Reproductive toxicities of tetradecyltrimethylammonium chloride and tetradecyltrimethylammonium bromide on Caenorhabditis elegans over four consecutive generations

doi:10.21203/rs.3.rs-3528355/v1

Quaternary ammonium compounds (QACs) become emerging pollutants and their toxicities earn increasing attentions. So far, their reproductive toxicities were poorly investigated, and their effects over generations were even less explored. In the present study, reproductive toxicities of two QACs, i.e., tetradecyltrimethylammonium chloride (TTAC) and tetradecyltrimethylammonium bromide (TTAB) were studied on Caenorhabditis elegans with a consecutive exposure over four generations (from F1 to F4). The effects of TTAC on total reproduction showed stimulation and inhibition which oscillated from F1 to F4, and such oscillation was also observed in the effects on initial reproduction. The effects of TTAB on the total reproduction commonly showed stimulation over generations. The greatest stimulation was in F2, and it was accompanied with inhibition on the initial reproduction but stimulation on the reproduction duration. Further mechanisms exploration demonstrated that both TTAC and TTAB significantly disturbed the levels of SPE8, SPE9, Vg, MSP and VAB-1 and the expressions of vab-1, ceh-18, set-2, met-2 and mes-4 over generations. Such disturbances demonstrated that both QACs impacted the reproductive processes in multiple aspects including oocyte meiosis, gonadal support and germline development. Further analysis also showed that the effects of both TTAC and TTAB in parents were connected with those in the offspring, which highlighted the conjunctive roles of reproduction in responses of adjacent generations. In addition, the differences the effects of TTAC and TTAB also demonstrated the anionic influences on the QACs’ toxicities.

Multigenerational effect

Oocyte meiosis

Gonadal support

Germline development

Anionic influence

Quaternary ammonium compounds (QACs) have wide application in disinfectants, biocides, environmental remediation and even carbon capture (Abe and Kishimura 2022, Roy and Ahmaruzzaman 2022, Mai et al. 2023). Their discharge into the environment during application and through effluents and sludge earned increasing attentions on their toxicities (Jardak et al. 2016, Mohapatra et al. 2023). It was reported that QACs showed mutagenic effects in bioluminescence assays (Dmochowska et al. 2016), growth inhibition and respiratory damage in beagles, mice and rats (Luz et al. 2020, Park et al. 2023), and even promotion on resistance gene transfer (Han et al. 2019, Liu et al. 2023). However, their toxicities still need more studies to fully demonstrate their environmental impacts on ecosystem and human health.

The reproductive toxicities are very important in ecological risk and hazard evaluation. It was reported that QACs significantly decreased reproduction, caused birth defects and impacted the development of ovaries in mice and rats (Jiao et al. 2017, Hrubec et al. 2021, Matsumoto et al. 2021). In the yeast assays and in vitro cell line studies, QACs impacted hormones that are important in reproduction (Hrubec et al. 2021, Liwarska-Bizukojc et al. 2021). Notably, the reproduction process connects adjacent generations and its changes by pollutants can represent intergenerational influences. As expected, QACs (e.g., didecyldimethyl ammonium chloride and alkyl dimethyl benzyl ammonium chloride) indeed impacted the body weight of the rat offspring in the exposure over generations (Luz et al. 2020). However, it remained poorly reported the reproductive toxicities of QACs over generations and also urged systematic exploration on the mechanisms.

Reproduction involves a series of subtle processes with the various regulations. In Caenorhabditis elegans, the reproduction includes (1) spermiogenesis, which is triggered by spermatocyte protein 8 (SPE8) and promoted by vitellogenin (Vg) (Han et al. 2010, Ellis and Stanfield 2014); (2) oogenesis, which includes mitogen-activated protein kinase (MAPK) activation, binding of major sperm protein (MSP) to VAB-1 Eph receptor protein-tyrosine kinase, POU-homeoprotein (ceh-18) in gonadal sheath cells and also Gα_o/i and Gα_s signaling pathways (Govindan et al. 2006, Yamamoto et al. 2006); and (3) the sperm-oocyte interactions and fertilization which are ensured with SPE9 (Marcello and Singson 2010). The process also requires epigenetic regulations by histone methylation at H3K4 (set-2), H3K9 (met-2) and H3K36 (mes-4) sites (González-Aguilera et al. 2013, Herbette et al. 2017). The reproduction of C. elegans was widely to employed to investigate toxicities of environmental pollutants, e.g., (Wang et al. 2018, Huang et al. 2023, Liu et al. 2024). Changes in aforementioned processes explained the reproductive toxicities of ionic liquids (ILs) (Yue et al. 2021, Wang et al. 2023). Therefore, they are expected to explain the reproductive toxicities of QACs.

