Kokke BPA et al. (1998) FEBS Lett "Caenorhabditis elegans small heat-shock proteins Hsp12.2 and Hsp12.3 form tetramers and have no chaperone-like activity."

de Jong WW, Boelens WC, Leroux MR, Candido EPM, Kokke BPA

[FEBS Lett, 1998]

Four 12.2-12.6 kDa small heat-shock proteins (sHSPs) of Caenorhabditis elegans are the smallest known members of the sHSP family. They essentially comprise the characteristic C-terminal 'alpha-crystallin domain' of the sHSPs, having a very short N-terminal region, and lacking a C-terminal tail. Recombinant Hsp12.2 and 12.3 are characterized here. Far-UV CD spectra reveal, as for other sHSPs, predominantly a beta-sheet structure. By gel permeation and crosslinking, they are the first sHSPs shown to occur as tetramers, rather than forming the usual large multimeric complexes. Exceptionally, too, both appear devoid of in vitro chaperone-like abilities. This supports the notion that tetramers are the building blocks of sHSP complexes, and that higher multimer formation, mediated through the N-terminal domains, is a prerequisite for chaperone-like activity.

Kokke BPA et al. (2001) Cell Stress Chaperones "The lack of chaperonelike activity of Caenorhabditis elegans Hsp12.2 cannot be restored by domain swapping with human alphaB-crystallin."

Kokke BP, Boelens WC, Kokke BPA, de Jong WW

[Cell Stress Chaperones, 2001]

The small heat shock proteins Hsp 12.2 and (alphaB-crystallin differ in that the former occurs as tetramers, without chaperonelike activity, whereas the latter forms multimers and is a good chaperone. To investigate whether the lack of chaperone activity of Hspl 2.2 is primarily due to its tetrameric structure or rather to intrinsic sequence features, we engineered chimeric proteins by swapping the N-terminal, C-terminal, and tail regions of Hsp12.2 and alphaB-crystallin, designated as n-c-t and N-C-T, respectively. Three of the chimeric sHsps, namely N-c-T, n-c-T, and N-C-t, showed nativelike secondary and quaternary structures as measured by circular dichroism and gel permeation chromatography. Combining the conserved a-crystallin domain of Hsp12.2 with the N-terminal and tail regions of (YB-crystallin (N-c-T) resulted in multimeric complexes, but did not restore chaperonelike activity. Replacing the tail region of Hsp12.2 with that of alphaB-crystallin (n-c-T) did not alter the tetrameric structure and lack of chaperone activity. Similarly, providing (alphaB-crystallin with the tail of Hsp12.2 (N-C-t) did not substantially influence the multimeric complex size, but it reduced the chaperoning ability, especially for small substrates. These results suggest that the conserved alpha -crystallin domain of Hsp12.2 is intrinsically unsuitable to confer chaperonelike activity and confirms that the tail region in alphaB-crystallin modulates chaperonelike capacity in a substrate-dependent manner.

Wang Y et al. (2023) Ecotoxicol Environ Saf "Neurotoxicity of bisphenol A exposure on Caenorhabditis elegans induced by disturbance of neurotransmitter and oxidative damage."

Zhang L, Wang Y, Wang S, Chen L, Ye T, Gai T, Zhang W

[Ecotoxicol Environ Saf, 2023]

Bisphenol A (BPA) is putatively regarded as an environmental neurotoxicant found in everyday plastic products and materials, however, the possible neurobehavioral adverse consequences and molecular mechanisms in animals have not been clearly characterized. The nematode Caenorhabditis elegans has become a promising animal model for neurotoxicological researches. To investigate the dose-effect relationships of BPA-induced neurotoxicity effects, the locomotion behavior and developmental parameters of the nematode were determined after BPA exposure. The present data demonstrated that BPA caused neurobehavioral toxicities, including head thrashes and body bends inhibition. In addition, when C. elegans was exposed to BPA at a concentration higher than 2 μM, growth and survival rate were decreased. The serotonergic, dopaminergic and GABAergic neurons were damaged by BPA. Furthermore, lower levels of mRNA expression related to dopamine, serotonin and GABA were detected in the worms exposed to 50 μM BPA. Increased SOD-3 expression might be adaptive response to BPA exposure. Moreover, oxidative damage triggered by BPA was manifested by changes in GST-4 expression, accompany with abnormity of ATP synthesis, but not nuclear localization of DAF-16/FOXO. Finally, we showed that epigallocatechin-3-gallate partially rescued BPA-induced reactive oxygen species (ROS) production and neurobehavioral toxicity. Altogether, the neurobehavioral and developmental toxicity of BPA may be induced by neurotransmission abnormity and oxidative damage. The present data imply that oxidative stress is linked to neuronal damage and neurobehavioral harm resulting from developmental BPA exposure.

Chen, Y. et al. (2015) International Worm Meeting "Overlapping and Distinct Effects of Bisphenol A and its Substitute Bisphenol S on Germ Cells."

