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. 2025 Feb 19;14:101966. doi: 10.1016/j.toxrep.2025.101966

Preconception exposure to perfluorooctanesulfonic acid (PFOS) and perfluorobutanesulfonic acid (PFBS) impaired reproduction via insulin/insulin-like growth factor signaling pathway without effects on the second generation in Caenorhabditis elegans

Sida Li a, Yiren Yue a, Zhuojia Qian a, Zixuan Teng a, John M Clark b, Alicia R Timme-Laragy c, Yeonhwa Park a,⁎
PMCID: PMC11891744  PMID: 40066201

Abstract

In previous studies, preconception exposure to perfluorooctanesulfonic acid (PFOS) and perfluorobutanesulfonic acid (PFBS) reduced the reproductive capacity and altered the development of the offspring of C. elegans. However, the specific pathways involved in these observations were not determined. Thus, we investigated how preconception exposure to PFOS (40 μM) and PFBS (2000 μM) affected embryonic nutrient loading and offspring development. Preconception exposure to 40 μM PFOS significantly reduced nutrient loading to embryos via vit-6 (vitellogenin) and rme-2 (low-density lipoprotein particle receptor). The insulin/insulin-like growth factor signaling pathway (IIS), daf-2 (homolog of human insulin receptor precursor) and daf-16 (homolog of human forkhead box O) played a role in altering the reproductive capacity caused by preconception exposure to PFOS. Preconception exposure to PFBS did not affect nutrient loading but reduced reproductive health via IIS as well as nhr-49 (homolog of human hepatocyte nuclear factor 4α). In addition, preconception exposure to PFOS or PFBS resulted in no multigenerational effects on the reproductive health of F1 offspring worms. Preconception exposure to PFOS disrupted parental nutrient production and loading, reproduction, and offspring development, while PFBS impaired lipid metabolism and offspring development at higher doses than PFOS.

Keywords: PFOS, PFBS, Caenorhabditis elegans, Reproductive toxicity

Graphical Abstract

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Highlights

  • •

    PFOS elicits reproductive toxicity via insulin/insulin-like growth factor pathway (IIS).

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    PFBS did not affect nutrient loading but reduced reproductive health via IIS and nhr-49.

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    Preconception exposure to PFOS reduces nutrients in embryos, but not PFBS.

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    Preconception exposure to PFOS and PFBS does not affect reproductive health of F1.

1. Introduction

Per- and polyfluoroalkyl substances (PFAS) are a group of fluorosurfactants used in various applications, including the manufacturing of cookware, food packaging, and stain repellants [1]. Among them, perfluorooctanesulfonic acid (PFOS) is historically one of the most used surfactants. It has been banned in many countries due to its environmental persistence, but it is still used in some developing countries [2]. As an alternative to PFOS, perfluorobutanesulfonic acid (PFBS), a short-chain PFAS with four carbons instead of eight, has been introduced based on its shorter biological half-life of about one month compared to about five years for PFOS in humans [3], [4]. Among the many aspects of PFOS toxicity, reproductive health has not been extensively studied. Additionally, there is a lack of information on the safety of PFBS as a replacement for PFOS. Thus, the goal of the current study was to determine the effects of preconception exposure to PFOS and PFBS on reproductive health, including muti-generational effects, using Caenorhabditis elegans as a model system.

Since first being used as a model for studying developmental biology in the 1960s, the free-living nematode C. elegans is currently being widely used in numerous life science endeavors [5], [6], [7]. It possesses many advantages over vertebrate animal models, including easy handling, transparent small body size, short lifecycle with relatively large progeny numbers, a completely sequenced genome, and many mutant and transgenic strains available at low cost. More importantly, its genome has orthologs for more than 65 % of human disease-related genes [7], [8]. All these properties make C. elegans an excellent model for studying environmental toxicants-related pathologies.

