XB-ART-60703
Curr Res Toxicol
2024 Jan 01;6:100169. doi: 10.1016/j.crtox.2024.100169.
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Comparing the effects of three neonicotinoids on embryogenesis of the South African clawed frog Xenopus laevis.
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Neonicotinoids (NEOs) are widely used insecticides that are ubiquitous in agricultural use. Since NEOs are found in natural waters as well as in tap water and human urine in regions where NEOs are widely used, NEOs pose a potential hazard to non-target organisms such as animals and humans. Some of the commonly detected NEOs are imidacloprid (IMD), thiamethoxam (TMX), and its metabolite clothianidin (CLO). Although previously published scientific information, including an assessment of the environmental risks, particularly for bees, had resulted in a ban on the outdoor use of these three NEOs in the EU - their use is now only permitted in closed greenhouses - these NEOs continue to be used in agriculture in many other parts of the world. Therefore, a detailed study and comparison of the effects of NEOs on the embryonic development of non-target organisms is needed to further define the risk profiles. Embryos of the South African clawed frog Xenopus laevis, a well-established aquatic model, were exposed to different concentrations of IMD, TMX, or CLO (0.1-100 mg/L) to study and compare the possible effects of a single contaminant in natural water bodies on early embryogenesis. The results included a reduced body length, a smaller orbital space, impaired cranial cartilage and nerves, and an altered heart structure and function. At the molecular level, NEO exposure partially resulted in an altered expression of tissue-specific factors, which are involved in eye, cranial placode, and heart development. Our results suggest that the NEOs studied negatively affect the embryonic development of the non-target organism X. laevis. Since pesticides, especially NEOs, pollute the environment worldwide, it is suggested that they are strictly controlled and monitored in the areas where they are used. In addition, the question arises as to whether pesticide metabolites also pose a risk to the environment and need to be investigated further so that they can be taken into account when registering ingredients.
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Species referenced: Xenopus laevis
Genes referenced: actc1 alcam egr2 myh6 pax6 pnma2 rax sox3 tnnt2 twist1
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Phenotypes: Xla Wt + CLO (0.1-1mg/L) (Fig. 4 AB) [+]
Xla Wt + CLO (100mg/L)
(Fig. 12 AB)
Xla Wt + CLO (100mg/L) (Fig. 2 C)
Xla Wt + CLO (100mg/L) (Fig. 6 ABC)
Xla Wt + CLO (100mg/L) (Fig. 7 ABC)
Xla Wt + CLO (100mg/L) (Fig. 8 AB)
Xla Wt + CLO (100mg/L) (Fig. 9 AB)
Xla Wt + CLO (100mg/L) (Sup. Fig. 3 CD)
Xla Wt + CLO (10-100mg/L) (Fig. 4 AB)
Xla Wt + CLO (10-100mg/L) (Fig 5. ABCD)
Xla Wt + CLO 50mg/L) (Fig. 10 ABC)
Xla Wt + CLO 50mg/L) (Fig. 11 AB)
Xla Wt + CLO 50mg/L) (Fig. 6 ABC)
Xla wt + IMD (0.1-1mg/L) (Fig. 4 AB)
Xla Wt + IMD (10-100mg/L) (fig 4 AB)
Xla Wt + IMD (10-100mg/L) (Fig 5. ABCD)
Xla Wt + Imidacloprid (100mg/l) (Fig 2. AB)
Xla Wt + Imidacloprid (100mg/l) (Fig. 2 C)
Xla Wt + Imidacloprid (100mg/l) (Fig. 6 ABC)
Xla Wt + Imidacloprid (100mg/l) (Fig. 7 ABC)
Xla Wt + Imidacloprid (100mg/l) (Fig 8 AB)
Xla Wt + Imidacloprid (100mg/l) (Fig. 9 AB)
Xla Wt + Imidacloprid (10mg/L) (Fig 2. AB)
Xla Wt + Imidacloprid (50mg/L) (Fig. 10 ABC)
Xla Wt + Imidacloprid (50mg/L) (Fig. 11 AB)
Xla Wt + Imidacloprid (50mg/L) (Fig. 2 C)
Xla Wt + Imidacloprid (50mg/L) (Fig. 6 ABC)
Xla Wt + TMX (0.1-1mg/L) (Fig. 4 AB)
Xla wt + TMX (100mg/L) (Fig. 12 AB)
Xla wt + TMX (100mg/L) (Fig. 2 C)
Xla wt + TMX (100mg/L) (Fig. 3 B)
Xla wt + TMX (100mg/L) (Fig. 6 ABC)
Xla wt + TMX (100mg/L) (Fig. 8 AB)
Xla wt + TMX (100mg/L) (Fig. 9 AB)
Xla wt + TMX (100mg/L) (Sup. Fig. 3 AB)
