Low dose effects of bisphenol A

Figures & data

Table 1. Endpoints demonstrating non-monotonicity in in vitro and in vivo low dose studies of BPA

Study type	Model system	Endpoint	Doses tested
In vitro	Primary prostate mesenchymal cells	Total DNA content, Total RNA content	10 doses between 10^−13 and 10^−4 M
In vitro	mLTC-1 Leydig tumor cells	Candidate gene expression	5 doses between 10^−8 and 10^−4 M
In vitro	Primary pancreatic islets (mouse)	Insulin content of islets	5 doses between 10^−10 and 10^−6 M
In vitro	Adipose tissue (primary, human)	Adiponectin release	4 doses between 10^−10 and 10^−7 M
In vitro	Primary ovarian follicles (mouse)	Meiosis II abnormalities	5 doses between 3x10^−9 and 3 × 10^−5 M
In vitro	Primary hypothalamic neurons (rat)	Synaptic density	4 doses between 10^−9 and 10^−6 M
In vitro	Primary granulosa cells (rat)	Progesterone production	4 doses between 10^−7 and 10^−4 M
In vitro	GH3/B6/F10 pituitary tumor cells	Prolactin release	10 doses between 10^−15 and 10^−6 M
In vitro	Umbilical vein endothelial cells	Tube morphology	3 doses between 10^−9 and 10^−6 M
In vitro	Primary ventricular myocytes (rat)	Fractional shortening	5 doses between 10^−12 and 10^−6 M
In vitro	3T3-L1 preadipocytes	Lipid accumulation	4 doses between 10^−9 and 10^−6 M
In vitro	HepG2 hepatocellular cancer cells	Production of mitochondrial superoxide anions	7 doses between 10^−12 and 10^−4 M
In vitro	Fetal testes (human)	Testosterone secretion	4 doses between 10^−12 and 10^−5 M
In vitro	HBL-100 breast epithelial cells	Cell proliferation	7 doses between 10^−11 and 10^−5 M
In vivo	Mouse, developmental exposure	Body weight at weaning	Subcutaneous: 5000, 10 000, 20 000 µg/kg/day
In vivo	Mouse, developmental exposure	Body weight in adulthood	Oral: 50, 500, 5000, 50 000 µg/kg/day
In vivo	Mouse, developmental exposure	Mammary gland morphology	Oral: 0.6, 3, 6, 12, 120, 600, 1200 µg/kg/day
In vivo	Mouse, adult exposure	Mammary tumors, tumor volume, number of metastases	Oral: 0.5, 5, 50, 500 µg/kg/day
In vivo	Mouse, adult exposure	Adipose tissue weight, plasma insulin, blood triglyceride levels, liver gene expression	Oral: 5, 50, 500, 5000 µg/kg/day

Table 2. Examples of adverse endpoints in laboratory animals

Species/sex	Exposure type	Endpoint	Effective doses (µg/kg/day)
Mouse/both	Developmental	Anxiety behaviors	10, 20, 500, 8000
Mouse/female	Developmental	Measures of adiposity	50, 260
Rat/Female	Developmental	Altered brain physiology	50, 20 000
Mouse/Female	Developmental	Response of mammary gland to hormones	0.25
Mouse/Male	Adult	Sperm count	2
Mouse/Male	Development + Adult	Sperm motility	500, 5000
Rat/Male	Developmental	Prostatic PIN lesions after hormone challenge	10
Mouse/Male	Developmental	Immune response to infection	0.3, 3
Mouse/Male	Adult	Immune response to infection	22 800, 45 600
Rat/Female	Developmental	Response of mammary gland to chemical carcinogens	250
Mouse/Female	Developmental	Response of mammary gland to chemical carcinogens	25, 250
Mouse/Female	Pubertal	Chromosomal abnormalities in oocytes	200
Mouse/Female	Developmental	Ovarian cysts	1, 100, 1000
Rat/Male	Developmental	Fetal resorptions in unexposed female mates	100, 200, 400, 800, 1600
Rat/both	Developmental	Body weight on high fat diet	50, 70
Mouse/Female	Pregnancy	Glucose tolerance, fasting insulin levels during pregnancy	10
Mouse/Female	Pregnancy	Glucose and insulin sensitivity months after pregnancy	100
Mouse/Male	Developmental	Blood glucose, fasting insulin levels	10
Mouse/Female	Developmental	Lifetime fecundity	0.025, 25
Mouse/Female	Developmental	Lifetime fertility	25
Sheep/Female	Developmental	Follicular reserve	50
Rat/both	Developmental	Glucose tolerance, insulin tolerance	50
Rat/Male	Adult	Fasting blood glucose, insulin levels	0.005, 0.5, 50, 500
Rhesus monkey/ female	Developmental	Abnormal meiosis	400
Rat/Female	Developmental	Milk yield, milk protein content	0.7, 64
Mouse/Male	Adult	Plasma glucose	5, 50, 500

