00)b	6.50 (4.00 – 10.00)b
Spongiotrophoblast
²Maternal vascularisation	15.00 (10.00 – 21.00)a	17.00 (12.00 – 22.25)a	24.00 (16.50 – 9.75)b	31.00 (23.00 – 42.00)b
² Trophoblast indiferentiate cells	5.00 (4.00 – 7.00)a	9.00 (7.00 – 12.00)b	7.50 (5.25 – 10.00)b	8.00 (5.00 – 11.00)b
² Trophoblast intermediate cells	16.50 (12.25 – 19.75)	14.50 (12 – 17.25)	15.50 (11.00 – 20.00)	14.00 (12.00 – 19.25)
² Trophoblast giant cells	2.00 (1.00 – 4.00)	2.00 (1.00 – 4.00)	2.00 (1.25 – 3.00)	2.00 (1.00 – 3.00)
²Syncytial cells	0.00 (0.00 – 0.00)a	0.00 (0.00 – 0.00)a	0.00 (0.00 – 1.00)b	0.00 (0.00 – 1.00)b
²Mesenchyme	58.50 (53.25 – 65.00)a	55.00 (50.25 – 60.25)a	49.50 (43.00 – 55.00)b	41.50 (31.00 – 48.50)b

Parameter	Control	CT400	CT800	CT1200
¹Number of fetuses examined/ number of litter	41/5 (12.19%)a	38/25 (65.79%)b	25/16 (64.00%)b	21/13 (61.90%)b
Malformation of sternal centers	4 (9.76%)a	21 (55.26%)b	6 (24.00%)a	12 (57.14%)b
Xiphoid process absent	1 (2.44%)a	4 (10.53%)a	5 (20.00%)b	1 (4.76%)a
Malformation of the supraoccipital	0a	14 (36.84%)b	3 (12.00%)a	0a
Absence of caudal vertebrae	0a	0a	4 (16.00%)bc	0ac
Malformation of the xiphoid process	1 (2.44%)	6 (15.79%)	0a	2 (9.52%)a
Absence of hamulus	0	1 (2.63%)	1 (4.00%)	0
Bipartite vertebral centrum	0	1 (2.63%)	0	0
Absence of manubrium	0	0	3 (12.00%)	0
Malformation of the manubrium	0	0	1 (4.00%)	0
Incomplete ossification of the skull	0	0	1 (4.00%)	0
Four caudal vertebrae	0	0	2 (8.00%)	0
Malformation of the basisphenoide	0	0	0	1 (4.76%)
Points of ossification
²Phalanges of the fore limb (right)	5.44 ± 0.95a	4.34 ± 1.46b	5.68 ± 0.75a	5.28 ± 0.96a
²Phalanges of the fore limb (left)	5.22 ± 1.13a	4.37 ± 1.50bc	5.64 ± 0.86a	5.28 ± 0.96ac
²Metatarsals (right)	4.00 ± 0.00a	3.97 ± 0.16ac	3.88 ± 0.33bc	4.00 ± 0.00ac
²Metatarsals (left)	4.00 ± 0.00a	3.97 ± 0.16ac	3.88 ± 0.33bc	4.00 ± 0.00ac
²Metacarpals (right)	3.71 ± 0.46	3.68 ± 0.47	3.76 ± 0.44	3.86 ± 0.36
²Metacarpals (left)	3.73 ± 0.45	3.66 ± 0.48	3.76 ± 0.44	3.86 ± 0.36
²Sternebrae	3.93 ± 0.34	3.74 ± 0.50	3.52 ± 0.92	3.76 ± 0.54
²Caudal vertebrae	3.15 ± 0.42a	2.63 ± 0.59bc	2.52 ± 1.19ac	2.86 ± 0.48ac

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[tfnI] ¹Values expressed as median (Q1-Q3). ²Values expressed as mean ± SD. ANOVA with a posteriori Tukey test. Different letters indicate statistically significant difference (p <0.05). Exposed groups to chlorothalonil and thiophanate-methyl at doses of 400 (CT400), 800 (CT800) or 1200 mg -1kg bw -1 day (CT1200).