In previous studies, embryonic exposure to PFOS impacted pancreatic development in zebrafish, including dose-dependent increases in the occurrence of abnormal islet morphology, decreased islet size, and decreased pancreas length [9]. In addition, maternal preconception exposure to PFBS also impacted egg and offspring development in zebrafish by reducing embryo survival and altering embryo development, which was modulated by Nuclear factor erythroid 2-related factor 2a (Nrf2a) [10]. Previously, we reported that preconception exposure to PFOS and PFBS significantly reduced the reproductive capacity and altered the development of F1 offspring in C. elegans [11]. Specifically, preconception exposure to PFOS significantly reduced nutrient loading in embryos. However, the expression of VIT-2 protein in eggs, which is one of the 6 yolk proteins comprising yolk lipoprotein complexes involved in nutrient loading, was increased after preconception treatment with PFOS [11]. Preconception exposure to PFBS, however, did not significantly reduce nutrient loading into embryos, and expression of VIT-2 in embryos was decreased [11]. To understand these inconsistencies, we conducted experiments to determine further the effects of preconception exposure to either PFOS or PFBS on nutrient loading, reproductive health, and offspring development, including their target pathways, using C. elegans.

2. Materials and methods

2.1. Materials

Perfluorooctanesulfonic acid (PFOS, 40 % in dimethyl sulfoxide, catalog no. 77283, lot 101406188), perfluorobutanesulfonic acid (PFBS, 97 %, catalog no. 562629, lot MKCB6204), ampicillin, and carbenicillin were purchased from Sigma-Aldrich Co. (St. Louis, MO). Luria-Bertani medium, biological agar, and peptone were purchased from Fisher Scientific Inc. (Pittsburgh, PA). Triglyceride kit (Infinity™ Triglyceride Reagent) used for triglyceride measurement and Hoechst 33,258 (>98 %) used for DNA quantification were purchased from Thermo Fisher Scientific Inc. (Middletown, VA). For protein quantification, Bio-Rad DC protein assay kit was purchased from Bio-Rad Co. (Hercules, CA). Escherichia coli OP50 and C. elegans strains, including N2, Bristol (wild type), DH1033 [sqt-1(sc103) II; bIs1 X], CB1370 [daf-2(e1370) III], GR1307 [daf-16(mgDf50) I], and RB1716 [nhr-49(ok2165) I] were obtained from Caenorhabditis Genetics Center (Minneapolis, MN).

3. Methods

3.1. C. elegans maintenance and treatments

C. elegans were cultured as previously described [7], [11] with non-pathogenic bacterial E. coli OP50 as the food source. The population was synchronized using the bleaching method [12]. PFOS or PFBS stock solution (x1000) were prepared in dimethyl sulfoxide (DMSO) and used for a final concentration of 40 μM PFOS and 2000 μM PFBS with 0.1 % DMSO based on the previous report [11], and the control was treated with 0.1 % DMSO only. To eliminate the potential interference of E. coli OP50 on the target compounds, heat-killed E. coli OP50 was used for all treatments, prepared by heat treatment at 65°C for 30 min [11]. For most of the analyses using F0 generation worms and embryos, treatments were started from the late L4/young adult stage for 1 day at 20°C in S-complete liquid media supplemented with test chemicals, ampicillin (100 μg/mL), carbenicillin (50 μg/mL), and heat-killed E. coli OP50 (8 mg wet weight/mL). For the analyses of the offspring generation, F0 worms were treated under the same condition mentioned above for 2 days to obtain enough eggs that allowed the collection of sufficient numbers of offspring worms for the following F1 parameters analyses, as C. elegans reproduction reached its peak on the 2nd day of adulthood [13].

3.2. L1 starvation assay

To determine nutrient load into embryos, the L1 starvation assay was used as previously described [14]. Approximately 30,000 L1 worms were synchronized in 3 mL of sterilized M9 buffer (day 0), placed in a 15 mL centrifuge tube, and kept at 20ºC without food. At each time point, three 20 μL samples (about 200 worms) were taken and placed on plates with E. coli. Worms were allowed to grow for 3 days, reaching the L4/young adult stage, and the total numbers were counted. The count from day 1 of starvation served as the control and the denominator for calculating the percentage of worms that recovered after 3 days of starvation [14].

3.3. Reverse transcription-quantitative real-time PCR (RT-qPCR)

Real-time qPCR was performed as previously described [15]. Total RNA was extracted by Trizol. A high-capacity cDNA reverse transcription kit (Applied Biosystems, Cat#4368814, Forster City, CA) was used to generate cDNA. Real-time PCR was performed using the StepOnePlus™ Real-Time PCR system (Applied Bio-systems, Foster City, CA). TaqMan™ gene expression assays used were vit-2 (Ce02505533_g1), vit-6 (Ce02456457_g1), rme-2 (Ce02463891_g1). and ama-1(Ce02462726_m1, an internal control).