Allard, P., Yang, X., Chen, Y., Shu, L., Lee, D.

[International Worm Meeting, 2015]

Bisphenol S (BPS), one substitute of Bisphenol A (BPA), is increasingly used in the "BPA-free" plastic manufacturing industry since the toxic effects of BPA have come under heavy scrutiny. Sharing a similar structure and bioactivity with BPA makes BPS a potential threat to human health. However, information about its toxicity is still limited. In this study, the reproductive toxicities of BPA and BPS are investigated and compared using the nematode Caenohabditis elegans (C.elegans). Worms were grown in media with 125, 250 and 500muM BPA and/or BPS. The Bisphenols' effects on adult worms' fertility, germline apoptosis and chromosomal integrity of oocytes were investigated. We observed a dose-response effect for both BPA and BPS with regards to apoptotic germ cell number, embryonic lethality and reduction in brood size, a reflection of fertility. Since meiotic errors could lead to germline apoptosis, aneuploidy formation and even sterility, Bisphenls' effect on the expression of SYP-1 and RAD-51, two critical elements of the meiotic program, were examined. Surprisingly, while both BPA and BPS show ability to impact the formation and disassembly of SYP-1 in the germ cell nucleus, only BPA but not BPS affects the expression and localization of RAD-51 in the germline suggesting a specific effect of BPA on the recombination machinery. To fully reveal the differences between their mechanisms of toxicity, RNA sequencing was also carried out to distinguish the overlapping and distinct effects of BPA and BPS on the transcriptome of germ cells. As a summary, our results show that BPS, like BPA, carries reproductive toxicity. However, some of their mechanisms of toxicity are distinct, especially with regards to the meiotic recombination, and need to be further studied. .

Zhou D et al. (2016) Environ Toxicol Chem "Ecotoxicological evaluation of low-concentration bisphenol A exposure on the soil nematode Caenorhabditis elegans and intrinsic mechanisms of stress response in vivo."

Zhou D, Lin KF, Yang J, Li H, Liu YD, Lu Q

[Environ Toxicol Chem, 2016]

As a representative species of nematodes, Caenorhabditis elegans is an attractive animal model for evaluating ecotoxicological effects and intrinsic mechanisms of stress response in vivo. To acquire a better knowledge of environmental effects of bisphenol A (BPA), ecotoxicological evaluations were conducted using C. elegans upon the physiological (growth, locomotion behaviors, and reproduction), biochemical (lipofuscin accumulation, reactive oxygen species production, and cell apoptosis), and molecular (stress-related genes expressions) responses. Nematodes were exposed to BPA (0.001 to 10M) in two assay systems (L4 larvae for 24h and L1 larvae for 72h). BPA exposure could significantly (p<0.05) alter body length, locomotion behaviors, brood size, cell apoptosis, and selected stress-related genes expressions. At the physiological level, BPA exerted adverse effects on nematodes at the g/L level in both assay systems, with head thrashes as the most sensitive endpoint. At the biochemical level, apoptosis degree showed increases at concentrations above 0.1M in both assay systems. At the molecular level, BPA induced increases in selected stress-related genes expressions, even at the lowest tested concentration. In addition, BPA induced cell apoptosis was suggested as a potential mode of action, resulting in the adverse physiological effects. Therefore, BPA exposure was speculated to impose developmental, reproductive, and neurobehavioral toxicities on C. elegans, and caused variations of stress-related genes expressions. This article is protected by copyright. All rights reserved.

Zhou D et al. (2016) Chemosphere "The chronic toxicity of bisphenol A to Caenorhabditis elegans after long-term exposure at environmentally relevant concentrations."

Zhou D, Yu Y, Lin K, Yang J, Cui C, Liu Y, Li H

[Chemosphere, 2016]

To investigate biological effects of bisphenol A (BPA) over the long term, the model animal Caenorhabditis elegans was used to conduct the chronic exposure. C.elegans were exposed to BPA (0.0001-10M) from L4 larvae to day-10 adult in the present chronic toxicity assay system. Multiple endpoints at the physiological (growth, locomotion behaviors and lifespan), biochemical (lipofuscin accumulation), molecular (stress-related genes expressions), and population (population size) levels were examined. At the physiological level, BPA exposure induced significant negative effects on the indicators. Among the endpoints, head thrash was most sensitive and the detection limit was 0.001M. At the biochemical level, BPA exposure induced no significant effects on lipofuscin accumulation. At the molecular level, BPA induced strong stress responses invivo. At the population level, the population size was significantly decreased in the treatment groups from 0.1 to 10M. Compared to the previous short-term toxicity evaluation, long-term exposure to BPA induced a more obvious response at the same concentration, and the phenomenon might be due to cumulative toxic effects. By the Pearson correlation analyses, cep-1 was speculated to act as an important role in BPA-induced chronic toxicity on C.elegans.

Tan L et al. (2015) Toxicol Lett "Bisphenol A exposure accelerated the aging process in the nematode Caenorhabditis elegans."