Xla Wt + TMX (10-100mg/L) (Fig 4 AB)
Xla Wt + TMX (10-100mg/L) (Fig 5. ABCD)
Xla Wt + TMX (10mg/L) (Fig. 2 C)
Xla Wt + TMX (50mg/L) (Fig. 10 ABC)
Xla Wt + TMX (50mg/L) (Fig. 11 AB)
Xla Wt + TMX (50mg/L) (Fig. 2 C)
Xla Wt + TMX (50mg/L) (Fig. 6 ABC)
Xla Wt + CLO (100mg/L) (Fig. 2 C)
Xla Wt + CLO (100mg/L) (Fig. 6 ABC)
Xla Wt + CLO (100mg/L) (Fig. 7 ABC)
Xla Wt + CLO (100mg/L) (Fig. 8 AB)
Xla Wt + CLO (100mg/L) (Fig. 9 AB)
Xla Wt + CLO (100mg/L) (Sup. Fig. 3 CD)
Xla Wt + CLO (10-100mg/L) (Fig. 4 AB)
Xla Wt + CLO (10-100mg/L) (Fig 5. ABCD)
Xla Wt + CLO 50mg/L) (Fig. 10 ABC)
Xla Wt + CLO 50mg/L) (Fig. 11 AB)
Xla Wt + CLO 50mg/L) (Fig. 6 ABC)
Xla wt + IMD (0.1-1mg/L) (Fig. 4 AB)
Xla Wt + IMD (10-100mg/L) (fig 4 AB)
Xla Wt + IMD (10-100mg/L) (Fig 5. ABCD)
Xla Wt + Imidacloprid (100mg/l) (Fig 2. AB)
Xla Wt + Imidacloprid (100mg/l) (Fig. 2 C)
Xla Wt + Imidacloprid (100mg/l) (Fig. 6 ABC)
Xla Wt + Imidacloprid (100mg/l) (Fig. 7 ABC)
Xla Wt + Imidacloprid (100mg/l) (Fig 8 AB)
Xla Wt + Imidacloprid (100mg/l) (Fig. 9 AB)
Xla Wt + Imidacloprid (10mg/L) (Fig 2. AB)
Xla Wt + Imidacloprid (50mg/L) (Fig. 10 ABC)
Xla Wt + Imidacloprid (50mg/L) (Fig. 11 AB)
Xla Wt + Imidacloprid (50mg/L) (Fig. 2 C)
Xla Wt + Imidacloprid (50mg/L) (Fig. 6 ABC)
Xla Wt + TMX (0.1-1mg/L) (Fig. 4 AB)
Xla wt + TMX (100mg/L) (Fig. 12 AB)
Xla wt + TMX (100mg/L) (Fig. 2 C)
Xla wt + TMX (100mg/L) (Fig. 3 B)
Xla wt + TMX (100mg/L) (Fig. 6 ABC)
Xla wt + TMX (100mg/L) (Fig. 8 AB)
Xla wt + TMX (100mg/L) (Fig. 9 AB)
Xla wt + TMX (100mg/L) (Sup. Fig. 3 AB)
Xla Wt + TMX (10-100mg/L) (Fig 4 AB)
Xla Wt + TMX (10-100mg/L) (Fig 5. ABCD)
Xla Wt + TMX (10mg/L) (Fig. 2 C)
Xla Wt + TMX (50mg/L) (Fig. 10 ABC)
Xla Wt + TMX (50mg/L) (Fig. 11 AB)
Xla Wt + TMX (50mg/L) (Fig. 2 C)
Xla Wt + TMX (50mg/L) (Fig. 6 ABC)
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Graphical Abstract |
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Fig. 1. Timeline of X. laevis Development and Stability of the Different NEOs. A. X. laevis embryogenesis and analytical methods. After the fertilization, the 2-cell-stage embryos were incubated in the control and NEO (IMD/TMX/CLO) solutions until they reached the desired stage. Embryos at stage 23 (four incubations days), stage 28 (five incubation days) and stage 32 (seven incubation days) were used for WMISH staining. For the morphological phenotype as well as the detailed and functional analyses we used stage 44/45 embryos that had been incubated in a NEO solution for 14 days. B. Experimental setup. Two times 15 X. laevis embryos at stage 2 were incubated in 5 mL of different NEO solutions (0.1 – 100 mg/L) or 0.1x MBSH (control) at 14 °C. C. Experimental conditions. To determine the exact NEO concentrations on day 1, two sets of 1 and 100 mg/L NEO solutions were sent to an analytical lab. The same solutions were analyzed after 14 days to determine possible changes in concentrations over the incubation time. Abbreviations: NEO, neonicotinoid; IMD, imidacloprid; TMX, thiamethoxam; CLO, clothianidin; M1, measurement 1; M2, measurement 2; d, days; WMISH, whole mount in situ hybridization; mL, milliliter; mg/L, milligram per liter. |
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Fig. 2. Influence of IMD, TMX and CLO on the Mobility and Heart Rate of X. laevis. A. Mobility of stage 44/45 embryos during two hours. Effect of IMD (left column), TMX (middle column) or CLO (right column) on the embryos mobility. B. Total distance moved at stage 44/45. The total distance moved by stage 44/45 embryos from two to three embryo batches during two hours was studied. C. Measurement of the heart rate at stage 44/45. The heartbeats of stage 44/45 embryos after exposure to IMD (left panel), TMX (middle panel) or CLO (right panel) were counted for one minute. Abbreviations: IMD, imidacloprid; TMX, thiamethoxam, CLO, clothianidin; mg/L, milligram per liter; cm, centimeter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Fig. 