3.4. Triglyceride and protein quantification

Embryos were collected and water washed 3 times to remove treatment and E. coli OP50 and sonicated in 0.05 % Tween 20 for 3 min [11]. To determine triglyceride and protein in embryos/eggs, pre-treated F0 nematodes were bleached to collect eggs. Measurements of triglyceride and protein were performed with the commercial kits: Infinity™ Triglyceride Reagent and Bio-Rad DC protein assay kit, respectively. DNA was quantified as the internal control, as previously reported with Hoechst 33,258, and used to normalize triglyceride and protein levels [16].

3.5. Nutrient update into embryos

Yolk nutrient uptake was measured using the transgenic C. elegans strain DH1033 [sqt-1(sc103) II; bIs1 X]. This strain labels VIT-2 with green fluorescence protein (GFP), as VIT-2 is one of the 6 yolk proteins comprising yolk lipoprotein complexes. After being treated with 40 μM PFOS or 2000 μM PFBS for 24 hours from L4 / young adult stage, worms were anesthetized with 10 mM NaN3, mounted on a microscopic slide, capped with a coverslip, and images taken using Nikon Eclipse Ti-U (Nikon Instruments Inc., Melville, NY). Since the major target of yolk lipoprotein complexes occurs in the early stages of embryos [17], the GFP intensities of the early-stage embryos, which have less than 64 cells, were quantified by using the Image J software (U. S. National Institutes of Health Bethesda, MD).

3.6. Reproductive capacity determination

To study the reproductive capacity, individual pre-treated worms were transferred to freshly prepared E. coli-seeded NGM plates every day until reproduction ceased. Daily brood size and progeny number were recorded. Hatchability was calculated as the ratio of progeny number to brood size [11].

3.7. Statistical analyses

Data was analyzed by one-way analysis of variance (ANOVA) followed by the Tukey-Kramer multiple comparison test with Graphpad Prism (version 8.4.3, Graphpad Software, LLC.). L1 starvation data were analyzed by two-way analysis of variance (ANOVA) with time and treatment as variables using the PROC MIXED procedure, followed by the Tukey-Kramer multiple comparison test with Statistical Analysis System software (SAS Institute, Cary, NC). Groups were considered statistically different when P < 0.05 compared to the control.

4. Results

4.1. Preconception exposure to PFOS, but not PFBS, decreased the nutrient loading into embryos

Our previous report found that preconception exposure to 40 μM PFOS significantly decreased the nutrient contents in embryos, while the VIT-2::GFP intensity in the eggs (a protein marker for nutrient loading) was increased [11]. Preconception exposure to 2000 μM PFBS, however, did not alter the nutrient contents of embryos but significantly reduced their VIT-2::GFP intensities [11]. To clarify this situation, we first conducted the L1 starvation assay. This assay is designed to determine nutrient loads in embryos as the lifespan of these hatched worms directly reflects the quantity of nutrients transferred to the embryos due to the lack of additional nutrients in the medium [18], [19], [20]. As shown in Fig. 1, there was a significant reduction in the lifespan of offspring worms (F1) with preconception exposure to PFOS, but not with PFBS, compared to the control (p < 0.001). The reduced survival of worms following preconception exposure to PFOS is not likely due to the toxicity of PFOS, as we have previously determined that these worms can develop into adults [11]. These results suggest that the embryos following PFOS preconception exposure have less nutrients compared to those from the control [20], [21], [22].

Fig. 1.

Fig. 1

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Effects of preconception exposure of PFOS and PFBS on the survival time of L1 C. elegans. Synchronized L4 or young adult worms were exposed to treatments with either a control solution (0.1 % DMSO), 40 μM PFOS, or 2000 μM PFBS for one day at 20°C. Subsequently, the collected eggs were hatched and cultured at 20°C in a nutritionally deprived liquid medium. The numbers of surviving worms were recorded by averaging the count from 5 sets of worm samples every three days. Data are mean±S.E. (n = 3). The group exposed to 40 μM PFOS exhibited a significant difference compared to the control and the 2000 μM PFBS group (p < 0.0001).

