Table 1.
Human studies – developmental origins of adult reproductive dysfunction associated with environmental factors.
| Environmental Factor | Exposure Window | Study Details/Observation Window | Phenotype | Reference(s) |
|---|---|---|---|---|
| Female | ||||
| DES | In utero (beginning in the first trimester) | 15–22 years of age (n=7/8) | Vaginal clear-cell adenocarcinoma (P<0.00001) | [39, 40] |
| DES | In utero | 16–20 years of age (n=5/6) | Vaginal clear-cell adenocarcinoma | [208] |
| DES | In utero | Diethylstilbestrol Adenosis (DESAD) Project (n=1,655) | Structural anomalies of the cervix or vagina | [47] |
| DES | In utero | Nurses’ Health Study II, prospective cohort study (n=84,446)/25–42 years of age | Endometriosis (RR = 1.8; 95% CI: 1.2–2.8) | [53] |
| DES | In utero | NIEHS Uterine Fibroid Study (n=504 white women)/35–49 years of age | Uterine leiomyoma (OR = 2.4; 95% CI: 1.1–5.4) (n=14/19) | [15] |
| DES | In utero | NIEHS Sister Study (n=19,972 non-Hispanic white women)/35–59 years of age | Greater risk of early fibroid diagnosis (RR = 1.42; 95% CI: 1.13–1.80) | [209] |
| DES | In utero | NIEHS Sister Study (n=3,201 black women)/35–59 years of age | Early-onset uterine fibroids (RR = 2.02; 95% CI: 1.28–3.18) (n=13/42) | [55] |
| DES | In utero (beginning in the first trimester) | Nurses’ Health Study II, prospective cohort study (n=102,164 premenopausal women)/25–42 years of age | Uterine leiomyoma (adjusted HR = 1.21; 95% CI: 1.02–1.43) | [56] |
| DES | In utero | Population-based case-control study (n=310 cases; n=727 controls) | Endometriosis (adjusted OR = 2.0; 95% CI: 0.8–4.9) | [54] |
| PCB | In utero | 8 years of age (n=33) | Greater proportion of shorter fundi lengths (P=0.025), and uteri lengths (P<0.05) | [73] |
| Soy formula | Infancy | Cohort study (females: n=128 soy formula; n=268 cow milk formula)/20–34 years of age | Longer duration of menstrual bleeding (adjusted mean difference, 0.37 days; 95% CI, 0.06–0.68; P=0.02), greater discomfort with menstruation (unadjusted RR = 1.77; 95% CI: 1.04–3.0; (n=23/128) P=0.04) | [51] |
| Soy formula | Infancy | NIEHS Sister Study (n=19,972 non-Hispanic white women)/35–59 years of age | Greater risk of early fibroid diagnosis (RR = 1.25; 95% CI: 0.97–1.61) | [209] |
| Soy formula | Infancy (≤4 months of age) | Avon Longitudinal Study of Parents and Children (ALSPAC) (n=2,920 girls)/8–14.5 years of age | 25% higher risk of menarche (HR = 1.25; 95% CI, 0.92, 1.71) | [62] |
| Soy formula | Infancy | NIEHS Sister Study (n=3,201 black women)/35–59 years of age | Early-onset uterine fibroids (RR = 1.26; 95% CI: 0.83–1.89) (n=19/96) | [55] |
| Soy formula | Infancy | The Black Women’s Health study (n=23,505 premenopausal African-American women)/23–50 years of age | Uterine leiomyoma (IRR = 1.0; 95% CI: 0.86–1.16*) | [59] |
| Soy formula | Infancy | The NIEHS Study of Environment, Lifestyle & Fibroids (SELF) cohort study (n=1,696 African-American women)/23–34 years of age | Uterine fibroid prevalence (adjusted PR = 0.9; 95% CI: 0.7, 1.3*), 32% increase in the diameter of the largest fibroid (95% CI: 6%, 65%), 127% increase in total tumor volume (95% CI: 12%, 358%) | [60] |
| Soy formula | Infancy | Population-based case-control study (n=310 cases; n=727 controls) | Endometriosis (adjusted OR = 2.4; 95% CI 1.2–4.9) | [54] |
| BPA | Adult | Women undergoing IVF (n=174)/18–45 years of age | Decreased number of oocytes (overall and mature) | [69] |
| Male | ||||
| DES | In utero | OMEGA Dutch cohort study (n=4/205 exposed boys; n=8/8,727 unexposed boys) | Increased risk of hypospadias (PR = 21.3; 95% CI: 6.5–70.1) | [80] |
