A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men

Feiby L Nassan; Brent A Coull; Niels E Skakkebaek; Anna-Maria Andersson; Michelle A Williams; Lidia Mínguez-Alarcón; Stephen A Krawetz; Janet E Hall; Elizabeth J Hait; Joshua R Korzenik; Jennifer B Ford; Alan C Moss; Russ Hauser

doi:10.1016/j.envres.2017.09.025

A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men

Feiby L Nassan, Brent A Coull, Niels E Skakkebaek, Anna-Maria Andersson, Michelle A Williams, Lidia Mínguez-Alarcón, Stephen A Krawetz, Janet E Hall, Elizabeth J Hait, Joshua R Korzenik, Jennifer B Ford, Alan C Moss, Russ Hauser

Department of Clinical Medicine

8 Citations (Scopus)

Abstract

Background Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease (IBD). Objectives Taking advantage of different mesalamine formulations with/without DBP, we assessed whether DBP from mesalamine (>1000x background) altered serum hormones. Methods Men (N=73) with IBD participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background) at baseline crossed-over for 4 months to DBP-mesalamine (high) and then crossed-back for 4 months to non-DBP mesalamine (B₁HB₂-arm) and vice versa for men on DBP-mesalamine at baseline (H₁BH₂-arm). We divided H₁BH₂-arm at the median (H₁<3yrs or H₁≥3yrs). We estimated crossover and crossback % changes in serum reproductive hormones using multivariable linear mixed effect models. Results When B₁HB₂-arm (26 men,134 samples) crossed-over, luteinizing hormone decreased 13.9% (95% confidence interval(CI): −23.6,−3.0) and testosterone, inhibin-B, and follicle-stimulating hormone (FSH) marginally decreased; after crossback all increased 8–14%. H₁BH₂-arm, H₁≥3yrs (25 men,107samples) had no changes at crossover or crossback whereas in H₁BH₂-arm,H₁<3yrs (22 men,100 samples) after crossover, inhibin-B increased 13.2% (CI: 4.2,22.9), FSH decreased 9.9% (CI: −17.9,−1.1) and after crossback, inhibin-B further increased 11.3%, and FSH marginally increased. Conclusions High-DBP exposure may disrupt pituitary-gonadal hormones that largely reversed after exposure removal, but only in men with no or short previous high-exposure history. Paradoxically, men with longer duration of high-DBP exposure, exposure removal did not change hormone levels, suggesting that long-term high-DBP exposure may alter the pituitary-gonadal axis and make it insensitive to exposure changes.

Original language	English
Journal	Environmental Research
Volume	160
Pages (from-to)	121-131
Number of pages	11
ISSN	0013-9351
DOIs	https://doi.org/10.1016/j.envres.2017.09.025
Publication status	Published - 2018

Keywords

Adult
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage
Cross-Over Studies
Dibutyl Phthalate/adverse effects
Endocrine Glands/drug effects
Gonadal Hormones/blood
Gonadotropins, Pituitary/blood
Humans
Male
Mesalamine/administration & dosage
Plasticizers/adverse effects
Prospective Studies

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10.1016/j.envres.2017.09.025

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Nassan, F. L., Coull, B. A., Skakkebaek, N. E., Andersson, A.-M., Williams, M. A., Mínguez-Alarcón, L., Krawetz, S. A., Hall, J. E., Hait, E. J., Korzenik, J. R., Ford, J. B., Moss, A. C., & Hauser, R. (2018). A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men. Environmental Research, 160, 121-131. https://doi.org/10.1016/j.envres.2017.09.025

Nassan, FL, Coull, BA, Skakkebaek, NE, Andersson, A-M, Williams, MA, Mínguez-Alarcón, L, Krawetz, SA, Hall, JE, Hait, EJ, Korzenik, JR, Ford, JB, Moss, AC & Hauser, R 2018, 'A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men', Environmental Research, vol. 160, pp. 121-131. https://doi.org/10.1016/j.envres.2017.09.025

@article{76158b90c3bf40eaaff799b7afa94d01,

title = "A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men",

abstract = "Background Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease (IBD). Objectives Taking advantage of different mesalamine formulations with/without DBP, we assessed whether DBP from mesalamine (>1000x background) altered serum hormones. Methods Men (N=73) with IBD participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background) at baseline crossed-over for 4 months to DBP-mesalamine (high) and then crossed-back for 4 months to non-DBP mesalamine (B1HB2-arm) and vice versa for men on DBP-mesalamine at baseline (H1BH2-arm). We divided H1BH2-arm at the median (H1<3yrs or H1≥3yrs). We estimated crossover and crossback % changes in serum reproductive hormones using multivariable linear mixed effect models. Results When B1HB2-arm (26 men,134 samples) crossed-over, luteinizing hormone decreased 13.9% (95% confidence interval(CI): −23.6,−3.0) and testosterone, inhibin-B, and follicle-stimulating hormone (FSH) marginally decreased; after crossback all increased 8–14%. H1BH2-arm, H1≥3yrs (25 men,107samples) had no changes at crossover or crossback whereas in H1BH2-arm,H1<3yrs (22 men,100 samples) after crossover, inhibin-B increased 13.2% (CI: 4.2,22.9), FSH decreased 9.9% (CI: −17.9,−1.1) and after crossback, inhibin-B further increased 11.3%, and FSH marginally increased. Conclusions High-DBP exposure may disrupt pituitary-gonadal hormones that largely reversed after exposure removal, but only in men with no or short previous high-exposure history. Paradoxically, men with longer duration of high-DBP exposure, exposure removal did not change hormone levels, suggesting that long-term high-DBP exposure may alter the pituitary-gonadal axis and make it insensitive to exposure changes.",