3. Effect of IMD, TMX and CLO on the Embryonic Body Length of X. laevis. A. Body length at stage 44/45. Dorsal views of embryos at stage 44/45 showed the development of control and NEO-exposed embryos. B. Measurement of body length at stage 44/45. Head-tail length measurements (red dotted line in A) of embryos of one to two representative embryo batches after exposure to IMD (left panel), TMX (middle panel) or CLO (right panel) were compared to control embryos. Abbreviations: IMD, imidacloprid; TMX, thiamethoxam, CLO, clothianidin; mg/L, milligram per liter; mm, millimeter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Fig. 4. Effect of IMD, TMX and CLO on the Embryonic Eye Area of X. laevis. A. Eye area at stage 44/45. Lateral views of the eyes (black arrowheads show smaller eyes) of control embryos and stage 44/45 embryos after exposure to IMD (left column), TMX (middle column) or CLO (right column). B. Measurement of eye area at stage 44/45. Eye area measurement of one to two representative embryo batches (the area measured is highlighted in red in the control embryo shown in the left corner in A). Comparison of eyes from the control group to eyes after exposure to IMD (left panel), TMX (middle panel) or CLO (right panel). Abbreviations: IMD, imidacloprid; TMX, thiamethoxam, CLO, clothianidin; mg/L, milligram per liter; mm2, square millimeter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Fig. 5. Influence of IMD, TMX and CLO on the Molecular Basis of X. laevis Eye Development. A. rax expression area at stage 23. Anterior views of the eye-specific gene rax at stage 23. Representative images of the expression area (highlighted in red) after exposure to IMD (left column), TMX (middle column) or CLO (right column) compared to control embryos. The area of IMD- and CLO-treated embryos is reduced (black arrowheads). B. Measurement of rax area at stage 23. Quantification of the total expression area of the eye-specific gene rax of one embryo batch. C. rax expression intensity at stage 23. Anterior views of the eye-specific gene rax at stage 23. Representative images showing the intensity of the rax expression. Less intense expression is measured after an exposure to IMD and TMX (black arrowheads). D. Measurement of rax intensity at stage 23. Statistical evaluation of the normalized mean intensity of rax expression of one embryo batch. Abbreviations: IMD, imidacloprid; TMX, thiamethoxam, CLO, clothianidin; mg/L, milligram per liter; mm2, square millimeter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Fig. 6. Cranial Cartilage Development of X. laevis after Exposure to IMD, TMX or CLO. A. Cranial cartilage at stage 45. Exposure to IMD (left column), TMX (middle column) and CLO (right column) resulted in changes in branchial arch area (pink arrowheads) and to a deformation and tightening of the Meckel cartilage angles (blue arrowheads) at stage 45. B. Measurement of the branchial arch area at stage 45. Branchial arch area measurement (measurement as by pink area in the left control in A). Both sides of one embryo batch were measured and the average value was determined. C. Measurement of Meckel cartilage angle at stage 45. The angle (blue dotted line in A) of the Meckel cartilage of one embryo batch was measured. Abbreviations: IMD, imidacloprid; TMX, thiamethoxam, CLO, clothianidin; mg/L, milligram per liter; mm2, square millimeter; °, degrees; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Fig. 7. Effect of IMD, TMX and CLO on the Cranial Nerve Development. A. Cranial nerves at stage 45. Dorsal views of IMD, TMX or CLO-treated embryos compared to control embryos at stage 45 made visible through 3A10 antibody staining. B. Measurement of cranial nerves at stage 45. Quantification of the ratios between the cranial nerve length to the root of the head area (yellow dotted circle in A) at stage 45 after an exposure of one to three embryo