4.2. Preconception exposure to PFOS or PFBS influenced embryonic nutrient loading

To better understand how nutrient loading was affected by PFOS or PFBS, we determined if preconception exposure to PFOS or PFBS influenced the other critical targets in embryo nutrient loading. There are three major steps to determine total nutrients in embryos: 1) synthesis of yolk nutrients in the parent worm’s intestine, 2) transfer of yolk nutrients to the oocytes by endocytosis in the germline, and 3) utilization of the loaded nutrients during hatch and development in the fertilized embryos [20], [21], [23].

There are six genes (vit-1, vit-2, vit-3, vit-4, vit-5, and vit-6) that encode vitellogenins, which are essential for yolk protein formation in C. elegans (Suppl. Fig. S1) [24]. We selected vit-2 and vit-6 to represent the vitellogenin expressions for Complex B and A, respectively [20], [24]. Preconception exposure to PFOS or PFBS had no significant effect on the expression of vit-2 (Fig. 2). However, vit-6 was significantly down-regulated by preconception exposure to PFOS (30 %, p = 0.0024) but not by PFBS, compared to the control. These results suggest that preconception exposure to PFOS influenced yolk protein synthesis, while PFBS did not.

Fig. 2.

Fig. 2

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Effect of preconception exposure of PFOS and PFBS on the RNA expressions of vit-2, vit-6, and rme-2 in worms. Results are presented as mean ± S.E. (n = 4–8, each contained ∼3000 worms). Means with different letters indicate statistically differences (p < 0.05).

Next, we measured rme-2, which encodes the receptor responsible for yolk protein endocytosis that binds to vitellogenins and transports them into developing oocytes, playing a critical role in delivering nutrients for embryos [17], [23], [25], [26]. The mRNA expression levels of rme-2 were significantly down-regulated in response to preconception exposure to PFOS (38 %, p = 0.0026) compared to the control but not by PFBS exposure (Fig. 2). This suggests that yolk protein transportation was negatively influenced by PFOS (Fig. 1).

Our previous study reported that preconception exposure to PFOS increased the VIT-2::GFP intensity in embryos but PFBS decreased it [11]. Thus, we conducted additional experiments focused on VIT-2 levels in the embryos with less than 64 cells (early stages of embryo development, Suppl. Fig. S2), which allowed us to determine if loaded nutrients in the yolk were utilized differently during embryo development. We observed significantly increased VIT-2::GFP fluorescent intensity in the early-stage embryos following preconception exposure to PFOS, suggesting a higher VIT-2 load (Suppl. Fig. S2). In contrast, PFBS preconception treatment had no effects on VIT-2 in the early stages of embryos (Suppl. Fig. S2). These results suggest that preconception exposure to PFBS had no impact on VIT-2 loading into embryos and that reduced VIT-2 in the previous observation after preconception exposure to PFBS may have been due to the utilization of nutrients during the development.

4.3. Effects on reproduction after preconception exposure to PFOS or PFBS were abolished in daf-2 and daf-16 null mutants

Next, we determined the effects of preconception exposure to PFOS or PFBS using mutants to identify the potential mechanisms underlying their impact on reproduction. The insulin/insulin-like growth factor signaling pathway (IIS) regulates energy homeostasis and plays a significant role in reproduction [27]. Loss of function in daf-2, the gene responsible for the insulin/IGF-1 signaling (IIS) receptor in C. elegans, results in delayed reproductive aging, an extended fertile period, and sustained oocyte quality, which relies on the FOXO transcription factor, encoded by daf-16, and its expression is required in both the intestine and muscle tissues [7], [28], [29], [30]. Preconception exposure to 40 μM PFOS or 2000 μM PFBS for 24 hours, from the late L4 or young adult stage, had no significant effects on brood size, progeny number, or hatchability compared to the respective controls in daf-2 null mutant (Fig. 3) and the daf-16 null mutant (Fig. 4). These results suggest that previously observed reduced reproduction capacity after preconception exposure to PFOS or PFBS [11] requires the IIS pathway regulators, daf-2 and daf-16.

Fig. 3.

Fig. 3

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Influence of preconception exposure of PFOS and PFBS on the reproductive capacities of daf-2 null mutant C. elegans. Synchronized L4/young adult worms were exposed to either a control solution (0.1 % DMSO), 40 μM PFOS, or 2000 μM PFBS for 1 day at 20°C. Following the treatment, worms were randomly selected for reproduction analysis. Daily brood size (A) was determined by counting the number of laid eggs, while progeny numbers (B) were recorded as the quantity of hatched offspring. Hatchability (C) was calculated as the ratio of progeny number to brood size. Results are presented as mean ± S.E. (n = 7–12, collected from 3 independent experiments). Means with different letters indicate statistically differences (p < 0.05).

