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. Author manuscript; available in PMC: 2024 Feb 5.
Published in final edited form as: Environ Res. 2023 Oct 20;240(Pt 2):117435. doi: 10.1016/j.envres.2023.117435

Neonatal per- and polyfluoroalkyl substance exposure in relation to retinoblastoma

Yixin Chen a, Kimberly C Paul b, Douglas I Walker c, Dean P Jones d,e, Xuexia Wang f, Beate R Ritz a,b, Julia E Heck a,g,*
PMCID: PMC10842486  NIHMSID: NIHMS1938243  PMID: 37866539

Abstract

Background:

Neonatal per- and polyfluoroalkyl substance (PFAS) exposure can disrupt hormonal homeostasis and induce neuro- and immunotoxicity in children. In this exploratory study, we investigated associations between PFAS levels in neonatal dried blood spots and retinoblastoma risk.

Materials and methods:

This study included 501 retinoblastoma cases born from 1983 to 2011 and 899 controls frequency-matched by birth year (20:1 matching ratio), born to 755 US-born and 366 Mexico-born mothers in California. Perfluorooctanesulfonic acid (PFOS), perflurooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) feature intensities were identified from neonatal blood spots from California newborn Genetic Disease Screening Program. Using logistic regression, we assessed whether an interquartile range (IQR) increase of PFAS levels or having above-mean levels of PFAS in blood affects retinoblastoma risk overall or its subtypes (i.e., unilateral, bilateral). We assessed children of US-born and Mexico-born mothers, separately.

Results and Discussion:

Among all children, above-mean PFOS levels at birth increased the odds of retinoblastoma overall by 29% (95% Confidence Interval (CI): 1.00, 1.67) and unilateral retinoblastoma by 42% (95% CI: 1.03, 1.97). For children of Mexico-born mothers, we estimated the highest odds of retinoblastoma overall (adjusted odds ratio (aOR): 1.67; 95% CI: 1.06, 2.66) and bilateral retinoblastoma (aOR: 2.06; 95% CI: 1.12, 3.92) with above-mean PFOS levels. Among children of US-born mothers, higher PFOS levels increased the odds of unilateral retinoblastoma by 15% (95% CI: 0.99, 1.35) for each IQR increase and by 71% among children with above-mean PFOS levels (95% CI: 1.04, 2.90). In addition, for children of US-born mothers, PFOA increased the odds of retinoblastoma overall (aOR: 1.41; 95% CI: 1.00, 2.02 for above-mean levels, aOR: 1.06; 95% CI: 0.98, 1.16 per IQR increase). PFNA was not associated with retinoblastoma risk.

Conclusions:

Our results suggested that PFOS and PFOA might contribute to retinoblastoma risk in children born in California.

Keywords: Per- and polyfluoroalkyl substance, Retinoblastoma, Neonatal dried blood spots, Metabolomics, Mexico-Born, US-Born

1. Introduction

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals widely used in consumer products and industrial applications because of their stain-proof, water-proof, grease-proof, and heat resistant properties (Cadore et al., 2009). Humans can be exposed to PFAS from multiple sources with the primary ones being diet (contaminated food or migration of PFAS from food packaging or cookware), drinking water, consumer products, household dust, and ambient air via routes that include dermal contact, ingestion, and inhalation (D’eon and Mabury, 2011; Domingo, 2010; Jogsten et al., 2012).

Of all types of PFAS, legacy long-chain PFAS such as perfluorooctanesulfonic acid (PFOS), perflurooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA) are the most produced and previously studied in terms of adverse health effects (Agency for Toxic Substances and Disease Registry (ATSDR), 2018). The phase-out of PFOS and PFOA in the US began in 2000 and 2006, (United States Environmental Protection Agency, 2000, 2006) respectively. Blood concentrations of PFOS and PFOA detected in the US population declined >80% and 60% from 1999 to 2014 (Centers for Disease Control and Prevention, 2016). But because the half-life of these ‘forever chemicals’ is long (Centers for Disease Control and Prevention, 2015), PFAS were still detected in >98% of all serum samples in 2013–2014 National Health and Nutrition Examination Survey (NHANES) participants including children ages 3–11 years (Calafat et al., 2019; Ye et al., 2018).

Known adverse health effects of PFAS include disruption of hormonal homeostasis, neuro- and immunotoxicity in children, and there is a growing interest in understanding all of the health impacts of early-life exposure to PFAS on child health (Anderko and Pennea, 2020). PFAS can be passed from an expectant mother to her developing offspring via placental transfer and breastfeeding (Sunderland et al., 2019). Toxicity to the developing eye was reported in laboratory animals for PFOA and PFOS, with evidence of gene suppression related to the structural integrity of the eye’s lens (Yeung et al., 2007) and delayed eye opening (Lau et al., 2003). Prenatal PFAS exposure also appears to contribute to adverse birth outcomes such as preterm birth and low birthweight, (Meng et al., 2018; Wikström et al., 2020) which may be risk factors for retinoblastoma (Spector et al., 2009; Seppälä et al., 2021). Carcinogenicity of PFAS has been investigated in adults, and PFOA has been classified as a Group 2B carcinogen by the International Agency for Research on Cancer (International Agency for Research on Cancer, 2016).