batches to IMD, TMX or CLO. Statistical evaluations of the lengths of N. opticus (pink dotted lines in A), N. trigeminus (blue dotted lines in A) and N. mandibularis (green dotted lines in A) are performed. C. Detailed structure of cranial nerves at stage 45. Dorsal overview and detailed imaging of 3D models of the stained cranial nerves are shown. Cranial nerves appear thinner and less structured after exposure to IMD, CLO and TMX. Abbreviations: IMD, imidacloprid; TMX, thiamethoxam, CLO, clothianidin; No, Nervus opticus; Nt, Nervus trigeminus; Nm, Nervus mandibularis; mg/L, milligram per liter; mm, millimeter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Fig. 8. Effect of IMD, TMX and CLO on the Expression of the Cranial Placode-Specific Gene sox3. A. sox3 expression at stage 32. Lateral view of embryos after WMISH staining with the cranial placode-specific gene sox3 showing the epibranchial placodes VII (pink dotted line), IX (orange dotted line) and X (blue dotted line). B. Measurement of sox3 expression lengths at stage 32. Length measurement of the different epibranchial placodes of one embryo batch. IMD and CLO lead to changes in the length of eP X (blue arrowhead in A), and TMX to a shortening of eP IX (orange arrowhead in A). Abbreviations: IMD, imidacloprid; TMX, thiamethoxam, CLO, clothianidin; eP, epibranchial placode; mg/L, milligram per liter; mm, millimeter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Fig. 9. Effect of an Exposure to IMD, TMX and CLO on the Development of Heart Edema in X. laevis. A. Heart edema at stage 44/45. Exposure to IMD (left column), TMX (middle column) and CLO (right column) led to the formation of heart edema (black arrowheads) at stage 44/45. B. Analysis of embryos with heart edema at stage 44/45. Statistical evaluation of embryos with heart edema from four independent embryo batches. Abbreviations: IMD, imidacloprid; TMX, thiamethoxam, CLO, clothianidin; mg/L, milligram per liter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Fig. 10. Effect of IMD, TMX and CLO Exposure on the Heart Size of X. laevis. A. Isolated hearts at stage 44/45. Images of isolated hearts after an exposure to IMD (left column), TMX (middle column) and CLO (right column) compared to control hearts. Atria (pink arrowheads) and ventricles (turquoise arrowheads) appear wider. B. Measurement of atrium width at stage 44/45. Measurement of atrial width (pink dotted line in A) after IMD, TMX and CLO incubation. C. Measurement of ventricle width at stage 44/45. Measurement of the ventricle width (turquoise dotted line in A) was also performed. Abbreviations: IMD, imidacloprid; TMX, thiamethoxam, CLO, clothianidin; mg/L, milligram per liter; mm, millimeter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Fig. 11. Structural Analyses of X. laevis Cardiac Development after IMD, TMX and CLO Exposure. A. Heart morphology at stage 44/45. Ventral views of the hearts in the embryos from two embryo batches after Tnnt2 antibody staining at stage 44/45. The percentages stated indicate the proportion of embryos with an abnormal heart structure (IMD: control: 11.64 % of 52 embryos, 50 mg/L: 78.00 % of 50 embryos, 100 mg/L: 86.36 % of 44 embryos; TMX: control: 20.61 % of 58 embryos, 50 mg/L: 24.07 % of 54 embryos, 100 mg/L: 21.67 % of 60 embryos; CLO: control: 13.21 % of 53 embryos, 50 mg/L: 26.92 % of 52 embryos, 100 mg/L: 54.35 % of 46 embryos). B. Detailed heart structure at stage 44/45. Detailed analysis of the heart structure of randomly selected embryos using the confocal microscope. The sections and 3D models of the heart are shown for each NEO and each concentration. The heart muscle tissue appears deformed and less organized at higher NEO concentrations. Abbreviations: IMD, imidacloprid; TMX, thiamethoxam, CLO, clothianidin; a, atrium; v, ventricle; oft, outflow-tract; mg/L, milligram per liter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Fig. 