For additional details about the study designs and citations for these various studies, see Table S3.

Figure 1. Low dose effects of BPA on liver enzymes. (A) In vitro studies examining the effects of BPA on hepatocyte enzyme production and production of reactive oxygen species (ROS). (B) Four in vivo laboratory rodent studies examined the effects of low dose BPA exposures on production of liver enzymes. (C) Summary of epidemiology studies examining effects of BPA on liver enzymes. Open circles indicate applied doses that did not induce significant effects (A and B) or populations that were unaffected (C). Red circles indicate doses that significantly increased the measure of interest (A and B) or populations that were significantly affected (C). Blue circles indicate doses that significantly decreased the measure of interest (A).

Figure 2. Low dose effects of BPA on insulin signaling. (A) Insulin responses in cultured pancreatic islets. (B) Low dose effects of BPA on insulin levels in lab rodents. (C) Summary of epidemiology studies examining relationships between type II diabetes and urinary concentrations of BPA. Open circles indicate applied doses that did not induce significant effects (A and B) or populations that were unaffected (C). Red circles indicate doses that significantly increased the measure of interest (A and B) or populations that were significantly affected (C). Blue circles indicate doses that significantly decreased the measure of interest (B).

Figure 3. Low dose effects of BPA on select neurobehaviors. (A) Effects of BPA on anxiety behaviors in the open field test. (B) Effects of BPA on spatial learning and memory in rodents in the Morris water maze. (C) Epidemiology studies examining relationships between maternal urinary BPA concentrations and neurodevelopmental parameters in children. Open circles indicate applied doses that did not induce significant effects (A and B) or populations that were unaffected (C). Red circles indicate doses that significantly increased the measure of interest (A) or populations that were significantly affected (C). Blue circles indicate doses that significantly decreased the measure of interest (A and B).

Figure 4. Low dose BPA alters the response of the mammary gland to environmental challenges. (A) In vitro studies reveal that BPA exposures confer chemotherapeutic resistance in mammary cells. (B) Low doses of BPA induce preneoplastic and neoplastic lesions in the rodent mammary gland, and alter adult challenges with carcinogenic agents. Open circles indicate applied doses that did not induce significant effects (A and B). Blue circles indicate doses that significantly decreased the measure of interest (A). Red circles indicate doses that significantly increased the measure of interest (B). Gray circles indicate doses that induced the adverse effect noted, but statistics were not performed.

Figure 5. Low dose effects of BPA on the ovary. (A) Effects of developmental exposures on ovarian endpoints, including adverse effects that manifest in adulthood. (B) Summary of in vitro studies showing effects of BPA on hormone production and enzyme activity in ovarian cells. (C) Effects of adult exposures on ovarian endpoints in rodents. (D) Summary of epidemiology studies examining relationships between BPA exposure metrics and ovarian response in women undergoing IVF. Open circles indicate applied doses that did not induce significant effects (A–C) or populations that were unaffected (D). Red circles indicate doses that significantly increased the measure of interest (A–C) or populations that were significantly affected (D). Blue circles indicate doses that significantly decreased the measure of interest (B). Gray circles indicate doses that induced the adverse effect noted, but statistics were not performed.