A ‘two-hit hypothesis’ has been proposed by Knudson to explain genetic mechanisms underlying retinoblastoma as two separate mutation events must occur for this cancer to be initiated (Knudson, 1971). There are two clinical forms of retinoblastoma: hereditary (40%) and non-hereditary (60%) (Rao and Honavar, 2017). In non-heritable retinoblastoma, both mutations occur in a single retinal cell (somatic mutation), while in heritable retinoblastoma, the first RB1 gene mutation occurs in the germline and predisposes the child to the cancer but a second (somatic) mutation in retinal cells is necessary for retinoblastoma development (Rao and Honavar, 2017). All bilateral cases are heritable with most cases usually having a first germline de novo mutation in gametes of paternal origin (Rao and Honavar, 2017; Kato et al., 1994). Among unilateral cases, 10–15% are heritable (Rao and Honavar, 2017). Several risk factors for retinoblastoma were identified in epidemiologic studies. Older paternal age is considered an independent risk factor for hereditary retinoblastoma (Yip et al., 2006). Other risk factors with supportive evidence that need further investigation include being the child of a US-born Hispanic mother, exogenous factors such as low-quality diet, maternal pre-pregnancy underweight, air toxics, low sunlight exposure in early life, parental occupational exposure to hazardous agents, and possibly human papillomavirus infection (Ghosh et al., 2013; Heck et al., 2015b; MacCarthy et al., 2009, Heck et al., 2012, 2015a, Bunin et al., 1989, Heck et al., 2013).

To the best of our knowledge, no previous studies have evaluated the association between PFAS and childhood cancer including retinoblastoma. This exploratory study investigates associations between PFAS we identified in dried neonatal blood spots (i.e., PFOS, PFOA, and PFNA) and the risk of developing childhood retinoblastoma.

2. Methods

Human subject permissions were obtained from the California Committee for the Protection of Human Subjects, the University of California, Los Angeles, and the University of North Texas.

2.1. Study population and sample collection

Our study population belongs to the Smoking and Embryonal Tumor Study, a large population-based case-control study of all childhood cancers. Children born in California from 1983 to 2011 and aged ≤5 years at diagnosis (diagnosed between 1988 and 2013) were included. Cases were identified with International Classification of Childhood Cancer, Third edition (ICCC-3) code 050, (Surveillance Epidemiology and End Results Program, 2008) and were selected from the California Cancer Registry, and controls were frequency-matched by year of birth (20:1 matching ratio) and randomly selected from California birth rolls (Heck et al., 2012). For our untargeted metabolomics sub-study, 1400 mother-child pairs (501 retinoblastoma cases and 899 controls) with available neonatal blood spots were randomly selected from this study population.

In California, neonatal blood samples are routinely obtained from newborns by heel-sticks between 12 and 48 h after birth and placed on specialized filter paper (i.e., Guthrie card), (Pitt, 2010) dried at room temperature for at least 3 h, and mailed to the state laboratory for analyses (California Department of Public Health, 2018). After routine genetic testing, leftover blood spots are stored at −20 °C by the California newborn Genetic Disease Screening Program. We previously reported that the metabolites assessed on these blood spots are largely stable with some variation by the type of metabolite over the years (He et al., 2023). We obtained each mother-child pair’s data from birth records, including demographic and gestational information.

2.2. High-resolution metabolomics

Neonatal blood spots were analyzed using liquid chromatography with high resolution mass spectrometry (LC-HRMS; Thermo Scientific Fusion Orbitrap Tribrid Mass Spectrometer) using established methods (Liu et al., 2020). Samples were punched using a 5 mm hole punch and treated with 2:1 acetonitrile in water (containing a mixture of stable isotopic internal standards). Samples were mixed for 12 h at 0–4 °C in the dark, and then centrifuged to remove particulate matter. The resulting supernatant was analyzed in triplicate using hydrophilic interaction liquid chromatography (HILIC) with positive electrospray ionization (ESI) and C18 hydrophobic reversed-phase chromatography with negative ESI for quantification of PFAS (Liang et al., 2018). The mass spectrometer was operated using ESI mode at a resolution of 120, 000 and a mass-to-charge ratio (m/z) range 85–1275. Blood spot samples were analyzed in batches of 40. To evaluate system performance, we used two separate quality assessment methods. Our first QC sample was NIST 1950, (Simon-Manso et al., 2013) which was analyzed at the beginning and end of the entire analytical run. The second QC sample (Q-Std) included commercially purchased plasma pooled from an unknown number of males and females. Q-Std was analyzed at the beginning, middle, and end of each batch of 40 samples for normalization, control of background noise, batch effect evaluation and post hoc quantification. Raw data files were extracted and aligned using apLCMS (Yu et al., 2009) with modifications by xMSanalyzer (Uppal et al., 2013). Uniquely detected ions consisted of mass-to-charge ratio (m/z), retention time (rt), and ion abundance, referred to as metabolite features. Prior to data analysis, metabolite features were batch corrected using wavelet analysis and we confirmed that there were no batch effects after batch correction (Deng et al., 2019). Only metabolomic features with median coefficients of variation among technical replicates <30% and Pearson correlation >0.7 were included in further analyses.