The present study aimed to explore the reproductive toxicity of two representative QACs, i.e., tetradecyltrimethylammonium chloride (TTAC) and tetradecyltrimethylammonium bromide (TTAB) with an exposure over four consecutive generations. The toxicity mechanisms were explored changes in SPE8, Vg, vitellogenin (Vn), MAPK, MSP and VAB-1, and the expressions of genetic and epigenetic regulating genes. Further hierarchical cluster analysis (HCA) and correlation analysis were employed to explore the connections among indicators underlying the reproductive toxicities over generations.

2.1. Chemicals

Tetradecyltrimethylammonium chloride (TTAC, CAS No.: 4574-04-3, 99%) and tetradecyltrimethylammonium bromide (TTAB, CAS No.: 1119-97-7, 99%) were purchased from Adamas-beta. Stock solutions were prepared with sterile K-medium (0.051 M NaCl and 0.032 M KCl) and their nominal concentrations were arranged as 0.88 mg/L.

2.2. Preparation of organism

Wild-type N2 C. elegans were cultured on nematode growth medium (NGM) agars at 20 ºC temperature with Escherichia coli OP50 as food (Yu et al. 2017). Gravid nematodes were lysed with fresh-made clorox solution (1% NaClO and 0.5 mol/L NaOH) to obtain age-synchronized eggs which were used in subsequent experiments (Yue et al. 2021).

2.3. Multi-generational reproduction

For the exposure, 200.0 mL warm NGM containing 2.0 mL stock solutions or sterile K-medium solutions (served as the control) was aliquoted into 10 petri dishes as replicates in each group (Yu et al. 2017, Yue et al. 2021). The exposure concentration was 0.0088 mg/L, at which TTAC and TTAB did not provoke significant lethality (less than 5%). The NGM agars further received same amounts of E. coli OP50 to form a bacterial lawn. At last, the NGM agars received same amounts of age-synchronization nematode eggs to start the F1 exposure.

On the 3rd day in F1, adult nematodes were used for reproduction measurement, preparation for next generation exposure and sample collection. Briefly, 48 adult nematodes in every group were transferred daily onto 24 new NGM agars (i.e., two adults per agar) containing the same TTAC/TTAB or K-medium solutions to measure initial reproduction (offspring within the first 72 h), total reproduction and reproduction duration (Yu et al. 2017, Liu et al. 2020). Another 100 adult nematodes in each group including the control were transferred onto ten replicate agars containing the same TTAC/TTAB or K-medium solutions. With the adults discarded after 24 h, the newly laid eggs started the F2 exposure (Yue et al. 2021). The rest nematodes were collected as samples for subsequent assays. Through the same way, the multi-generational exposure lasted for 4 consecutive generations (i.e., F1 to F4).

2.4. Biochemical assays

Nematode samples were homogenized in ice bath and centrifuged at 4 ºC, and the supernatants were aliquoted into new centrifuge tubes for subsequent bioassays (Liu et al. 2020, Yue et al. 2021). The contents or activities of MSP, VAB-1, SPE-9, SPE-8, Vg, vitellin (Vn) and MAPK were determined via microplate reader using the commercial enzyme-linked immune-sorbent assay (ELISA) kits (Shanghai Zhanshi Biotechnology Co. LTD). They were normalized as their portions against the total protein (TP, measured via BCA protein assay kits) in the same sample.

