In Utero Exposure to Benzophenone-2 Causes Hypospadias Through an Estrogen Receptor Dependent Mechanism

Hsieh, Michael H.; Grantham, Erin C.; Liu, Benchun; Macapagal, Reginald; Willingham, Emily; Baskin, Laurence S.

doi:10.1016/j.juro.2007.03.190

Cited by 42 publications

(23 citation statements)

References 15 publications

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“…Unfortunately, histopathological examination of the peripheral nerves and muscles around the forelimbs and spinal cord in the thoracic region was not performed in this study. However, no locomotor abnormalities were detected in these groups and similar reduced grip strengths have not been reported in the repeated-dose toxicity studies using benzophenone and related compounds [2,3,5,21,22]. In addition, it has been reported that changes in grip strength are associated with locomotor abnormalities in rats given a number of neurotoxic compounds [23][24][25][26][27][28].…”

Section: Discussionsupporting

confidence: 68%

Endocrine-Mediated Effects of a Benzophenone Related Chemical, 2,3,4,4'-Tetrahydroxybenzophenone, Based on Uterotrophic Assay, Hershberger Assay, and Subacute Oral Toxicity Study

Yamasaki¹

2012

J Clin Toxicol

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The purpose of this study was to investigate the endocrine-mediated effects of a benzophenone-relative compound, 2,3,4,4'-tetrahydroxybenzophenone, based on the OECD protocols. In the uterotrophic assay, female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and the uterine weight of rats given the 300 and 1,000 mg/kg doses of the test chemical increased. In the Hershberger assay, the test chemical was orally administered at doses of 0, 60, 200, and 600 mg/kg/day to castrated male SD rats for 10 consecutive days beginning on postnatal day 56, and no changes were observed. On the other hand, when the test chemical was orally administered at doses 0, 60, 200, and 600 mg/kg/day for at least 28 days, serum T4 values decreased in male rats in the 600 mg/kg group. This suggests a mechanism of action related to the inhibition of thyroid peroxidase. The uterotrophic assay used in this study showed that the chemical has estrogen-agonist properties, however, estrogenic effects were not observed in a 28-day repeated-dose toxicity study. On the other hand, endocrine-mediated effects such as thyroid hormone dysfunction were detected in growing rats based on the results of the OECD test guideline No. 407.

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Section: Discussionsupporting

confidence: 68%

Endocrine-Mediated Effects of a Benzophenone Related Chemical, 2,3,4,4'-Tetrahydroxybenzophenone, Based on Uterotrophic Assay, Hershberger Assay, and Subacute Oral Toxicity Study

Yamasaki¹

2012

J Clin Toxicol

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“…For example, BP-2 has been associated with hypospadias in mice (38). The estrogenic effects of BP-2 have been demonstrated in fathead minnows where dose-dependent relationships were observed with gonad histology (testes had fewer spermatocytes), secondary sex characteristics and reproduction (39).…”

Section: Discussionmentioning

confidence: 99%

Urinary concentrations of benzophenone-type ultraviolet light filters and semen quality

Louis

Chen

Kim

et al. 2015

Fertility and Sterility

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Objective To assess benzophenone-type ultra violet (UV) filter concentrations, chemicals used in sunscreen and personal care products, and semen endpoints. Design Cohort. Setting 16 counties in Michigan and Texas Participants 413 men provided semen and urine samples, 2005–2009. Five UV filters were quantified (ng/mL) in urine using liquid chromatography-triple-quadrupole mass spectrometry: BP-1 (2,4-dihydroxybenzophenone), BP-2 (2,2′,4,4′-tetrahydroxybenzophenone), BP-3 (2-hydroxy-4-methoxybenzophenone), BP-8 (2,2′-dihydroxy-4-methoxybenzophenone), and 4-OH-BP (4-hydroxybenzophenone). Using linear regression, beta coefficients (β) and 95% confidence intervals (CIs) for each chemical dichotomized at the 75th percentile and Box-Cox transformed semen endpoint were estimated, after adjusting for age, BMI, cotinine, season, and site. Interventions None. Main Outcome Measures 35 semen endpoints. Results BP-2 was associated with diminished sperm concentration (β=−0.74; 95% CI −1.41, −0.08), straight (β=−4.57; 95% CI −8.95, −0.18) and linear movement (β=−3.15; 95% CI −6.01, −0.30), more immature (β=0.38; 95% CI 0.15, 0.62) sperm, and a decreased percentage of other tail abnormalities (β=−0.16; 95% CI −0.31, −0.01). BP-8 was associated with decreased hypo-osmotic swelling (β=−2.57; 95% CI −4.86, −0.29) and higher acrosome area (β=1.14; 95% CI 0.01, 2.26). No associations were observed for BP-1, BP-3 or 4OH-BP. Conclusion The findings suggest that specific UV filters may be associated with some aspects of semen endpoints, but await future corroboration.

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“…In other studies, BP-2 was shown to have an agonistic effect on fish (rainbow trout) and human ERs, and was found to be selective for human ERβ in an in vitro bioassay (Molina-Molina et al, 2008). BP-2 was also tested in pregnant mice to determine its impact on fetuses, where it was found that BP-2 may be a cause of hypospadia which is an abnormality in the reproductive organs of male fetuses (Hsieh et al, 2007). Additionally, BP-2 suppresses T4 (thyroid hormone), but not T3, and has estrogenic activity in rats (Seidlova-Wuttke et al, 2005).…”

Section: Screening Of Home Products For Estrogenic Activitymentioning

confidence: 99%

Engineered Nuclear Hormone Receptor-Biosensors for Environmental Monitoring and Early Drug Discovery

Gierach¹,

Wood²

2011

Biosensors for Health, Environment and Biosecurity

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In Utero Exposure to Benzophenone-2 Causes Hypospadias Through an Estrogen Receptor Dependent Mechanism

Abstract: These findings suggest that benzophenone-2 may cause hypospadias via signaling through the estrogen receptor. Further study of human benzophenone-2 exposure and its effects is needed to support this hypothesis.

Cited by 42 publications

References 15 publications

Endocrine-Mediated Effects of a Benzophenone Related Chemical, 2,3,4,4'-Tetrahydroxybenzophenone, Based on Uterotrophic Assay, Hershberger Assay, and Subacute Oral Toxicity Study

Endocrine-Mediated Effects of a Benzophenone Related Chemical, 2,3,4,4'-Tetrahydroxybenzophenone, Based on Uterotrophic Assay, Hershberger Assay, and Subacute Oral Toxicity Study

Urinary concentrations of benzophenone-type ultraviolet light filters and semen quality

Engineered Nuclear Hormone Receptor-Biosensors for Environmental Monitoring and Early Drug Discovery

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