The HILIC assay was also performed on blank spaces for a sample of cards to assess background contamination of the Guthrie card and we did not find evidence for contamination.

PFAS identification was conducted by matching accurate mass and retention time to authentic reference standards analyzed under identical conditions using tandem mass spectrometry (Go et al., 2015). We were able to identify PFOS, PFOA, and PFNA in our blood sample. The m/z ratio was 498.9302 for PFOS, 412.9666 for PFOA, and 462.9629 for PFNA, while the retention time was 120 s for PFOS, 77 s for PFOA and 137 s for PFNA. PFAS intensities were log2 transformed. For participants with PFAS levels below the detection limits, we used a value equal to half of the minimum feature intensity observed for each PFAS.

Samples were considered outliers based on principal component analysis of their metabolomic profiles, and N = 10 were excluded from our analyses. Our final sample included 497 retinoblastoma cases and 893 control children.

2.3. Statistical analysis

We reported means, standard deviations (SDs), medians, and interquartile ranges (IQRs) for detected PFAS in dried blood spots.

The PFAS were only weakly correlated (∣r∣ < 0.15). We applied unconditional logistic regression models to determine associations between each PFAS (i.e., PFOS, PFOA, PFNA) and retinoblastoma (all cases, unilateral and bilateral only) individually. A model including all available PFAS (i.e., PFOS, PFOA, PFNA) was additionally performed to assess the impacts of all PFAS on retinoblastoma.

According to the Shapiro-Wilk test for skewness and the Lilliefors test for kurtosis, we found the PFAS exposure (i.e., PFOS, PFOA, PFNA) distribution in our study population to be right-skewed (positive skewness coefficients and all P values < 0.0001). Hence, we assessed associations of retinoblastoma with log2-transformed PFAS feature intensities, used the IQR increase as our continuous variable and also dichotomized the PFAS exposure (above vs. below mean).

Data from 1999 to 2000 and 2003–2004 NHANES showed that non-Hispanic white women in the US had higher serum concentrations of PFAS including PFOS, compared to Mexican Americans (Calafat et al., 2007). Although we have previously observed maternal birthplace to be related to retinoblastoma risk among Hispanics, (Heck et al., 2016) the sample size did not allow us to assess associations stratified by maternal birthplace as well as race and ethnicity. Therefore, we tested for interaction between maternal birthplace and PFAS exposure (above mean vs. below mean) only on the additive scale among all children. We found no formally statistically significant additive interaction (confidence intervals for the relative excess risk due to interaction (RERI) crossed the null) (Supplemental Table 1). We nevertheless conducted and report the results for stratified analyses based on maternal birthplace, either US-born or Mexico-born women (all ethnic groups, combined).

To control for confounders in addition to birth year (matching factor), we adjusted for the following covariates that were previously linked to retinoblastoma and/or PFAS exposure, (Buekers et al., 2018; Heck et al., 2012; Jian et al., 2018; Park et al., 2019; Yip et al., 2006) including maternal age (<20, 20–29, ≥30), maternal race and ethnicity (White non-Hispanic, Hispanic of any race, other), US-born mother (Yes/No), mother’s years of education (≤11 years, 12 years, 13–15 years, ≥16 years), and census-based neighborhood SES (Yost et al., 2001). For analyses among Mexico-born and US-born mothers, the covariate for maternal birthplace was left out of the model.

We examined the heterogeneity of estimated retinoblastoma risks and its subtypes with PFAS exposure by conducting Cochran’s Q tests.

All statistical tests were performed using R version 4.2.2. A p-value of <0.05 was used to formally define statistical significance for the test for heterogeneity.