2.5. Gene expression analysis

The total RNA was isolated using TRIzol reagent and functioned as templates to synthesize cDNA according to the instruction of M-MLV, Promega (Li et al. 2020). Subsequent real-time polymerase chain reaction (RT-PCR) with SYBR Green Master Mix was performed on Applied Biosystems 7900HT Fast Real-Time PCR System (USA). The primers (Table S1 in Supporting information) were designed with Primer Premier (6.0, Premier Biosoft Inc., CA). The gene expressions were quantified using the 2^−ΔΔCT method with gpd-1 as the reference gene.

2.6. Data presentation and statistical analysis

Data in each sample were presented as fold-change against those in the concurrent control in the same generation (Liu et al. 2020, Yue et al. 2021). Significant differences between control and treatment and among generations were analyzed via two-way ANOVA with Tukey post hoc test at the level of 0.05 (p < 0.05). The hierarchical component analysis (HCA) and Pearson’s rank correlation statistics were performed to explore further connection among the indicators (Yu et al. 2019, Yue et al. 2021).

3.1. Multi-generational reproductive effects of TTAC and TTAB

Results showed that TTAC caused significant stimulation on the total reproduction in F1, inhibition in F2, stimulation again in F3 and inhibition in F4 (Fig. 1(A)). Moreover, the effects of TTAC on the initial reproduction were generally similar to those on the total reproduction. Notably, the effects of TTAC on the reproduction duration showed inhibition in F1 and stimulation in F2 to F4. The stimulation on the reproduction duration in F2 and F4 spared more time for reproduction but it was not enough to compensate the inhibition on initial reproduction, and therefore resulted in the inhibition in the total reproduction. Summing up, the multi-generational reproductive effects of TTAC showed oscillatory changes between stimulation and inhibition over generations. Moreover, the effects were mainly resulted from the influences on the initial reproduction which was not compensated by the prolonged reproduction duration.

(Fig. 1 around here)

In the aspect of TTAB, it showed stimulation on the total reproduction in all generations with the greatest stimulation in F2 (Fig. 1(B)). It showed stimulation on the initial reproduction in F1, F3 and F4, but inhibition in F2. It also commonly stimulated the reproduction duration in all generations. In other words, the reproductive increases by TTAC in F1, F3 and F4 were resulted from both initial reproduction and reproduction duration. Meanwhile, the reproductive increases in F2 were mainly resulted from longer reproduction duration instead of the initial reproduction. The different results of TTAC and TTAB showed the influences of anions on the reproductive toxicities of QACs.

3.2. Multi-generational effects of TTAC and TTAB on essential reproduction proteins

Multi-generational effects of TTAC on essential reproduction proteins are showed in Fig. 2(A). In F1, TTAC inhibited MSP and Vg, and stimulated VAB-1, SPE9 and SPE8. In F2, it stimulated MSP and SPE8, and inhibited SPE9, Vg and MAPK. In F3, it inhibited MSP, VAB-1, SPE9 and Vn, and stimulated Vg and MAPK. In F4, it stimulated MSP and Vn, and inhibited VAB-1 and Vg. Summing up, effects of TTAC oscillated between stimulation and inhibition on all proteins over generations. Combining the biochemical effects, the IBR values were 2.21, 2.17, 2.10 and 2.34 in F1 to F4, respectively. Compared with the IBR value in the control (2.60), the overall effects of TTAC commonly showed inhibition Fig. 2(C).

Effects of TTAB on the proteins also showed oscillation between stimulation and inhibition over generations (Fig. 2(B)). The IBR values were 2.43, 2.12, 2.18 and 2.34 in F1 to F4, respectively. The overall effects of TTAB also commonly inhibition.