Fig. 4.

Fig. 4

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Influence of preconception exposure of PFOS and PFBS on the reproductive capacities of daf-16 null mutant C. elegans. Synchronized L4/young adult worms were exposed to either a control (0.1 % DMSO), 40 μM PFOS, or 2000 μM PFBS for 1 day at 20°C. Following treatment, worms were randomly selected for reproduction analysis. Daily brood size (A) was determined by counting the number of laid eggs, while progeny numbers (B) were recorded as the quantity of hatched offspring. Hatchability (C) was calculated as the progeny number divided by brood size. Results are presented as mean ± S.E. (n = 9–10, collected from 3 independent experiments).

4.4. Preconception exposure to PFBS, but not PFOS, impacted reproduction via NHR-49

It has previously been reported that one of the major targets of PFOS and PFBS is peroxisome proliferator-activated receptor-α (PPARα) [31], [32], [33], [34]. Thus, we next tested if preconception exposure to PFOS or PFBS elicits their impact on reproduction via NHR-49, the homolog to the mammalian PPARα [7], [35]. Preconception exposure to PFOS reduced brood size (36 %, p = 0.0388) but did not affect progeny number or hatchability compared to the control in nhr-49 null mutant (Fig. 5). These results were similar to what was observed in the wild-type worms [11], suggesting that the effects of preconception exposure to PFOS on reproductive ability were independent on nhr-49. However, there were no significant differences in reproductive capacity following preconception exposure to PFBS over the control in nhr-49 null mutants (Fig. 5). These results suggests that any effects of preconception exposure to PFBS on reproduction depend on nhr-49.

Fig. 5.

Fig. 5

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Influence of preconception exposure of PFOS and PFBS on the reproductive capacities of nhr-49 null mutant C. elegans. Synchronized L4/young adult worms were exposed to either a control (0.1 % DMSO), 40 μM PFOS, or 2000 μM PFBS for 1 day at 20°C. Following the treatment, worms were randomly selected for reproduction analysis. Daily brood size (A) was determined by counting the number of laid eggs, while progeny numbers (B) were recorded as the quantity of hatched offspring. Hatchability (C) was calculated as the ratio of progeny number to brood size. Results are presented as mean ± S.E. (n = 5, collected from 2 independent experiments). Means with different letters indicate statistically differences (p < 0.05).

4.5. Preconception exposure to PFOS influenced embryonic nutrient composition independent of daf-16

Next, we determined if alterations in nutrient loading in embryos following preconception exposure to PFOS or PFBS depended on the daf-16. Since daf-16 is the primary downstream regulator of daf-2, the result of daf-16 can be used to infer if the effects of PFOS or PFBS mediate the function of daf-2 as we were not able to collect enough embryos from the daf-2 mutant to conduct these experiments. Preconception exposure to PFOS decreased triglyceride (TG) non-significantly (21 %,p = 0.1248) and protein levels by 36 % (p = 0.0020), respectively, compared to control embryos of daf-16 null mutant (Fig. 6), which mimics the trends we observed in wild-type C. elegans [11]. This finding suggests that preconception exposure to PFOS altered embryonic nutrient composition independently of the DAF-16. However, there were no significant effects of the preconception exposure of PFBS on the embryonic TG or protein levels (Fig. 6). Since there were no effects of preconception exposure to PFBS on nutrient loading in either wild-type or daf-16 null mutant worms, it is not conclusive if PFBS elicits any significant impact on nutrient loading via daf-16.

Fig. 6.

Fig. 6

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Effects of preconception exposure of PFOS and PFBS on embryonic nutrient composition in daf-16 null mutant C. elegans. Synchronized L4/young adult worms were exposed to either a control (0.1 % DMSO), 40 μM PFOS, or 2000 μM PFBS for 2 days at 20°C. Subsequently, eggs were collected from ∼5000 worms and the levels of embryonic triglycerides (A) and protein content (B) were measured and then normalized by DNA concentration. Results are presented as mean ± S.E. (n = 4). Means with different letters indicate statistically differences (p < 0.05).