3. Results

In our study population, the average age of diagnosis for unilateral retinoblastoma was 22.1 months (SD = 14.5 months), while the average age of diagnosis for bilateral retinoblastoma was 9.3 months (SD = 8.7 months). Table 1 presents the demographic characteristics of the 1390 study subjects. Among all, 755 (54.3%) children had US-born mothers, 366 (26.3%) had Mexico-born mothers and 269 (19.4%) had mothers born in other foreign countries. A greater proportion of fathers of cases were ≥30 years of age (57.9%, 288 of 497) than of controls (53.1%, 474 of 893). Parents of children with bilateral retinoblastoma had more years of formal education, with 22.0% of mothers and 22.5% of fathers having at least a college degree versus 16% of parents in controls.

Table 1.

Demographic characteristics of the study population.

Characteristics, N (%) Control (N =
893)		 Case (N = 497)
Unilateral (N =
279)		 Bilateral (N =
218)
Birth year
1983–1990 185 (20.7) 51 (18.3) 20 (9.2)
1991–2000 353 (39.5) 111 (39.8) 98 (45.0)
2001–2011 355 (39.8) 117 (41.9) 100 (45.9)
Maternal birthplace
US 483 (54.1) 156 (55.9) 116 (53.2)
Mexico 236 (26.4) 66 (23.7) 64 (29.4)
Other foreign countries 174 (19.5) 57 (20.4) 38 (17.4)
Maternal age
<20 100 (11.2) 25 (9.0) 23 (10.6)
20–29 462 (51.7) 159 (57.0) 106 (48.6)
≥30 331 (37.1) 95 (34.1) 89 (40.8)
Paternal age
<20 32 (3.6) 10 (3.6) 10 (4.6)
20–29 387 (43.3) 115 (41.2) 68 (31.2)
≥30 474 (53.1) 150 (53.8) 138 (63.3)
Missing 0 4 2
Maternal race/ethnicity
White non-Hispanics 303 (33.9) 83 (29.8) 69 (31.7)
Hispanic of any race 422 (47.3) 131 (47.0) 105 (48.2)
Other/not specified 168 (18.8) 65 (23.3) 44 (20.2)
Paternal race/ethnicity
White non-Hispanics 261 (29.2) 81 (29.0) 63 (28.9)
Hispanic of any race 407 (45.6) 125 (44.8) 102 (46.8)
Other/not specified 225 (25.2) 73 (26.2) 53 (24.3)
Census-based socioeconomic status index level
1 (Low) 194 (21.7) 71 (25.5) 51 (23.4)
2 248 (27.8) 62 (22.2) 61 (28.0)
3 196 (22.0) 63 (22.6) 39 (17.9)
4 135 (15.1) 50 (17.9) 45 (20.6)
5 (High) 116 (13.0) 32 (11.5) 21 (9.6)
Missing 4 1 1
Maternal education
≤11 years 252 (28.2) 68 (24.4) 71 (32.6)
12 years 233 (26.1) 80 (28.7) 52 (23.9)
13–15 years 155 (17.4) 56 (20.1) 35 (16.1)
≥16 years 145 (16.2) 46 (16.5) 48 (22.0)
Missing 108 29 12
Paternal education
≤11 years 214 (24.0) 66 (23.7) 59 (27.1)
12 years 226 (25.3) 78 (28.0) 54 (24.8)
13–15 years 146 (16.4) 40 (14.3) 31 (14.2)
≥16 years 142 (15.9) 52 (18.6) 49 (22.5)
Missing 165 43 25
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Due to the similarity of results between the model with all three PFAS and the models for each individual PFAS, we only reported results for PFAS from each individual model. Table 2 shows the log2-transformed PFAS feature distribution in our study. Mean values for PFAS were all slightly higher in cases than in controls, but median values were similar. More cases had an above-mean value for PFOS and PFOA than controls (PFOS: 74.9% vs. 70.3%; PFOA: 75.9% vs. 73.5%), but this was reversed for PFNA (PFNA: 71.2% of cases vs. 75.1% of controls). Among children of Mexico-born mothers, cases tended to have lower measures for PFOA and PFNA than controls, but not for PFOS. For cases and controls, children with US-born mothers had higher PFOS measures than those children with Mexico-born mothers.

Table 2.

The distribution of PFAS a in the study population, by case-control status and maternal birthplace.