(Fig. 2 around here)

3.3. Multi-generational effects of TTAC and TTAB on genetic regulations

In F1, TTAC upregulated all gene expressions (Fig. 3(A)). In F2, it upregulated the expressions of set-2, met-2, mes-4 and vab-1 and downregulated those of ceh-18. In F3, it upregulated the expressions of set-2, mes-4 and vab-1, and downregulated those of ceh-18 and gsa-1. In F4, it upregulated expressions of set-2, met-2, mes-4, vab-1 and gsa-1, and downregulated those of ceh-18. The IBR values were 13.4, 3.72, 2.43 and 2.60 in F1 to F4, respectively. Compared with the IBR value of the control (2.74), the overall effects of TTAC on gene expressions were stimulatory in F1 and F2, and inhibitory in F3 and F4 (Fig. 3(C)).

(Fig. 3 around here)

In F1, TTAB did not show significant influences on all gene expressions (Fig. 3(B)). In F2, it upregulated the expressions of set-2, met-2, mes-4, vab-1 and gsa-1, and downregulated those of ceh-18. In F3, it upregulated the expressions of set-2, mes-4, vab-1 and gsa-1, and downregulated those of ceh-18. In F4, it upregulated expressions of set-2, mes-4, vab-1 and gsa-1, and downregulated those of met-2 and ceh-18. Collectively, the expression levels showed oscillation between upregulation and downregulation over generations. The IBR values were 2.33, 9.51, 2.86 and 2.60 in F1 to F4, respectively (Fig. 3(C)). The overall effects of TTAB on gene expressions were inhibitory in F1 and F4 and stimulatory in F2 and F3.

3.4. Overall analysis on multi-generational effects of TTAC and TTAB

In the HCA results, the effects of TTAC on reproduction (including initial reproduction, total reproduction and reproduction duration) and reproduction-related proteins (including MSP, VAB-1, SPE9, SPE8, Vg and Vn) in F1 were closed clustered showing close connection (Fig. 4(A)). Interestingly, the effects of TTAC on the gene expressions in F1 were more closely connected with the effects on reproduction in F2. Moreover, the effects on expressions of vab-1, ceh-18 and gsa-1 in F2 were also more closely connected with those on reproduction in F3. In addition, the effects on SPE-8, Vg, Vn and MAPK and those on the gene regulation in F3 were also more closely connected with the effects on reproduction in F4. Summing up, the effects of TTAC on parents were closely connected with those on the offspring. The effects of TTAB in parent generations were also closely related with those on the offspring (Fig. 4B). Moreover, the effects of TTAC in F1 were even connected with those in F3 and F4, and the effects of TTAB in F1 and F2 also showed close connection with those in F4. That is to say, the close connection among indicators expanded over adjacent generations.

(Fig. 4 around here)

(Tables 1 & 2 around here)

Table 1 Pearson’s correlation between reproduction and biochemicals, between reproduction and gene expressions, and between biochemicals and gene expressions in the toxicities of tetradecyltrimethylammonium chloride (TTAC).

TTAC	IR	TR	MSP	VAB-1	SPE-9	SPE-8	Vg	Vn	MAPK	set-2	met-2	mes-4	vab-1	ceh-18	gsa-1
IR	-	1.000	0.612	0.733	0.741	0.740	0.758	0.651	0.813	0.695	0.701	0.751	0.756	0.836	0.718
TR		-	0.618	0.739	0.746	0.747	0.763	0.656	0.815	0.698	0.704	0.756	0.762	0.838	0.721
MSP			-	0.964*	0.948*	0.973*	0.976*	0.988*	0.941*	0.539	0.585	0.724	0.766	0.553	0.413
VAB-1				-	0.992*	0.998*	0.964*	0.980*	0.959*	0.737	0.770	0.876	0.907*	0.751	0.638
SPE-9					-	0.985*	0.949*	0.980*	0.969*	0.771	0.808	0.900*	0.918*	0.779	0.670
SPE-8						-	0.978*	0.981*	0.964*	0.699	0.733	0.849	0.884*	0.725	0.602
Vg							-	0.968*	0.978*	0.567	0.608	0.744	0.783	0.627	0.471
Vn								-	0.964*	0.636	0.683	0.800	0.828	0.640	0.512
MAPK									-	0.660	0.704	0.810	0.828	0.715	0.570
set-2										-	0.997	0.971*	0.950*	0.973*	0.982*
met-2											-	0.981*	0.959*	0.967*	0.966*
mes-4												-	0.994*	0.956*	0.922*
vab-1													-	0.940*	0.897*
ceh-18														-	0.978*
gsa-1															-

*, at 0.05 level.