4.6. Preconception exposure to PFOS or PFBS did not influence reproduction in the second generation (F1) of C. elegans

Based on our previous observations that preconception exposure to PFOS or PFBS led to significant impairment in the development of F1 worms [11], experiments were conducted to determine if these chemicals have multigenerational effects by measuring the reproductive capacity of the F1 generation. Results in Fig. 7 show no effects of preconception exposure to PFOS or PFBS during the F0 generation on the reproductive capacity of the F1 generation, measured by brood size, progeny number, and hatchability.

Fig. 7.

Fig. 7

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The preconceptual exposure to PFOS and PFBS had no influence on the reproductive capacity of the second generation of wild-type C. elegans. Synchronized L4/young adult worms were exposed to either a control (0.1 % DMSO), 40 μM PFOS, or 2000 μM PFBS for 1 day at 20°C. Subsequently, eggs were collected, allowed to hatch (F1), and cultivated until reaching the young adult stage at 20°C. Randomly selected offspring worms (F1) were then utilized for the reproduction analysis. Daily brood size (A) was determined by tallying the number of laid eggs, while progeny number (B) was ascertained by counting the number of total hatched worms. Hatchability (C) was calculated as the ratio of progeny number to brood size. Results are presented as mean ± S.E. (n = 9–10, collected from 3 independent experiments).

5. Discussion

In the current study, we determined that preconception exposure to 40 μM PFOS significantly reduced nutrient loading to embryos via vit-6 and rme-2 dependently, but not daf-16. Additionally, preconception exposure to 40 μM PFOS reduced reproduction capacity via daf-2 and daf-16 dependently, but not dependent on nhr-49. Preconception exposure to 2000 μM PFBS, however, had no effect on either yolk protein synthesis or nutrient loading, while daf-2 and daf-16 contributed to a reduced reproductive capacity. We did not observe, however, any significant effects from preconception exposures to PFOS or PFBS on the reproductive capacity of F1 offspring. Overall results are summarized in Fig. 8, which includes results from our previous publication for comparison [11].

Fig. 8.

Fig. 8

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Overview of the effects of preconception exposure to PFOS and PFBS on reproductive health in C. elegans. The wild-type C. elegans results are from our previous study [11]. PFOS, perfluorooctanesulfonic acid; PFBS, perfluorobutanesulfonic acid; daf-2, abnormal DAuer Formation protein-2, the homolog of the insulin/insulin-like growth factor-1 receptor; daf-16:, abnormal DAuer Formation protein-16, the homolog of mammalian Forkhead box O transcription factor; nhr-49, nuclear hormone receptor-49, a homolog of the peroxisome proliferator-activated receptor-α.

Previously, it was reported that preconception exposure to PFOS inhibits reproductive capacity, nutrient loading, embryonic development, growth rates, pancreatic morphology, and nutrient metabolism in C. elegans, Drosophila melanogaster, and zebrafish [9], [10], [11], [36], [37], [38], [39]. In comparison, preconception exposure to PFBS impacts reproduction and metabolism but to a lesser extent than PFOS, requiring higher concentrations to manifest [4], [10], [11], [34], [40], [41]. The current results are consistent with these previous observations, including the insulin and insulin-like growth factor signaling pathway as a target of PFOS and PFBS [11]. In addition, we observed that nutrient transport may play a key role in reduced nutrient loading to oocytes after preconception exposure to PFOS.

In C. elegans, yolk proteins are synthesized in the intestine of adult hermaphrodites and transported to the germline, where yolk protein constitutes 37 % of the total protein in embryos [22]. The vit gene family encodes a group of yolk protein vitellogenins and plays a critical role in oocyte nutrient loading (Suppl. Fig. S1) [20], [21], [25]. Given the high metabolic cost of vitellogenin synthesis [21], [42], the vitellogenin genes are tightly regulated by multiple factors [20], [43], [44], such as nutritional status, environmental conditions, and the depletion of parental energy and tissues [20], [22], [43], [44]. In addition, there is a known compensation mechanism between yolk proteins YP170 (including YP170A and YP170B) and YP115/88: when the synthesis of one is suppressed, the other increases within the hermaphrodite parent worms to meet reproductive demands and adapt to environmental changes [45]. Thus, this compensatory mechanism may explain the discrepancy observed in our study: an increase in VIT-2 levels transferred into embryos while vit-6 expression is reduced in parent worms. Additional studies are required to determine the roles of PFOS and PFBS in the upstream transcriptional regulation of vitellogenins, such as unc-62, which is a homolog of human Meis homeobox 1 that is essential for embryonic development, reproduction, and aging [46]. As a key transcriptional activator of vitellogenins, loss of function unc-62 increases the expression of nearly all intestinal genes, including the vit family [46]. However, the impact of PFAS on unc-62 in C. elegans remains poorly understood.