All cases (N = 497)
 Unilateral (N = 279)
 Bilateral (N = 218)
 Control (N = 893)
Mean (SD) Median (IQR) Mean (SD) Median (IQR) Mean (SD) Median (IQR) Mean (SD) Median (IQR)
Among all mothers
PFOS 15.5 (2.9) 16.2 (1.6) 15.6 (2.8) 16.3 (1.6) 15.4 (3.0) 16.1 (1.7) 15.4 (2.9) 16.2 (1.8)
PFOA 17.0 (3.3) 18.2 (1.8) 17.1 (3.2) 18.1 (1.9) 17.0 (3.5) 18.2 (1.6) 16.8 (3.5) 18.1 (2.0)
PFNA
 15.7 (1.3)
 16.0 (0.9)
 15.6 (1.4)
 16.0 (0.9)
 15.7 (1.2)
 16.0 (0.8)
 15.6 (1.4)
 16.1 (0.8)
Among US-born mothers
All cases (N = 272)
 Unilateral (N = 156)
 Bilateral (N = 116)
 Control (N = 483)
PFOS 16.1 (2.1) 16.4 (1.5) 16.3 (2.0) 16.5 (1.4) 16.0 (2.2) 16.3 (1.6) 15.9 (2.5) 16.4 (1.6)
PFOA 17.1 (3.2) 18.2 (1.6) 17.2 (2.9) 18.0 (1.6) 17.0 (3.6) 18.3 (1.5) 16.8 (3.6) 18.1 (2.0)
PFNA
 15.6 (1.4)
 16.0 (0.9)
 15.6 (1.5)
 16.0 (1.0)
 15.7 (1.3)
 16.1 (0.9)
 15.6 (1.5)
 16.1 (0.8)
Among Mexico-born mothers
All cases (N = 130)
 Unilateral (N = 66)
 Bilateral (N = 64)
 Control (N = 236)
PFOS 14.7 (3.6) 15.9 (1.8) 14.6 (3.6) 15.9 (1.9) 14.7 (3.5) 15.9 (1.5) 14.4 (3.3) 15.6 (2.4)
PFOA 16.7 (3.6) 18.1 (2.2) 16.3 (3.9) 17.9 (2.7) 17.1 (3.2) 18.2 (1.5) 17.0 (3.4) 18.1 (1.7)
PFNA 15.6 (1.4) 15.9 (0.8) 15.6 (1.4) 15.9 (0.9) 15.5 (1.4) 15.9 (0.7) 15.7 (1.4) 16.0 (0.7)
Dichotomized above-mean exposure b
Among all mothers
PFOS, N (%) 372 (74.9) 214 (76.7) 158 (72.5) 628 (70.3)
PFOA, N (%) 377 (75.9) 208 (74.6) 169 (77.5) 656 (73.5)
PFNA, N (%)
 354 (71.2)
  
 193 (69.2)
  
 161 (73.9)
  
 671 (75.1)
  
Among US-born mothers
All cases (N = 272)
 Unilateral (N = 156)
 Bilateral (N = 116)
 Control (N = 483)
PFOS, N (%) 224 (82.4) 134 (85.9) 90 (77.6) 378 (78.3)
PFOA, N (%) 210 (77.2) 120 (76.9) 90 (77.6) 345 (71.4)
PFNA, N (%)
 190 (69.9)
  
 108 (69.2)
  
 82 (70.7)
  
 356 (73.7)
  
Among Mexico-born mothers
All cases (N = 130)
 Unilateral (N = 66)
 Bilateral (N = 64)
 Control (N = 236)
PFOS, N (%) 85 (65.4) 41 (62.1) 44 (68.8) 126 (53.4)
PFOA, N (%) 92 (70.8) 42 (63.6) 50 (78.1) 181 (76.7)
PFNA, N (%) 93 (71.5) 45 (68.2) 48 (75.0) 178 (75.4)
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Note.

Abbreviations: SD, standard deviation; IQR, interquartile range; PFAS, per- and polyfluoroalkyl substances; PFOS, perfluorooctane sulfonic acid; PFOA, perfluorooctanoic Acid; PFNA, perfluorononanoic acid.

a

The descriptive statistics were calculated on the log2-transformed scale.

b

The exposures were dichotomized based on mean value of the log2-transformed PFAS feature intensities of all study population (N = 1390).

Table 3 shows the associations between neonatal PFAS exposure and retinoblastoma. We observed that in children with above-mean PFOS measure the odds of developing retinoblastoma were increased (adjusted odds ratio (aOR) = 1.29; 95% confidence interval (CI): 1.00, 1.67), especially among unilateral cases (aOR = 1.42; 95% CI: 1.03, 1.97). This was seen in children of US-born mothers for unilateral retinoblastoma (aOR = 1.71; 95% CI: 1.04, 2.90), and in children of Mexico-born mothers for retinoblastoma overall (aOR = 1.67, 95% CI: 1.06, 2.66) but especially for bilateral cases (aOR = 2.06; 95% CI: 1.12, 3.92). For unilateral disease, the odds were slightly elevated among children of US-born mothers for PFOS [per IQR increase aOR = 1.15; 95% CI: 0.99, 1.35] and for PFOA (per IQR increase aOR = 1.09; 95% CI: 0.98, 1.23) when we used a continuous measure. With above the mean PFOA, the odds of retinoblastoma were increased by 41% (95% CI: 1.00, 2.02), compared to children of US-born mothers with below the mean PFOA. Among children of Mexico-born mothers, we found null associations of all retinoblastoma with exposure to PFOA and PFNA when using either a continuous measure or dichotomized exposure. Cochran’s Q tests did not indicate heterogeneity of retinoblastoma across subtypes.