keywords = "Adult, Anti-Inflammatory Agents, Non-Steroidal/administration & dosage, Cross-Over Studies, Dibutyl Phthalate/adverse effects, Endocrine Glands/drug effects, Gonadal Hormones/blood, Gonadotropins, Pituitary/blood, Humans, Male, Mesalamine/administration & dosage, Plasticizers/adverse effects, Prospective Studies",

author = "Nassan, {Feiby L} and Coull, {Brent A} and Skakkebaek, {Niels E} and Anna-Maria Andersson and Williams, {Michelle A} and Lidia M{\'i}nguez-Alarc{\'o}n and Krawetz, {Stephen A} and Hall, {Janet E} and Hait, {Elizabeth J} and Korzenik, {Joshua R} and Ford, {Jennifer B} and Moss, {Alan C} and Russ Hauser",

year = "2018",

doi = "10.1016/j.envres.2017.09.025",

language = "English",

volume = "160",

pages = "121--131",

journal = "Environmental Research",

issn = "0013-9351",

publisher = "Academic Press",

}

TY - JOUR

T1 - A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men

AU - Nassan, Feiby L

AU - Coull, Brent A

AU - Skakkebaek, Niels E

AU - Andersson, Anna-Maria

AU - Williams, Michelle A

AU - Mínguez-Alarcón, Lidia

AU - Krawetz, Stephen A

AU - Hall, Janet E

AU - Hait, Elizabeth J

AU - Korzenik, Joshua R

AU - Ford, Jennifer B

AU - Moss, Alan C

AU - Hauser, Russ

PY - 2018

Y1 - 2018

N2 - Background Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease (IBD). Objectives Taking advantage of different mesalamine formulations with/without DBP, we assessed whether DBP from mesalamine (>1000x background) altered serum hormones. Methods Men (N=73) with IBD participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background) at baseline crossed-over for 4 months to DBP-mesalamine (high) and then crossed-back for 4 months to non-DBP mesalamine (B1HB2-arm) and vice versa for men on DBP-mesalamine at baseline (H1BH2-arm). We divided H1BH2-arm at the median (H1<3yrs or H1≥3yrs). We estimated crossover and crossback % changes in serum reproductive hormones using multivariable linear mixed effect models. Results When B1HB2-arm (26 men,134 samples) crossed-over, luteinizing hormone decreased 13.9% (95% confidence interval(CI): −23.6,−3.0) and testosterone, inhibin-B, and follicle-stimulating hormone (FSH) marginally decreased; after crossback all increased 8–14%. H1BH2-arm, H1≥3yrs (25 men,107samples) had no changes at crossover or crossback whereas in H1BH2-arm,H1<3yrs (22 men,100 samples) after crossover, inhibin-B increased 13.2% (CI: 4.2,22.9), FSH decreased 9.9% (CI: −17.9,−1.1) and after crossback, inhibin-B further increased 11.3%, and FSH marginally increased. Conclusions High-DBP exposure may disrupt pituitary-gonadal hormones that largely reversed after exposure removal, but only in men with no or short previous high-exposure history. Paradoxically, men with longer duration of high-DBP exposure, exposure removal did not change hormone levels, suggesting that long-term high-DBP exposure may alter the pituitary-gonadal axis and make it insensitive to exposure changes.

AB - Background Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease (IBD). Objectives Taking advantage of different mesalamine formulations with/without DBP, we assessed whether DBP from mesalamine (>1000x background) altered serum hormones. Methods Men (N=73) with IBD participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background) at baseline crossed-over for 4 months to DBP-mesalamine (high) and then crossed-back for 4 months to non-DBP mesalamine (B1HB2-arm) and vice versa for men on DBP-mesalamine at baseline (H1BH2-arm). We divided H1BH2-arm at the median (H1<3yrs or H1≥3yrs). We estimated crossover and crossback % changes in serum reproductive hormones using multivariable linear mixed effect models. Results When B1HB2-arm (26 men,134 samples) crossed-over, luteinizing hormone decreased 13.9% (95% confidence interval(CI): −23.6,−3.0) and testosterone, inhibin-B, and follicle-stimulating hormone (FSH) marginally decreased; after crossback all increased 8–14%. H1BH2-arm, H1≥3yrs (25 men,107samples) had no changes at crossover or crossback whereas in H1BH2-arm,H1<3yrs (22 men,100 samples) after crossover, inhibin-B increased 13.2% (CI: 4.2,22.9), FSH decreased 9.9% (CI: −17.9,−1.1) and after crossback, inhibin-B further increased 11.3%, and FSH marginally increased. Conclusions High-DBP exposure may disrupt pituitary-gonadal hormones that largely reversed after exposure removal, but only in men with no or short previous high-exposure history. Paradoxically, men with longer duration of high-DBP exposure, exposure removal did not change hormone levels, suggesting that long-term high-DBP exposure may alter the pituitary-gonadal axis and make it insensitive to exposure changes.

KW - Adult

KW - Anti-Inflammatory Agents, Non-Steroidal/administration & dosage

KW - Cross-Over Studies

KW - Dibutyl Phthalate/adverse effects

KW - Endocrine Glands/drug effects

KW - Gonadal Hormones/blood

KW - Gonadotropins, Pituitary/blood

KW - Humans

KW - Male

KW - Mesalamine/administration & dosage

KW - Plasticizers/adverse effects

KW - Prospective Studies

U2 - 10.1016/j.envres.2017.09.025

DO - 10.1016/j.envres.2017.09.025

M3 - Journal article

C2 - 28978458

SN - 0013-9351

VL - 160

SP - 121

EP - 131

JO - Environmental Research

JF - Environmental Research

ER -

A crossover-crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men

Abstract

Keywords

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