12. Molecular Basis of X. laevis Cardiac Development after Exposure to IMD, TMX and CLO. A. mhcα expression area at stage 28. Area of expression of the cardiac-specific gene mhcα at stage 28. The area of expression is shown in red. B. Measurement of mhcα area at stage 28. Statistical analysis of mhcα expression area after exposure to IMD, TMX and CLO. C. mhcα expression intensity at stage 28. Ventral views of the intensity of mhcα expression at stage 28. The black arrowheads show a reduced intense expression after exposure to TMX and CLO. D. Measurement of mhcα intensity at stage 28. Normalized mean intensity of mhcα expression. Abbreviations: IMD, imidacloprid; TMX, thiamethoxam, CLO, clothianidin; mg/L, milligram per liter; mm2, square millimeter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Supplementary Fig. 1. Evaluation of X. laevis Embryos. A. Overview of visual morphological phenotype and WMISH analysis. All fixed control embryos from an independent embryo batch were compared under a light microscope. The control embryos from one embryo batch were placed next to each other, microscopically analyzed regarding their morphological appearance and a representative control embryo was selected. The representative control embryo was then microscopically compared to all other embryos (control and IMD/TMX/CLO-treated) of the same embryo batch, making it possible to detect any morphological changes. B. Selection of embryo batches for measurements. After the analyses of the independent embryo batches (four to eight batches) that are described in A were performed, one (WMISH) or two (morphological phenotype) representative embryo batches were selected for detailed examinations, for which each embryo was photographed and measured. Abbreviations: NEO, neonicotinoid; WMISH, whole mount in situ hybridization; n, number of embryos analyzed. |
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Supplementary Fig. 2. Mortality of X. laevis Embryos. Mortality at stage 44/45. Neither IMD, TMX, nor CLO in a concentration range of 0.1 mg/L to 100 mg/L resulted in any change in the mortality of X. laevis up to stage 44/45. Abbreviations: IMD, imidacloprid; TMX, thiamethoxam; CLO, clothianidin; mg/L, milligram per liter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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Supplementary Fig. 3. Molecular Basis of the Expression of Cranial Placode-Specific Genes. A. alcam expression at stage 32. Lateral views of the alcam expression of stage 32 embryos. B. Analysis of alcam expression at stage 32. Statistical evaluation of the percentage of embryos of four independent embryo batches with a reduced alcam expression. Embryos exposed to 100 mg/L TMX showed a reduced alcam expression compared to the control embryos. C. sox3 expression at stage 32. The expression of the cranial placode-specific gene sox3 was altered upon IMD and CLO exposure (black arrowheads). D. Analysis of sox3 expression at stage 32. The statistical analyses of four independent embryo batches resulted in a significantly increased number of embryos with a reduced sox3 expression after IMD and CLO exposure. Abbreviations: IMD, imidacloprid; TMX, thiamethoxam; CLO, clothianidin; mg/L, milligram per liter; n, number of embryos analyzed. Statistics: The statistical evaluation always refers to the comparison of the respective exposure group (IMD, TMX, CLO) with the control group (without NEO). |
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alcam (activated leukocyte cell adhesion molecule) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 32, lateral view of head region, anterior right, dorsal up. |
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sox3 (SRY-box 3) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 32, lateral view of head region, anterior right, dorsal up. |
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