Table 2 Pearson’s correlation between reproduction and biochemicals, between reproduction and gene expressions, and between biochemicals and gene expressions in the toxicities of tetradecyltrimethylammonium bromide (TTAB).

TTAB	IR	TR	MSP	VAB-1	SPE-9	SPE-8	Vg	Vn	MAPK	set-2	met-2	mes-4	vab-1	ceh-18	gsa-1
IR	-	0.846	0.968*	0.990*	0.980*	0.972*	0.976*	0.983*	0.980*	0.635	0.628	0.431	0.801	0.929*	0.717
TR		-	0.940*	0.895*	0.922*	0.945*	0.926*	0.926*	0.911*	0.931*	0.946*	0.836	0.980*	0.856	0.616
MSP			-	0.990*	0.982*	0.998*	0.996*	0.996*	0.982*	0.806	0.780	0.637	0.925*	0.893*	0.774
VAB-1				-	0.990*	0.991*	0.996*	0.997*	0.994*	0.718	0.702	0.531	0.867	0.919*	0.756
SPE-9					-	0.992*	0.991*	0.994*	0.997*	0.735	0.753	0.565	0.875	0.960*	0.664
SPE-8						-	0.997*	0.998*	0.990*	0.796	0.788	0.630	0.918*	0.921*	0.730
Vg							-	0.998*	0.994*	0.771	0.756	0.599	0.905*	0.913*	0.756
Vn								-	0.994*	0.762	0.753	0.586	0.896*	0.927*	0.735
MAPK									-	0.727	0.735	0.555	0.873	0.946*	0.697
set-2										-	0.966*	0.967*	0.968*	0.609	0.622
met-2											-	0.951*	0.937*	0.697	0.440
mes-4												-	0.881*	0.455	0.451
vab-1													-	0.758	0.717
ceh-18														-	0.436
gsa-1															-

*, at 0.05 level.

In the Pearson’s correlation results, the biochemical effects of TTAC (e.g., on MSP, VAB-1, SPE-9, SPE-8, Vg, Vn and MAPK) were well correlated with themselves and also occasionally with those on mes-4 and vab-1 expressions (Table 1). Meanwhile, the biochemical effects of TTAB showed correlations with themselves, but also with reproduction, and commonly with those on vab-1 and ceh-18 expressions (Table 2). The results demonstrated the connection among indicators and also the differences between TTAC and TTAB.

4.1. Multi-generational reproductive effects of TTAC and TTAB

The multigenerational reproductive effects showed oscillation between stimulation and inhibition over generations. The similar oscillations were also observed in multigenerational effects of imidazole-based ILs (Yue et al. 2021, Zhang and Feng 2022, Wang et al. 2023), pyridine-based ILs (Shi et al. 2021, Zhang et al. 2022), and antibiotics (e.g., sulfamethoxazole, enrofloxacin, ofloxacin and norfloxacin) (Li et al. 2020, Zhang et al. 2022, Zheng et al. 2022). Offspring in uterus prepared similar responses to their maternal experiences via fetal reprogramming for better adaptation to the environment (Li et al. 2020). However, such preparation does not guarantee the matching with the actual requirement of the offspring. Accordingly, the outcomes in the offspring can be stimulation, inhibition and even non-significant influences, therefore explaining the oscillatory changes over generations. More investigation is needed to establish models for predicting multigenerational effects in the future.

Similar to the effects of TTAB, pyridine-based ILs and antibiotics also caused consistent effects on the initial and total reproduction of nematodes (Shi et al. 2021, Zhang et al. 2022, Zhang et al. 2022). Meanwhile, the effects of TTAC in F2 showed inconsistence between effects on the initial reproduction and those on the total reproduction with compensation from longer reproduction duration. Notably, animals in the actual environment would reproduce as early as possible to ensure the population growth (Yu et al. 2017), and delayed reproduction with longer reproduction duration would be unrealistic due to accidental death or predation. Therefore, with or without compensation by longer reproduction duration, the reproductive toxicities of TTAC and TTAB would significantly influence the population growth and their ecological risks should be seriously considered in their application.

