Meiosis-mediated reproductive toxicity by fenitrothion in Caenorhabditis elegans from metabolomic perspective.

Fenitrothion (FNT), an organophosphorus insecticide, is widely detected in the living environment. The reproductive and endocrine toxicity of FNT to biological communities has been ever reported, but potential mechanism and reproductive toxicity dose effect remain unclear. In our study, we constructed Caenorhabditis elegans model to analyze the reproductive toxicity mechanism of FNT based on metabolomics and evaluated its reproductive toxicity dose effect using benchmark dose (BMD)method. Our results showed that FNT exposure significantly reduced brood size, number of germ cells, and delayed gonadal development in nematodes. Non-targeted metabolomics revealed that FNT exposure caused significant metabolic disturbances in nematodes, leading to a significant reduction in the synthesis of cortisol and melatonin, and the latter played a mediating role in the effects of FNT on number of germ cells. We further found that the levels of these two hormones were significantly negative correlated with the expression of the androgen receptor nhr-69 and affected the meiosis of germ cells by regulating the nhr-69/ fbf-1/2 /gld-3 /fog-1/3 pathway. Meanwhile, the study found the BMDL10s for N2 and him-5 mutant were 0.411 µg/L by number of germ cells and 0.396 µg/L by number of germ cells in the meiotic zone, respectively, providing a more protective reference dose for ecological risk assessment of FNT. This study suggested that FNT can affect androgen receptor expression by inhibiting cortisol and melatonin secretion, which further mediate the meiotic pathway to affect sperm formation and exert reproductive toxicity, and provides a basis for setting reproductive toxicity limits for FNT.

Non-targeted metabolomic profiling of atrazine in Caenorhabditis elegans using UHPLC-QE Orbitrap/MS.

The widespread use of the herbicides Atrazine (ATR) has been raised attention due to its ubiquitous occurrence in the environment. As an endocrine disruptor, ATR causes reproductive, immune, nervous system toxicity in biota. In this study, we aimed to investigate metabolic profile characteristics and potential metabolic biomarker that reflects specific damage in toxic effect after ATR exposure. Hence, a metabolomics study was performed to determine the significantly affected metabolites and the reproduction and locomotion of C. elegans were investigated. Mediation analysis was used to evaluate the mediating effect of metabolites on association between ATR exposure and toxic effect. ATR (≥0.04 mg/L) caused the significant dose dependent reduction of brood size and locomotion behavior, however, the body length and width were significantly decreased only in 40 mg/L group. These results suggesting that brood size, head thrashes and body bends are more sensitive indictor to assessment ATR toxicity in C. elegans. Meanwhile, metabolomics analysis revealed that ATR exposure can induce metabolic profiles significant alterations in C. elegans. We found that 9 metabolites significantly increased and 18 metabolites significantly decreased, such as phosphatidylcholine, GMP, CDP-choline, neopterin etc. Those alteration of metabolites were mainly involved in the pathways: glycerophospholipid metabolism, glycolysis/gluconeogenesis, folate biosynthesis, glycine, serine and threoninemetabolism, pyrimidine and purine metabolism. Overall, these changes are signs of possible oxidative stress and ATP synthesis disruption modification. Mediation analysis showed a significant indirect effect of ATR exposure on brood size, via 7,8-dihydroneopterin 2',3'-cyclic-p, and phosphatidylcholine might mediate association between ATR exposure and body bends, suggesting that 7,8-dihydroneopterin 2',3'-cyclic-p and phosphatidylcholine might be potentially specificity marker for brood size and body bend respectively. This preliminary analysis investigates metabolic characteristics in C. elegans after ATR exposure, helping to understand the pathways involved in the response to ATR exposure and provide potential biomarkers for the safety evaluation of ATR.

Transgenerational reproductive and developmental toxicity of tebuconazole in Caenorhabditis elegans.

The transgenerational reproductive and developmental toxicity of tebuconazole (TEB) in Caenorhabditis elegans was investigated over five generations (P0 - F4). Only parental C.elegans (P0) were exposed to TEB (0, 0.01, 0.1, 1, and 10 µg/L) for 24 h and the subsequent offspring (F1-F4) were grown under TEB-free conditions. TEB exposure caused dose-dependent reproductive defects and developmental impairments in C.elegans. In the P0 generation reproductive defects were observed such as: reduced brood size and embryo hatchability, prolonged generation time, retarded gonadal development, and slower germline proliferation, even at 0.01 µg/L, together with developmental toxicity with significant reduced body length and narrowed body width at 10 µg/L. Additionally, the brood size significantly reduced in F2, which began to recover from F3, but was still lower than the control in F4. The proportion of abnormalities increased significantly in F2 and reduced from F3, but was still higher than the control, suggesting that TEB could have cumulative potential and be passed to offspring through parental exposure. Furthermore, exposure to TEB (10 µg/L) in P0 significantly reduced the body length in F1, which began to recover from F2, and was the same level as the control in F4. There was a concentration-dependent increase in body width in F1-F4, with a significant increase only observed in F1 at 10 µg/L. Thus, parental exposure to TEB induced transgenerational defects in both reproduction and development, emphasizing the significance of considering bio-toxicity over multiple generations to conduct accurate assessment of environmental risks of toxicants.