Along with yolk protein synthesis, transportation of these yolk proteins to the germline is another critical step of nutrient loading to oocytes, via receptor-mediated endocytosis by rme-2 [22], [23]. The reduced yolk nutrients may affect offspring survival and development [20], [21] as observed in our previous study on delayed development and growth from F1 offspring after preconception exposure to PFOS and PFBS [11]. Although disruption in nutrient transport to yolk can lead to abnormal oocyte formation, reduced egg production, and lower embryo viability [17], [26], others reported that lack of yolk in F1 embryos (i.e., due to knocking out rme-2) does not affect reproduction capacities, such as brood size, reproductive timing, or embryo viability [18], [23]. Thus, the effects of preconception exposure to PFOS or PFBS on reduced reproductive capacity observed in our previous study may not be directly linked with reduced nutrient loading in oocytes and reduced rme-2 expression.

PFOS exposure has been previously reported to increase oxidative stress and inflammation, leading to insulin resistance and thereby disrupting IIS [47], [48]. By altering insulin receptor signaling and downstream pathways, such as activating protein kinase B (AKT) and FOXO1, PFOS exposure affects glucose homeostasis in adipose tissues and cells [49], [50], [51]. In zebrafish, maternal exposure to PFOS reduced the pancreatic islet size in both parents and offspring, dependent on Nrf2a [9], [36], [37], [38] and high concentrations of PFBS disrupted insulin receptor signaling through mechanisms comparable to those of PFOS, though its toxic effects were less than those of PFOS [10], [52]. In C. elegans, daf-2 (the homolog of IIS receptor) and its downstream target daf-16 (the homolog of Forkhead Box O) mitigate the effects on the reproduction caused by both PFOS and PFBS, which is consistent with the previous reports, possibly by regulating lipoprotein synthesis and energy metabolism [42], [43]. However, the significance of the current observations that preconception exposure to PFOS reduced embryo nutrient loading independent of daf-16 and rme-2 is unclear.

In addition to the insulin receptor signaling pathway, numerous studies indicate that PFOS activates peroxisome proliferator-activated receptor-α (PPAR-α), leading to hepatomegaly and affecting various processes regulated by PPARα in mice [33]. The current results show that preconception exposure to PFOS may reduce reproductive capacity independent of nhr-49, a homolog of mammalian PPARs in C. elegans [7], [53]. This finding is consistent with others reporting that PFOS-induced neonatal lethality and delayed eye-opening in rats are not dependent on PPARα activation [54].

Like PFOS, the current results suggest that preconception exposure to PFBS reduced reproductive capacity dependent on daf-2/daf-16 and nhr-49. This result is consistent with previous reports that low-dose PFBS exposure in early-life rats exhibited enhanced signaling pathways related to PPAR and unsaturated fatty acid biosynthesis [55]. Moreover, PFBS increased fat accumulation in 3T3-L1 and HepG2 cells via PPARγ-dependent pathway [34], [40]. However, it is less clear if preconception exposure to PFBS is linked with altered nutrient loading to oocytes and rme-2 expression dependent on nhr-49 seen in the current study. Based on current and previous observations that preconception exposure to PFBS reduced reproductive capacity without altering nutrient transport and loading to embryos, and delayed growth and development of the second generational worms, it is likely that the quality of nutrients, rather than quantity, in embryos, may have been affected by preconception exposure to PFBS. This will need to be further determined.