Table 3.

Effect estimates and 95% confidence interval for retinoblastoma in relation to neonatal PFAS exposure a.

 
 PFOS
 PFOA
 PFNA
Crude ORc (95% CI) Adjusted OR (95% CI) Crude ORc (95% CI) Adjusted OR (95% CI) Crude ORc (95% CI) Adjusted OR (95% CI)
Per IQR increase
Among all mothers d
Retinoblastoma 1.02 (0.95, 1.09) 1.02 (0.95, 1.09) 1.03 (0.97, 1.09) 1.03 (0.97, 1.09) 1.00 (0.94, 1.07) 1.00 (0.94, 1.07)
Unilateral cases 1.03 (0.95, 1.13) 1.03 (0.95, 1.14) 1.03 (0.96, 1.12) 1.04 (0.96, 1.13) 0.98 (0.91, 1.06) 0.98 (0.91, 1.06)
Bilateral cases 1.00 (0.91, 1.09) 0.99 (0.91, 1.09) 1.02 (0.94, 1.11) 1.02 (0.94, 1.11) 1.03 (0.94, 1.13) 1.03 (0.94, 1.13)
Among US-born mothers e
Retinoblastoma 1.09 (0.97, 1.23) 1.09 (0.97, 1.23) 1.06 (0.97, 1.15) 1.06 (0.98, 1.16) 1.00 (0.92, 1.09) 1.00 (0.92, 1.09)
Unilateral cases 1.14 (0.99, 1.34) 1.15 (0.99, 1.35) 1.08 (0.97, 1.21) 1.09 (0.98, 1.23) 0.99 (0.90, 1.09) 0.98 (0.89, 1.09)
Bilateral cases 1.03 (0.90, 1.22) 1.02 (0.88, 1.20) 1.03 (0.93, 1.16) 1.04 (0.94, 1.17) 1.02 (0.91, 1.16) 1.02 (0.91, 1.16)
Among Mexico-borne mothers
Retinoblastoma 1.04 (0.93, 1.17) 1.04 (0.93, 1.17) 0.96 (0.86, 1.08) 0.97 (0.86, 1.09) 0.96 (0.85, 1.09) 0.95 (0.84, 1.08)
Unilateral cases 1.03 (0.90, 1.20) 1.04 (0.90, 1.22) 0.91 (0.80, 1.05) 0.93 (0.81, 1.08) 0.99 (0.86, 1.17) 0.99 (0.85, 1.17)
Bilateral cases
 1.06 (0.92, 1.25)
 1.04 (0.89, 1.23)
 1.02 (0.88, 1.22)
 1.02 (0.87, 1.22)
 0.93 (0.80, 1.10)
 0.92 (0.78, 1.09)
Above mean exposure VS Below mean exposure b
Among all mothers d
Retinoblastoma 1.32 (0.91, 1.95) 1.29 (1.00, 1.67) 1.37 (0.97, 1.95) 1.16 (0.90, 1.50) 0.81 (0.58, 1.13) 0.79 (0.62, 1.02)
Unilateral cases 1.40 (1.03, 1.93) 1.42 (1.03, 1.97) 1.06 (0.78, 1.45) 1.10 (0.81, 1.51) 0.73 (0.54, 0.98) 0.73 (0.54, 0.99)
Bilateral cases 1.16 (0.84, 1.63) 1.14 (0.82, 1.62) 1.30 (0.92, 1.86) 1.29 (0.91, 1.85) 0.89 (0.64, 1.26) 0.88 (0.62, 1.25)
Among US-born mothers e
Retinoblastoma 1.28 (1.00, 1.65) 1.30 (0.89, 1.93) 1.15 (0.89, 1.48) 1.41 (1.00, 2.02) 0.79 (0.62, 1.02) 0.81 (0.58, 1.14)
Unilateral cases 1.69 (1.05, 2.85) 1.71 (1.04, 2.90) 1.33 (0.88, 2.06) 1.43 (0.94, 2.22) 0.80 (0.54, 1.19) 0.82 (0.54, 1.23)
Bilateral cases 1.01 (0.62, 1.67) 0.95 (0.58, 1.60) 1.45 (0.90, 2.38) 1.45 (0.90, 2.40) 0.82 (0.52, 1.29) 0.81 (0.51, 1.30)
Among Mexico-borne mothers
Retinoblastoma 1.68 (1.08, 2.64) 1.67 (1.06, 2.66) 0.74 (0.46, 1.20) 0.76 (0.47, 1.26) 0.78 (0.49, 1.29) 0.77 (0.46, 1.28)
Unilateral cases 1.43 (0.82, 2.52) 1.42 (0.80, 2.58) 0.53 (0.30, 0.96) 0.57 (0.31, 1.05) 0.70 (0.39, 1.30) 0.70 (0.38, 1.32)
Bilateral cases 2.08 (1.16, 3.84) 2.06 (1.12, 3.92) 1.13 (0.59, 2.28) 1.18 (0.61, 2.42) 0.90 (0.48, 1.76) 0.90 (0.46, 1.84)
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Note.