| DES | In utero | Combination US cohort study (n=10/3,916 exposed boys; n=3/1,746 unexposed boys) | Hypospadias prevalence (OR = 1.7; 95% CI: 0.4–6.8) | [81] |
| DES | In utero | Dutch cohort (n=21 exposed men; n=813 unexposed men) | Increased risk of hypospadias (adjusted OR = 2.3; 95% CI: 0.7–7.9) | [79] |
| DES | In utero | Combination cohort study (n=197/1,018 exposed men; n=159/1,018 unexposed men) | Infertility (RR = 1.3; 95% CI: 1.0–1.6) | [82] |
| DES | In utero | Collaborative cohort study (n=1,197 total exposed men; n=1,038 total unexposed men) | Cryptorchidism (RR = 1.9; 95% CI: 1.13.4) (n=38/1197) Epididymal cysts (RR = 2.5; 95% CI: 1.54.3) (n=55/1197) Inflammation/infection of the testes (RR = 2.4; 95% CI: 1.54.4) (n=49/1197) Exposure before 11th week of pregnancy: Cryptorchidism (RR = 2.9; 95% CI: 1.65.2) (n=29/625) Epididymal cyst (RR = 3.5; 95% CI: 2.06.0) (n =38/625) Inflammation/infection of testes (RR = 3.0; 95% CI: 1.75.4) (n=30/625) |
[77] |
| Tobacco smoking particulates | In utero | Cross-sectional European study (n=467/1,770 sons exposed to maternal smoking)/16–27 years of age | 20.1% reduction in sperm concentration (95% CI: 6.8, 33.5), 24.5% reduction in total sperm count (95% CI: 9.5, 39.5), 1.15 ml smaller testis size (95% CI: 0.66, 1.64), 1.85% lower sperm motility (95% CI: 0.46, 3.23), and 0.64% lower morphologically normal sperm (95% CI: −0.02, 1.30) | [90] |
| Tobacco smoking particulates | In utero | Danish “Healthy Habits for Two” cohort (n=347/5,109 sons exposed to maternal smoking)/18–21 years of age | Oligospermia (OR = 2.16; 95% CI: 0.68, 6.87) | [92] |
| PCB; PCDF | In utero | 16–18 years of age (n=12 total exposed men; n=23 total unexposed men) | 37.5% increase in abnormal sperm morphology (P<0.0001), 35.1% reduction in motile sperm (P=0.0058), and 25.5% reduction in rapidly motile sperm (P=0.017) | [93] |
| PFOA; PFOS* | In utero | Danish cohort (n=169)/19–21 years of age | 34% reduction in sperm concentration (P=0.01), and 34% reduction in total sperm count (P=0.001) | [210] |
| Dioxin | Lactation | 18–26 years of age (n=21 breast-fed sons/39) | Decreases in sperm concentration (P=0.002), total sperm count (P=0.02), progressive sperm motility (P=0.03), and total motile sperm count (P=0.01) | [211] |
| TCDD | Infancy (1–9 years), puberty (10–17 years), adulthood* (18–26 years) | 22 years after exposure (n=135 Caucasian men) | Infancy exposure group: decreases in sperm count (P=0.025), progressive sperm motility, (P=0.001), and total number of motile sperm (P=0.01) Puberty exposure group: stimulatory effect on semen parameters |
[91] |
| BPA | Adult | Chinese cohort (n=218 men with and without BPA exposure in the workplace) | Decreases in sperm concentration (adjusted (a)OR = 3.4; 95% CI, 1.4–7.9; P<0.001), total sperm count (aOR = 4.1; 95% CI, 1.7–9.9; P=0.004), sperm viability (aOR = 3.3; 95% CI, 1.4–7.5; P<0.001), and sperm motility (aOR = 2.3; 95% CI, 1.0–5.1; P<0.001) | [212] |
| BPA | Adult | 18–55 years of age (n=190) | Decreases in sperm concentration (adjusted (a)OR = 1.47; 95% CI, 0.85–2.54), total sperm count (aOR = 1.20; 95% CI, 0.71–2.03), sperm motility (aOR = 1.23; 95% CI, 0.83–1.80), and sperm morphology (aOR = 1.25; 95% CI, 0.77–2.06) | [213] |
DES indicates diethylstilbestrol; RR, relative risk; CI, confidence interval; NIEHS, National Institute of Environmental Health Sciences; OR, odds ratio; HR, hazard ratio; PCB, polychlorinated biphenyl;
*
, reported as not statistically significant;
IRR, incidence rate ratio; PR, Prevalence ratio; BPA, bisphenol A; IVF, in vitro fertilization; PCDF, polychlorinated dibenzofuran; PFOA, perflurorooctanoic acid; PFOS, perfluorooctane sulfonic acid, and TCDD, 2,3,7,8-tetrachlorodibenzodioxin.