Current and previous observations show that PFOS disrupts yolk protein transportation, lipid metabolism [11], [37], pancreatic development [38], and fat storage during embryogenesis [9], [36], [39]. PFBS, on the other hand, primarily influences fat synthesis and lipid metabolism, possibly due to its shorter chain length and faster elimination [4], [10], [11], [52]. The different outcomes following PFOS or PFBS exposure may result from varying internal concentrations of PFOS vs. PFBS. PFOS has a higher bioaccumulation potential and a longer half-life, as observed across various models, compared to PFBS [3]. Previous research has demonstrated that PFBS, much like PFOS, is rapidly absorbed and distributed throughout tissues [56]. However, tissue concentrations of PFBS were 5–40 times lower than those of PFOS at similar exposure levels, likely due to PFBS’s faster elimination rates across species [4], [56]; PFBS’s biological half-life varies significantly, approximately 4.5 hours in male rats, 95 hours in male monkeys, and 26 days in humans [4], [56], [57]. Although both compounds have similar tissue distribution patterns, PFBS is found in lower concentrations in liver and lung tissues, possibly due to differences in solubility, protein binding, and active transport mechanisms [58], [59], [60]. It was previously determined that even though a high concentration of PFBS (2000 μM) was used compared to PFOS (40 μM), internal concentrations of PFBS were significantly lower than those of PFOS-treated worms and embryos of C. elegans; 223 ng/mg DNA in worms and 23.6 ng/mg DNA in embryos with preconception exposure to 40 μM PFOS, vs. 4.6 ng/mg DNA in worms and 3.3 ng/mg DNA in embryos with preconception exposure to 2000 μM PFBS [11]. Thus, the current observations that the effects of preconception exposure to PFBS, which were less than those of PFOS, may have resulted from lower internal PFBS concentrations than PFOS.

Despite strict PFAS usage regulations, PFOS and PFBS continue to accumulate in the environment [2]. A recent water quality report of Pampulha Lake in Brazil indicates that PFBS had increased to its highest observed concentration, likely due to it replacing PFOS in the chemical industry, which resulted in a higher accumulation of PFBS in the fish from the lake [61]. Studies in China have also detected both PFOS and PFBS in dairy products, likely transferred through cows' drinking water and feed, with PFOS showing a higher accumulation rate in milk (30 %) compared to PFBS (9 %) [62]. Although PFBS appears less toxic than PFOS in comparative studies and human exposure to high experimental concentrations of PFBS is unlikely, there is still a need to determine the role of long-term repeated exposure to PFBS in humans.

While the results provide valuable insights, there are some limitations to consider. As mentioned earlier, the doses of PFOS and PFBS used in this study were based on our previous reports and are significantly higher than the levels typically encountered through natural environmental exposure in daily life [11]. These elevated concentrations were necessary to achieve comparable internal levels and facilitate mechanistic investigations in C. elegans. However, this raises questions about the direct relevance of the findings to real-world exposure scenarios. Additionally, the dosage applied to C. elegans cannot be directly extrapolated to humans due to fundamental differences in physiology, metabolism, and exposure pathways. Thus, while the results offer valuable insights into the potential mechanisms of action of PFOS and PFBS, further studies are needed to assess their effects under conditions that more closely mimic environmentally relevant exposures.

In conclusion, the current results show that preconception exposure to PFOS significantly reduced nutrient loading to embryos via vit-6 and rme-2 dependently, and daf-2 and daf-16 played a role in altering the reproductive capacity. Preconception exposure to PFBS did not affect nutrient loading but reduced reproductive health via daf-2, daf-16, and nhr-49. In addition, preconception exposure to PFOS and PFBS has no multigenerational effect on the reproductive health of F1 offspring worms. Overall, PFBS, as a substitute for PFOS, impairs lipid metabolism and development at higher doses than PFOS, but its safety under prolonged, low-dose exposure requires further investigation.

CRediT authorship contribution statement

Sida Li: Methodology, Visualization, Formal analysis, Investigation, Writing – original draft. Yiren Yue: Investigation, Formal analysis. Zhuojia Qian: Investigation, Formal analysis. Zixuan Teng: Investigation, Formal analysis. John M. Clark: Conceptualization, Writing, Funding acquisition. Alicia R. Timme-Laragy: Conceptualization, Writing, Funding acquisition. Yeonhwa Park: Conceptualization, Project administration, Supervision, Funding acquisition, Writing – review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This material is based upon work supported by NIH R01ES028201.

Handling Editor: Prof. L.H. Lash

Footnotes

Appendix A

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.toxrep.2025.101966.

Appendix A. Supplementary material

Supplementary material

mmc1.docx (653.3KB, docx)

Data availability

Data will be made available on request.

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Associated Data

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Supplementary Materials

Supplementary material

mmc1.docx (653.3KB, docx)

Data Availability Statement

Data will be made available on request.

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