Wang S, He M, Tan L, Wang Y, Liu D

[Toxicol Lett, 2015]

Bisphenol A (BPA) is a well-known environmental estrogenic disruptor that causes adverse effects. Recent studies have found that chronic exposure to BPA is associated with a high incidence of several age-related diseases. Aging is characterized by progressive function decline, which affects quality of life. However, the effects of BPA on the aging process are largely unknown. In the present study, by using the nematode Caenorhabditis elegans as a model, we investigated the influence of BPA exposure on the aging process. The decrease in body length, fecundity, and population size and the increased egg laying defection suggested that BPA exposure resulted in fitness loss and reproduction aging in this animal. Lifetime exposure of worms to BPA shortened the lifespan in a dose-dependant manner. Moreover, prolonged BPA exposure resulted in age-related behavior degeneration and the accumulation of lipofuscin and lipid peroxide products. The expression of mitochondria-specific HSP-6 and endoplasmic reticulum (ER)-related HSP-70 exhibited hormetic decrease. The expression of ER-related HSP-4 decreased significantly while HSP-16.2 showed a dose-dependent increase. The decreased expression of GCS-1 and GST-4 implicated the reduced antioxidant ability under BPA exposure, and the increase in SOD-3 expression might be caused by elevated levels of reactive oxygen species (ROS) production. Finally, BPA exposure increased the generation of hydrogen peroxide-related ROS and superoxide anions. Our results suggest that BPA exposure resulted in an accelerated aging process in C. elegans mediated by the induction of oxidative stress.

Ji YJ et al. (2004) Korean J Genet "Isolaton and characterization of bisphenol-A resistant mutants in Caenorhabditis elegans."

Song HO, Ahnn J, Park CS, Ji YJ

[Korean J Genet, 2004]

Endocrine disrupting chemicals (EDCs) are exogenous substances which can influence endocrine function in humans and other animals. Environmental exposure to these chemicals has been reported to affect sexual development and reproductive function in amphibians, crustaceans, and fish. Bisphenol-A (BPA) is a type of EDCs that can bind to estrogen receptor. First, we studied the effects of BPA on the survival of C. elegans and found a condition in which over 90% of the wild type worms were killed by BPA treatment.

Hornos Carneiro MF et al. (2019) Genetics "Antioxidant CoQ10 Restores Fertility by Rescuing Bisphenol A-Induced Oxidative DNA Damage in the Caenorhabditis elegans Germline."

Hornos Carneiro MF, Shin N, Kannan K, Karthikraj R, Barbosa F, Colaiacovo MP

[Genetics, 2019]

Endocrine-disrupting chemicals are ubiquitously present in our environment, but the mechanisms by which they adversely affect human reproductive health and strategies to circumvent their effects remain largely unknown. Here we show in <i>Caenorhabditis elegans</i>, that supplementation with the antioxidant Coenzyme Q10 (CoQ10) rescues the reprotoxicity induced by the widely used plasticizer and endocrine disruptor bisphenol A (BPA) in part by neutralizing DNA damage resulting from oxidative stress. CoQ10 significantly reduces BPA-induced elevated levels of germ cell apoptosis, phosphorylated checkpoint kinase 1 (CHK-1), double-strand breaks (DSBs) and chromosome defects in diakinesis oocytes. BPA-induced oxidative stress, mitochondrial dysfunction, and increased gene expression of antioxidant enzymes in the germline are counteracted by CoQ10. Finally, CoQ10 treatment also reduced the levels of aneuploid embryos and BPA-induced defects observed in early embryonic divisions. We propose that CoQ10 may counteract BPA-induced reprotoxicity through the scavenging of reactive oxygen species and free radicals and that this natural antioxidant could constitute a low-risk and low-cost strategy to attenuate the impact on fertility by BPA.

Allard P et al. (2010) Proc Natl Acad Sci U S A "Bisphenol A impairs the double-strand break repair machinery in the germline and causes chromosome abnormalities."

Colaiacovo MP, Allard P

[Proc Natl Acad Sci U S A, 2010]

Bisphenol A (BPA) is a highly prevalent constituent of plastics that has been associated with diabetes, cardiovascular disease, and an increased risk of miscarriages in humans. In mice, BPA exposure disrupts the process of meiosis; however, analysis of the affected molecular pathways is lagging and has been particularly challenging. Here we show that exposure of the nematode Caenorhabditis elegans to BPA, at internal concentrations consistent with mammalian models, causes increased sterility and embryonic lethality. BPA exposure results in impaired chromosome synapsis and disruption of meiotic double-strand break repair (DSBR) progression. BPA carries an anti-estrogenic activity in the germline and results in germline-specific down-regulation of DSBR genes, thereby impairing maintenance of genomic integrity during meiosis. C. elegans therefore constitutes a model of remarkable relevance to mammals with which to assess how our chemical landscape affects germ cells and meiosis.