It was known that QACs are cationic surfactants, and therefore most investigations were studied on cationic toxicity on various organisms (Luz et al. 2020, Suthar et al. 2022). The present study showed the different results of TTAC and TTAB, which showed the influences of anions on the reproductive toxicities. In future studies, the anionic influences should be considered in the QACs toxicities to more accurate evaluation on their ecological risks.

4.2. Mechanisms of the multi-generational reproductive effects

In the reproductive processes, the spermiogenesis is triggered via SPE8 and the sperm movement is promoted by Vg (Han et al. 2010, Ellis and Stanfield 2014), the oocyte meiotic maturation is regulated by MAPK activation and binding of MSP to VAB-1 (Govindan et al. 2006, Yamamoto et al. 2006), and the sperm-oocyte interactions and fertilization are ensured with SPE9 (Marcello and Singson 2010). At the molecular level, the expressions of vab-1, ceh-18, set-2, met-2 and mes-4 regulate the oocyte meiotic maturation, gonadal sheath cells and germline genome integrity (Govindan et al. 2006, Yamamoto et al. 2006, González-Aguilera et al. 2013, Herbette et al. 2017). The effects of TTAB on the reproduction showed positive correlations with those on the aforementioned biochemicals and those on the expressions of the aforementioned genes. Moreover, the effects of TTAB on the gene expressions (e.g., vab-1 and ceh-18) were also positively correlated with those on the biochemicals including MSP, SPE-9, Vg and MAPK. The correlation demonstrated that the reproductive toxicities of TTAB were well related with its impacts on the whole reproductive processes including oocyte meiosis, gonadal support and germline development. However, the effects of TTAC did not show such correlations as those in the results of TTAB, and therefore the differences supported the anionic influences on QACs toxicities as well.

Notably, the effects of both TTAC and TTAB in parents were connected with those in the offspring. The connection was also observed in the multi-generational effects of antibiotics and ILs (Zhang et al. 2022, Wang et al. 2023). Such connection supported that reproductive processes provided one essential tie to combine health over generations. Especially, the expressions of set-2, met-2 and mes-4 involved histone methylation (e.g., at H3K4, H3K9 and H3K36 sites) to preserve germline genome integrity and normal development (González-Aguilera et al. 2013, Herbette et al. 2017). Therefore, the connection in the effects between generations also supported the involvement of epigenetic modulation on the responses of offspring to the maternal experience (Yue et al. 2021). Therefore, further studies are still needed to explore the epigenetic mechanisms underlying the multigenerational consequences of pollutants.

Both TTAC and TTAB caused reproductive toxicities with changes over generations. The reproductive effects of TTAC showed oscillation between stimulation and inhibition over generations. The toxicities of TTAB on initial reproduction can be compensated by reproduction duration. Biochemical and gene expression results showed that TTAC and TTAB impacted oocyte meiosis, gonadal support and germline development. Moreover, the reproductive toxicities also involved epigenetic regulations on histone methylation. In addition, the results also demonstrated the anionic influences on the toxicities of QACs.

Ethical Approval:

Not applicable.

Consent to Participate and Publish:

All authors agreed with authorship and the content, and approved to submit the present version to be published.

Authors Contributions

Formal analysis, investigation and writing original draft were performed by Jing Zhang. Experiment performance and data curation were performed by Ruoqi Ding. Supervision, project administration and funding acquisition were performed by Zhenyang Yu.

Funding

This work was supported by National Key Research and Development Program of China (2021YFC3200803). The authors are sincerely grateful for their financial support.

Competing Interests

The authors have no relevant financial interests to disclose.

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20231030TableS1.docx

Reproductive toxicities of tetradecyltrimethylammonium chloride and tetradecyltrimethylammonium bromide on Caenorhabditis elegans over four consecutive generations

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Version 1

Abstract

Figures

1. Introduction

2. Method and Materials