Abbreviations: OR, odds ratio; CI, confidence interval; IQR, interquartile range; PFAS, per- and polyfluoroalkyl substances; PFOS, perfluorooctane sulfonic acid; PFOA, perfluorooctanoic Acid; PFNA, perfluorononanoic acid.

a

The exposure assessment was based on the log2-transformed scale.

b

The exposures were dichotomized based on mean value of the log2-transformed PFAS feature intensities of all study population (N = 1390).

c

The crude model was adjusted for birth year (matching factor).

d

The adjusted model was adjusted for birth year (matching factor), maternal age, maternal race and ethnicity, maternal birthplace, maternal education attainment, census tract SES.

e

The adjusted model was adjusted for birth year (matching factor), maternal age, maternal race and ethnicity, maternal education attainment, census tract SES.

4. Discussion

This is the first study linking neonatal PFAS exposure to retinoblastoma. We utilized PFAS metabolomic intensities in neonatal dried blood spots and found positive associations for retinoblastoma at higher levels of PFOS, especially unilateral retinoblastoma among all children. When stratifying by maternal birthplace, children of US-born mothers were more likely to develop unilateral retinoblastoma with higher neonatal PFOS exposure, while for children of Mexico-born mothers we found stronger associations with bilateral retinoblastoma. An increased odds in retinoblastoma was also estimated for higher levels of PFOA among children of US-born mothers, although no associations were observed among all children and children of Mexico-born mothers.

Several pathways involved in lipid metabolism such as fatty acid metabolism and the glycerophospholipid pathway are known to be related to retinoblastoma (Kohe et al., 2015; Yan et al., 2023). Fatty acid metabolism has been found to be disturbed among overweight and obese Hispanic children, (Alderete et al., 2019) while the glycerophospholipid pathway was altered among children diagnosed with nonalcoholic fatty liver disease related to PFAS exposure (Jin et al., 2020). In addition, a meta-analysis reported perturbations in lipid metabolism with PFAS exposure (Guo et al., 2022). The common pathways altered by PFAS exposure and previously reported to coincide with retinoblastoma cancer status supports the link we found between PFAS and retinoblastoma.

In our previous study, specific metabolites including linoleic acid, purine and N-Acetylneuraminic acid, as well as the vitamin A metabolism pathway as being related to retinoblastoma, suggesting a role for immune response in retinoblastoma (Yan et al., 2023). Although findings are not entirely consistent, immunomodulatory effects of PFAS have been previously described in epidemiologic as well as experimental studies (Ehrlich et al., 2023). For example, PFAS exposure was associated with lower levels of vaccine antibodies (especially for PFOA, PFNA, PFOS, Perfluorodecanoic acid (PFDA)), (Grandjean et al., 2012; Timmermann et al., 2020; Shih et al., 2021; Timmermann et al., 2022) and increased risks of infectious diseases (especially for PFOA, PFOS) (Dalsager et al., 2021; Impinen et al., 2019; Kvalem et al., 2020; Dalsager et al., 2016). Experimental studies suggested serum IgM and/or IgG concentrations to be negatively associated with PFOA (DeWitt et al., 2008; Yang et al., 2002) and PFOS (Lefebvre et al., 2008; Keil et al., 2008). The US National Toxicology Program declared that PFOA and PFOS are immunotoxins, thus it is possible that neonatal PFAS exposures affect children’s risk of retinoblastoma by impacting immune responses (National Toxicology Program, 2015).

Our study failed to detect any formally statistically significant additive interactions between maternal birthplace and PFAS exposures on the risk of retinoblastoma or its subtypes. This result reflects either insufficient sample size or the absence of effect modification by maternal birthplace. Nevertheless, the observed differences in effect estimates for children of US-born mothers and Mexico-born mothers will need to be reassessed in future larger studies.

Our findings showed stronger associations of PFOS exposure with unilateral retinoblastoma among children of US-born mothers, compared to those with Mexico-born mothers. One reason for the differences in the observed PFAS burden may be that US-born persons tend to consume lower-quality diets, including more fast food, compared to Mexican-born Americans (Duffey et al., 2008; Sharkey et al., 2011). PFAS coatings are commonly used for fast food packaging due to their grease-proof properties, (Schaider et al., 2017) and serum PFOS levels were previously found to be positively associated with the consumption of fast food, pizza, and microwave popcorn (Susmann et al., 2019). Furthermore, low-quality diets, including more fried foods, have previously been associated with higher risk of retinoblastoma (Lombardi et al., 2015). Because of the different dietary habits, children of US-born mothers might have higher PFOS levels than children of Mexico-born mothers, which subsequently puts them at a higher risk of unilateral retinoblastoma.

Increased odds of bilateral retinoblastoma were only seen among children of Mexico-born mothers. PFOS and PFOA may disturb spermatogenesis, causing chromosomal aneuploidies and DNA fragmentation of sperm cells (Governini et al., 2015). Since a first germline de novo mutation, which is mostly from gametes of paternal origin, is necessary for the development of bilateral retinoblastoma, (Kato et al., 1994; Rao and Honavar, 2017) it is possible that paternal or maternal exposure to PFAS preconceptionally predisposes the offspring to an increased risk of bilateral retinoblastoma. However, we did not have further information on specific mutations nor information on parental exposures to PFAS before conception, which might confound the associations between children’s neonatal PFAS exposure and the odds of bilateral retinoblastoma.

Exposure to PFNA showed mostly inverse associations, with confidence intervals crossing the null. However, PFNA was reported to cause miscarriage in several epidemiologic studies (Jensen et al., 2015). If PFNA reduced fetal survival, a live birth bias could occur, (Liew et al., 2015) and could explain our inverse associations for PFNA.

The study population consisted of retinoblastoma cases randomly selected from the California Genetic Disease Screening Program. Thus, we avoided selection bias due to differential participation in our study as neonatal bloodspots are obtained from more than 99% of all California children. The use of metabolomic markers and state records avoids recall bias.

We acknowledge several limitations. First, there may be confounding due to unknown or unmeasured parental risk factors such as maternal diet. Second, we assumed that the one-time collection of neonatal blood spots was representative of average exposure of PFAS during pregnancy. These neonatal samples are generally collected between 12 and 48 h after birth (California Department of Public Health, 2018). Given the relatively long half-life of the selected PFAS – known as forever chemicals - it is likely that PFAS concentrations did not degrade fast during pregnancy or were affected by the timing of sample collection after birth. Maternal serum PFAS and cord blood PFAS concentration were found to be strongly correlated (Kingsley et al., 2018). Furthermore, it has been reported that the elimination of PFOS, PFOA, PFNA from serum increases throughout pregnancy, with serum PFAS concentrations decreasing by 3–7% per month (Ding et al., 2020; Oh et al., 2022). Hence, the average exposure for neonates during pregnancy, should be higher than the levels we detected. Lastly, of the four legacy long-chain PFAS, we only identified three (i.e., we did not identify PFHxS). Future research is needed that explores a broader range of PFAS compounds to provide more comprehensive understanding of PFAS exposure and retinoblastoma risk.

This is the first paper to examine PFAS in relation to any type of pediatric cancer. Our study suggests adverse effects of neonatal exposure to PFAS, especially PFOS and PFOA, on retinoblastoma. Children of US-born mothers might be at higher risk of unilateral retinoblastoma with the exposure of PFOS and PFOA, while children of Mexico-born mothers might be at higher risk of bilateral retinoblastoma with the exposure of PFOS. Our study is warranted for further investigation on PFAS and childhood retinoblastoma and specifically among US-born and Mexico-born Mexican Americans.

Supplementary Material

Supplemental table

Acknowledgment

This work was supported by the National Institutes of Health grants R03CA252788, R21ES018960, R21ES019986 and the California Tobacco-Related Disease Research Program of the University of California, grant number 24RT-0033H. Ms. Yixin Chen was partially supported by National Cancer Institute, Department of Health and Human Services, Grant T32CA009142. The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscripts.

The biospecimens and data used in this study were obtained from the California Biobank Program, (SIS request number 565). The California Department of Public Health is not responsible for the results or conclusions drawn by the authors of this publication.

Footnotes

Authors credit statement

Ms. Chen: Methodology, Software, Formal analysis, Writing – original draft, Visualization; Dr. Paul: Validation, Writing – review & editing; Dr. Walker and Dr. Jones: Resources, Writing – review & editing; Dr. Wang: Validation, Writing – review & editing; Dr. Ritz: Supervision, Validation, Writing – review & editing; Dr. Heck: Conceptualization, Supervision, Validation, Writing – review & editing, Project administration, Funding acquisition

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.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.envres.2023.117435.

Data availability

Data sharing is regulated by the California Committee for the Protection of Human Subjects. With appropriate approvals, data will be shared on request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental table
NIHMS1938243-supplement-Supplemental_table.docx (20.8KB, docx)

Data Availability Statement

Data sharing is regulated by the California Committee for the Protection of Human Subjects. With appropriate approvals, data will be shared on request.

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